Current Research into a Cure for Type-1 Diabetes

Background on Four Types of Stem Cell Research

2012-01-23T20:05:00.000-08:00

This blog post contains general background information on four types of stem cell research. I'm writing it because the term "stem cells" is used to describe several different lines of research, and it is important not to mix them up. Good news from one type of "stem cell" research should never be used to suggest that a different type of "stem cell" research is going to be successful.

Quick Summary
Here is a very quick summary of four types of stem cell research:
1. "Burt" Reboots the body's immune system to stop the autoimmune attack. First, the patient is given very powerful drugs to shut down their immune system, then they are given drugs which causes the body to mobilize it's own adult stem cells to rebuild the immune system, without the autoimmune flaw. Has resulted in the best cure results of any research to date, but is also the most dangerous.
2. "Zhao" Patient's immune cells are removed and stem cells from the umbilical cord used to help retrain them to stop the autoimmune attack. The immune cells (without the stem cells) are then put back in the patient. Good results and appears to be much safer than Burt.
3. Several companies (example: Viacycte) are attempting to grow new beta cells from stem cells. They are taking undifferentiated stem cells and trying to find the recipe to cause those stem cells to differentiate into beta cells. None of this work is in human trials right now.
4. Many stem cell clinics (example: Xcell) will infuse bone marrow stem cells in the hopes that this will cause the patient to regrow beta cells and improve their type-1 diabetes. Although many clinics will provide this service, I have never seen a peer reviewed study showing that it improves type-1 diabetes.

How They Are Different

Burt
Burt's research does not use external stem cells. Rather, the patient is given a drug which "mobilizes" their own internal stem cells. People have several different forms of adult stem cells in their body. Part of Burt's protocol is to give the patient a drug which is well known to cause them to generate more of their own bone marrow stem cells, and cause these cells to be released into the blood stream.

Zhao
Zhao's research is very different from the rest, because he is not trying to grow beta cells from the stem cells. Instead, he is using them to train the immune cells not to attack beta cells. (This is sometimes called "curing autoimmunity".)

You may ask, "why should stem cells cure autoimmunity?" It's a very good question, and I don't know the answer. But I'm not an immunologist, and for me it is far more important that a treatment work, than that I understand how it works. Many treatments are used for years before we understand exactly why they work. (Aspirin is a 100+ year old example.)

Beta Cells from Stem Cells
There are several companies working on ways to differentiate beta cells from stem cells. Generally, they differ from each other two ways. First, in the kinds of stem cells they start with (embryonic from an embryo, embryonic from cord blood, or different types of adult cells or adult stem cells that have been treated in some way to make them undifferentiated). Second, in the recipe they use to transform these undifferentiated stem cells into beta cells.

Stem Cell Clinics
These guys harvest bone marrow stem cells from a person, and then put them back into that person or a different person. They differ in exactly how they put the stem cells back in (in the blood or directly in the organ that needs them), and also in what processing or separation is done to the bone marrow cells before being put back.

My opinion of the stem cell clinics is very low. They are a cash up front business without evidence that they help anyone. For example, to approve a new drug, the US FDA requires four clinical studies to show that it works and is safe. Currently, there is not one stem cell clinic, that has published even one peer reviewed study (that I have found), that shows that it works.

Most of these clinics are in third world countries, but there was one, called Xcell in Germany. Years ago, Xcell said that they were running two studies to show that their treatment would help type-1 and type-2 diabetics, respectively. Neither of these studies were ever published in a peer reviewed journal, and last year the German government shut down Xcell after an 18 month old baby died of complications from a stem cell treatment at the clinic. (And this after a 10 year old boy almost died after the same procedure!)

I often see these clinics cite Burt's work as peer-reviewed, scientific research that suggests their clinics are on the right track. But this work is wildly different from the work done at these clinics and the success of one does not support the treatment of the other. As an example: Burt uses three drugs in his trial. These clinics sometimes use one of those drugs, and sometimes none at all. They never use all three of them, and never get close to the same procedures that Burt uses. My guess is that you will see these guys citing Zhao's work soon as well, even though Zhao is using a totally different type of stem cells and not even putting in the patient.

Other Terms to Understand

Adult vs. Embryonic
These are the two types of stem cells that we have heard about for the longest, and the loudest. Much of the arguments about stem cells (especially in the US) are phrased in terms of Adult vs. Embryonic. However, I have come to believe that, while this difference is critical religiously, politically, and socially, that it is not important in terms of research aimed at curing type-1 diabetes.

The confusion comes from the fact that in the early days of stem cell research, embryonic stem cells were the only undifferentiated stem cells known. So when people talked about the power of embryonic stem cells, they were often talking about the power of undifferentiated cells. However, now we can get several different types of undifferentiated stem cells from adult sources, and from different embryonic sources.

Differentiated vs. Undifferentiated
A better way to talk about stem cells, is undifferentiated (and if so, what is their source) vs. differentiated (and if so, how were they differentiated). Differentiated stem cells are those which have already specialized into a specific type of cell. For example, a beta cell. Undifferentiated stem cells have the potential to do this, but have not yet done it. With the current research results, it appears that undifferentiated are not useful for growing beta cells in the simple minded way used by the current clinics. However, both Burt and Zhao have had success using them in other ways, and undifferentiated stem cells have not yet been tested (in people) as a source for growing beta cells.
A lot of the recent news in stem cell research is reporting on different ways to create different types of undifferentiated adult stem cells. These different type stem cells might have different properties and be good or bad at different things, but we really don't know yet.

Another type of research news that we have gotten recently, but is not as common, is success in turning different types of undifferentiated stem cells into beta cells. It is especially important to turn them into beta cells that generate insulin when presented with sugars. The has been some success at this, but none of it has progressed into human trials (that I know of) as yet. Even if they did, we would still need to either encapsulate them or cure the autoimmunity before they would be a cure for type-1.

Self vs. Others
Any kind of stem cells can be gotten from the person being treated (self) or from someone else (others). This is true for both embryonic stem cells, and adult stem cells. You can get embryonic stem cells (for example, from the cord blood) and use them on the person you got them from. Or you can get adult stem cells from that same person. Self stem cells are going to have fewer immune issues than those from others.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

Possible Cures for Type-1 in the News (January-2012).

2012-01-17T22:57:00.000-08:00

Osiris's Prochymal fails in a Phase-2 Clinical Trial
For background, please read my previous blogging on Osiris: http://cureresearch4type1diabetes.blogspot.com/search/label/Osiris

The PROCHYMAL treatment has been shown safe in several phase-I, II, and even III trials for several immune diseases, so they are trying it with type-1 diabetes. This is an adult (actually self) stem cell treatment. Since safety is established, they went straight to phase-II clinical trials. The company's description is this: "Prochymal is a preparation of mesenchymal stem cells specially formulated for intravenous infusion. The stem cells are obtained from the bone marrow of healthy adult donors."

The results were a total failure: no change in the primary end point (C-peptide after a meal), or in any of the secondary end points. No safety issues turned up. This was after 1 year, and they will continue to follow the patients for another year.

News coverage: http://www.thestreet.com/story/11362832/1/osiris-stem-cell-therapy-fails-diabetes-trial.html
BTW: most news coverage of type-1 research is superficial. They just repackage the press release, occasionally adding a quote or two from the company; sometimes not even that much. But this article in "The Street" is much better than that, and is fun to read.

Background on mesenchymal stem cells: http://en.wikipedia.org/wiki/Mesenchymal

Should We Give Up On Adult Stem Cells?

The short answer is "no". But the full answer is a lot more interesting, but will need to wait for another blog posting. The short version of my opinion is this: based on all the studies done so far, including this one, I don't think that just dumping a bunch of bone marrow stem cells into the body is likely to cure type-1 diabetes. But that does not apply to stem cells specifically tailored for insulin production, because they are quite different, and so far we have no experience with them in people. Remember that there are many different types of stem cells, and many different ways of differentiating stem cells, and many different uses of stem cells. So while there is considerable bad news for the simple minded idea of dumping in a bunch of bone marrow stem cells and expecting a cure, there are many other avenues still open. That is why I think I will need a whole blog entry to sort out possible stem cell cures.

Dr. Taback et al in Winnipeg Hope for Funding for Vitamin D Prevention Study

As part of my recent policy change to cover treatments designed to prevent type-1 diabetes, I'm starting to cover this potential clinical trial of Vitamin D. I previously blogged once on Vitamin D, here:
http://cureresearch4type1diabetes.blogspot.com/2010/08/cinnamon-and-vitamin-d.html

Dr. Taback has put in the paperwork to ask for funding for a large, prospective study to see if giving people Vitamin D will lower the rate of type-1 diabetes. The basic plan is to screen 60,000 babies to find about 5,000 at higher risk for type-1, and then give those babies about 2000 IU of Vitamin D per day (current suggested dose is 400 IU). And then follow them for years to see if fewer develop type-1.

Although no mechanism is known, a few studies [r3] have had promising results, so it makes a lot of sense to test this in a larger group. Previous promising studies are summarized in [r1,r2].

An older study [r4] showed that Vitamin D consumption during pregnancy was NOT associated with markers for type-1 diabetes. Although this [r5] study just published recently suggests that it is associated with type-1 diabetes. The newer study was of much higher quality than the older one for two reasons. First, it measured actual cases of type-1, not markers. Second, it measured actual Vitamin D levels in the person, while the older study had people fill out a questionnaire about diet (which is vastly less accurate).

News coverage: http://www.cbc.ca/news/health/story/2011/12/28/diabetes-type1-vitamin-d-chasing-cures.html

[r1] http://www.ncbi.nlm.nih.gov/pubmed/18339654
[r2] http://www.ncbi.nlm.nih.gov/pubmed/15671235
[r3] http://www.ncbi.nlm.nih.gov/pubmed/11705562
[r4] http://www.ncbi.nlm.nih.gov/pubmed/20369220
[r5] News: http://www.foodconsumer.org/newsite/Nutrition/Vitamins/low_prenatal_vitamin_d_type_1_diabetes_0117120243.html
Study: http://diabetes.diabetesjournals.org/content/61/1/175.short

OmniBio Will Start another AAT Clinical Trial

OmniBio is testing AAT, an anti-inflammatory drug, which the body makes naturally, and which is already FDA approved for people who have a rare condition where a person don't make enough of it on their own. They started with a 15 person, phase-I study, and about 11 months ago expanded to a 50 person study, which I would consider phase-II. They just announced that they will start another study for type-1 diabetes and one for Graft-vs-Host disease. That's good news, of course, but I'd be a little more excited if they announced the results from their initial 16 person study.

Previous blogging on AAT: http://cureresearch4type1diabetes.blogspot.com/search/label/AAT
Previous discussion of inflammation based cures: http://cureresearch4type1diabetes.blogspot.com/p/common-ideas-and-opinions.html

News article: http://www.marketwatch.com/story/omni-bio-to-conduct-new-human-clinical-trials-2012-01-13
Corporate web site: http://www.omnibiopharma.com/

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com
Mice cures: http://t1dcuredinmice.blogspot.com/

Zhao et al (Tianhe) Publish Successful Phase-I Results (in non-honeymoon diabetics)

2012-01-12T17:24:00.000-08:00

In my opinion, this is big news.
It's the result of a phase-I study, published in BioMed Central's Medicine Journal (which is peer reviewed) by a group of researchers working at the University of Illinois at Chicago and in China.

What Did These Guys Do?

This trial was done on people with established type-1 diabetes. Each person had a blood draw, and then a particular kind of immune cell was separated from the blood and specially processed. The processing phase used umbilical cord stem cells, but not the patient's own umbilical cord. (This was generic umbilical cord stem cells, not from the exact person being treated.) The immune cells were then put back in the person. The stem cells did not go into the person; they were only used for the external processing.

The goal was to teach the body's immune system to stop attacking beta cells. The researchers refer to this as "education", and refer to the processing device used as an "Stem Cell Educator".

The treatment was done once and I think it took about 10 hours. Patients were in the hospital for 2 days, but it's not clear to me if that was due to an over abundance of caution (this was a phase-I study, after all), or if it was really needed. This trial was done at the General Hospital of Jinan Military Command (Jinan, Shandong, China). The lead author of the paper is Yong Zhao, is an Assistant Professor at the University of Illinois at Chicago.

The patients averaged about 29 years old, and had had type-1 for an average of about 8.5 years. Patients were followed for a total of 40 weeks, but most of the results data was gathered at 4, 12, and 24 weeks after the procedure.

The researchers divided their patients into three groups. Group A (6 people) had some insulin production before treatment. Group B (6 people) had no measurable insulin production before treatment, and Group C (3 people) also had some insulin production before treatment, but they got a "sham" (or placebo) treatment.

What Results Did They Get?

There were no significant safety issues during the trial.

Average Daily Insulin Usage:
Group A's insulin requirement was down 38% at 12 weeks (from about 36 to 22 units/day).
Group B's insulin requirement was down 25% at 12 weeks (from about 48 to 36 units/day).
Group C's insulin requirements didn't change.

Note: earlier version of this blog had a typo in Group B's starting insulin units/day. Fixed here.

Average A1C levels:
Group A started at 8.73 and dropped to 7.67 at 4 weeks and to 6.82 at 12 weeks (almost 2 points overall).
Group B started at 12.2 and dropped to about 10.5 at 12 weeks.
Group C started at 9 and was at 8.7 at 12 weeks.
Note: I consider a drop of 1 to be important, although some researchers consider even a drop of 0.5 as important. Here we have drops of over 1.9 and 1.7.

Fasting C-peptide (ie. Body's ability to generate "basal" insulin at background levels)
All these numbers are average ng/ml, and are very approximate based on graphs in the paper.
Group A: Starts at about 0.35 and ends at about 0.8 at 24 weeks.
Group B: Starts at about 0 and ends at about 0.5 at 25 weeks.
Group C: Stays at about 0.4 at 4, 12, and 24 weeks.
Note: Non type-1 diabetics generally have a fasting C-peptide level between about 0.5 and 2.0. The paper's authors felt that 0.6 was the lower bound of normal C-peptide in the population being studied. So it is possible that Group A has moved into the bottom of the normal (for non-type-1 diabetics) range.

OGTT C-peptide (ie. Body's ability to generate "bolus" insulin in response to food)
All these numbers are average ng/ml, and are very approximate based on graphs in the paper.
Group A: Starts out generating 1 after a meal, at 4 weeks generates about 1.6, and at 12 weeks about 1.7.
Group B: Starts out generating about 0 after a meal, at 4 weeks generates about .05, at 12 weeks about 0.35, and at 40 weeks about 0.6.
Note: I don't know what "normal" is for this test, so can not compare either group to non type-1 diabetics.

The paper also contains data on immune system changes which the researchers felt showed significant improvement in autoimmunity. I can not evaluate those results.

Also interesting, the researchers are very specific in saying that they think this study shows that beta cells do regrow, in people, if the immune system stops attacking them:

Notably, our clinical data provide powerful evidence that reversal of autoimmunity leads to regeneration of islet β cells and improvement of metabolic control in long-standing T1D subjects.

My take on all this data is that there is no question that the body is generating more of it's own insulin after this treatment than before. And that happens in people who have had diabetes for a long time, and who are not generating any of their own insulin before treatment. That's huge. The results are large enough so that type-1 diabetics would see the improvement in their insulin usage and A1C numbers.

Discussion

Obviously, there is a lot of issues to discuss here:

Possible Conflict of Interest

I hate to start off with discussion of a conflict of interest, but in this case, the situation makes me nervous, so I'm discussing it first. In the paper's pre-publication version, it says:

Competing interests

The authors declare that they have no competing interests.

However, the unique and specialized equipment that they used in their clinical trial was manufactured by Tianhe Stem Cells Biotechnology. This equipment was central to the clinical trial. However, that company is connected to three of the authors (including both first and last authors). Here is a quote from the University of Illinois web page:

Tianhe is a stem cell biotechnology company commercializing the inventions emanating from the labs of Drs. Zhao, Mazzone and Holterman within the Departments of Medicine and Surgery at the University of Illinois at Chicago. With operations in both Illinois and overseas, the Company is pursuing the application of stem cells for the treatment of autoimmune diseases. Tianhe is initially pursuing the treatment of Type 1 diabetes through a clinical system which extracts the patient own stem cells and utilizes them to re-educate the patient’s faulty immune cells to prevent future immune response to the patient’s own insulin producing cell. [from http://otm.illinois.edu/sites/all/files/files/otm-annual-reportseptember-1final.pdf]

Obviously, I don't know the exact financial details involving the University, Tianhe, and the three researchers, but I would like to see more details before I accepted the claim that the authors had no competing interests! It certainly sounds like the researchers are testing equipment that they will make money off of, if it works. On the other hand, if this relationship gets this research to market quicker, and the research helps people with type-1 diabetes, then I'm all in favor of it. :-)

Missing Data

There are a couple of obviously missing data points. For example, Group A's 40 week post-meal C-peptide numbers are not reported. And 40 week fasting C-peptide data is not reported for any group. The trial design only collected insulin use and A1C data at 12 weeks, which is too bad. I would have like to see it at 24 or even 40 weeks as well.

There are also a few other odditites. For example: in Groups A and B (treated), about 2/3 of the patients are women, but Group C (placebo) is all male. Also, the Group B A1C before treatment averaged 12.2, which is a lot higher than you would see in the US (I hope!)

None of this is particularly unusual for a phase-I trial; and none of it makes me nervous about the results. It just makes me want to see data from a larger phase-II study.

Next Steps To Market

Getting a cure to market requires three things:
1. Scientific success.
2. Engineering and corporate success.
3. Regulatory approval.

This study is a solid, successful phase-I clinical trial. No doubt (in my mind) about that.
Plus, it is the first time this has been used in people, as far as I know, and there are obvious ways to improve it. More blood could be put through the machine. The blood could spend more time in the machine. It could be used repeatedly, etc. The classic goal of a phase-II trial is to figure out the best dosing, and I think these guys are well positioned to do that.

There is a clear engineering path to market. The "Educator" equipment is produced by Tianhe corporation, and I would expect that once the equipment is for sale, many doctors would be able to use it. It sounds to me like there is a clear way to make money off this, and so I would expect that (if it works scientifically) Tianhe will have no problems getting funding and getting the corporate structure required to build a business around using their equipment to treat/cure type-1 diabetes.

As for regulatory approval, I think there are two paths forward. The normal path to approval is a phase-II trial, and then two phase-III trials. The already completed phase-I trial took about a year, I would expect the phase-II to be about that long, maybe a little longer, and phase-III to be still longer. However, if they are successful and well funded, these guys could get to market in less than 10 years. Of course, the next question is, what will they make it to market with? Will the thing available be a treatment? A cure? A temporary cure? Fewer long term complications?

There is a second, much faster, path to approval, called the "surgical procedure exemption". I do not know all the details, but the FDA does not require that surgical procedures be proven "safe and effective" before a surgeon uses them. Under this exception the FDA does allow some treatments to be sold without full approval, if those treatments involve taking something out of the body, processing it in some simple ways, and then putting it back in. I don't know if this "educator" process would qualify or not.

I know some people are nervous about research done in China, and especially at a Chinese military hospital. I think this is my first detailed blog post on research done in China. I do want to point out that this trial has ethical approval from the review board at the University of Illinois at Chicago, and that it looks to me like the researchers followed US FDA standards in the trial, and international standards where applicable. I don't have detailed knowledge of FDA requirements, but it does look to me like, even at this early stage, these guys are working to eventual US FDA approval.

News Coverage: http://www.medscape.com/viewarticle/756691?src=emailthis
Clinical Trials Record: http://clinicaltrials.gov/ct2/show/NCT01350219
Full Paper: http://www.biomedcentral.com/content/pdf/1741-7015-10-3.pdf

Some general information on C-peptide values:
http://www.diabeteshealth.com/read/2000/09/01/2020/interpreting-your-c-peptide-values/

A Personal Note
2011 was an awful year for following clinical trials aimed a curing type-1 diabetes. We lost three phase-III clinical trials, and started zero new ones. In phase-I and phase-II trials, the successes seemed small; the failures, great. These results are a wonderful way to start 2012.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com/

New Blog: Cured In Mice! (And Other Blog News)

2012-01-07T11:05:00.000-08:00

I'm experimenting with a second blog, which I'm calling:
Cured In Mice! you can read it here: http://t1dcuredinmice.blogspot.com/
Although the formatting will change a little over the next few months.

My goal is to have one blog entry for every treatment reported to have cured or prevented type-1 diabetes in NOD mice, or any other animal.

Each entry will have the date the cure was reported, one or more links to news reports, press releases, or research papers, and maybe a paragraph on the cure, or quotes from the articles. But I don't plan to put in analysis or discussion in those blog entries. I'm leaving comments open for now, but I really only want comments to note when one of these cures moves to a later stage of research. I may close comments entirely in the future.

Each title will be of the form TREATMENT by DOCTOR at RESEARCH INSTITUTION. Two examples:
Glyphosine by Michels at Barbara Davis Centre for Childhood Diabetes
Escapsulated Beta Cells by Nuvilex at SG Austria

I will use tags to keep track of the basic type of cure being reported. For example, the tags "cure", "honeymoon", and "prevention" will describe when the intervention is effective. There will be tags for the basic types of cure "encapsulation", "immune modulation" etc. And tags for the animal involved (such as "BB rat", "NOD mice" or just "mice" if the exact type is not known.

Why a "Cured in Mice" Blog?

This blog exists because of frustration. My frustration at constantly hearing that type-1 diabetes had been cured in mice (again), but never hearing that it was cured in people. My way of dealing with this frustration is to try to keep track of the number of times people cure type-1 diabetes in animals. After all, the first step to understanding something, is to catalog it.

At the very least, this blog will help readers keep track of how many mice cures are developed each year, what happens to them, and how long it takes to happen. I hope that the data found will fuel other types of "research into research" on type-1 diabetes. It will also help track how long it takes to move from animal to human trials. Whenever a human trial starts, I'll be able to go back to this blog, and see when the same thing was first successful in animals. You can think of this blog as raw material for future research into type-1 cures in mice.

How You Can Help

If you hear of a cure for type-1 diabetes in any animal, then please shoot me a quick email. All you need to do is put "Cured in Mice" in the subject line and put the URL where the news was reported in the email. I can get all the information I need from there. Don't worry if you think others have already sent it in. I'd rather get extra emails than not enough. I'm especially interested in research done outside the USA or reported in languages besides English. (Because I don't read any other language, and get most of my news from USA-centric news sources, I'm much more likely to miss research that is reported on in another language or country.)

Getting Either Blog Emailed to You

If you're reading this on my blog web site, you can easily sign up to get these blog posts sent to you (either this "Cure Research" blog or the new "Cured in Mice" one). Just enter your email address in the "FOLLOW BY EMAIL" box on the right. In the past, I had to have a Google email group for this, but that's a lot of work that I don't need to do any more.

If you are getting this as part of the Google group, please add your email (as above) and unsubscribe to the Google group. I plan to shut down the Google group sometime in 2012.

Reminder About The Blog
There three ways you can help with this blog:
First, tell other people about it! Heartfelt testimonials are the best advertising.
Second, tell me about any clinical trials you know about that are not already covered here.
Third, ask me questions that you have. This tells me what I'm not explaining well, and where I need to put more information into my posts.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

Two Essays On Progress

2011-12-24T15:27:00.000-08:00

This blog posting consists of two separate essays on the nature of progress. It is background for understanding forward progress on a cure for type-1 diabetes, but also for other types of medical research.

Engineering Progress vs. Scientific Progress

Many people tend to mix up science and engineering. (They both use a lot of math, right?) But in my mind it is very important to understand the differences. English often doesn't have the right words or phrases to properly describe these differences, so it is hard to discuss them, but understanding them is very helpful in understanding type-1 cure research. I believe that a lot of the frustration that people feel as they follow this research would be alleviated, if they understood better the differences between scientific progress and engineering progress. Although even as we understand the differences, we also need to remember that curing type-1 diabetes is going to require both engineering progress and scientific progress.

Engineering progress is generally doing something you already do, but better. Scientific progress is learning something you don't already know. The most obvious difference, is that engineering work can be planned, even scheduled, but scientific breakthroughs can not. Sure you can plan and schedule scientific experiments, but not their results.

My belief is that curing type-1 diabetes will require at least one major scientific breakthrough, and probably at least one major piece of engineering progress as well. I don't think that engineering progress alone will cure type-1 diabetes. (The only exception to this would be the artificial pancreas, if you consider that a cure. I do believe that an AP can be created with just engineering progress.)

Why does this matter? Well first, because some people believe that the key to curing type-1 diabetes is to set schedules (with deadlines) for researchers. This is based on the idea that type-1 can be cured via engineering progress alone. It is engineering research that benefits from schedules, deadlines, etc.

I was at a JDRF research symposium in San Francisco a few months back, and there was one particularly bombastic guy there, who was really pissed off that JDRF did not set schedules to cure type-1 diabetes, and have deadlines based on those schedules. This guy worked in the financial side of an engineering company, so he understood the important of schedules and deadlines to engineering progress, but didn't seem to understand that scientific progress was fundamentally different. Or, maybe he thought that type-1 could be cured with engineering progress alone.

Another reason is this: engineering progress can (almost always) be assured by putting in money and time. Money and time will solve just about any engineering problem. And money is usually more important that time. Putting in more money will solve almost all engineering problems quicker. But that is not true of scientific progress. Sometimes scientific progress simply can not be made, because the thing is impossible. Sometimes forward progress needs a new understanding, which is based on luck or deep understanding or something else which can not simply be bought. (Putting more money into it raises the chances that you will get the breakthrough you need, but you're just playing with probabilities. Three is no predictability.)

Pushing scientific progress is much more a question of funding research in general, and making more researchers interested in working in that area, removing barriers to that kind of research, and making it easier (in general) to do that kind of research. Basically, you can only make breakthroughs more likely, rather than try to fund and schedule a specific breakthrough.

As an example, if you have a car that can go 90 miles per hour, and extra money, you can make a car that will go 110 MPH. You'll just put in a better motor, or better fuel, or make the frame lighter or something. But if you have a particle accelerator that can speed particles to 0.9 times the speed of light, then no amount of money or time is going to make so you can push those particles to 1.1 times the speed of light. (Because right now, no one knows how to make anything go faster than the speed of light.) The first is a question of engineering progress, the second is a question of scientific progress. You can solve the first with money, schedules, deadlines, etc. But not the second; at least not in a simple minded way.

The difference between engineering progress and scientific progress is one of the reasons why I'm a lot more positive about developing a "closed loop" artificial pancreas, then stopping the autoimmune attack. To put it bluntly: we already know how to build everything needed for an artificial pancreas. It is just a matter of engineering progress until we get one that works (and political progress until the FDA approves it). However, we do not know how to shut down the autoimmune attack. It will require a scientific breakthrough (and maybe more than one) to do that.

The take home point is that engineering progress and scientific progress (sometimes called "breakthroughs") are fundamentally different. The rules for one are completely different than the rules for the other. Applying the truth learned about one, to the other, results in bad decisions and wrong conclusions. And frustration. Lots of frustration. (As I said above, trying to applying deadlines and schedules, which help engineering progress, to scientific progress, is a classic example of this mistake.)

Finally, don't fall into the simple minded trap of thinking that science fuels engineering in a one-way direction. Sure, scientific breakthroughs are productized and mass produced via engineering progress. But in many cases, scientific breakthroughs are created based on tools which were previously created via engineering progress. The process is circular: Engineers give scientists tools; scientists give engineers breakthroughs; engineers use those breakthroughs to create all kinds of things, including new tools. The process repeats into the future, which brings up my next topic:

The Distribution of Knowledge

This essay is motivated by the following two quotes:

The future is here, now. It is just not evenly distributed. [r1]

The world is flat. [r2]

Now these two quotes express opposite ideas, a duality [d1]. The first says that there are differences between what is available here and what is available somewhere else, and the second says that things available elsewhere are also available here. They are both supposed to apply to goods, services, and (most importantly) knowledge. So which is right?

The idea behind the first quote, is that new discoveries take time to become available everywhere. This delay is partly caused by the speed of communications and partly by differences in wealth. For example, 1000 years ago a discovery made in South America would never be available in Europe, because there simply was no communications between the two of them. Even 100 years ago, discoveries made in far flung places, or in unusual languages or cultures might take decades to become well known in other parts of the world. However, it is also clear that today and in the future, more and more, "The world is flat." [r2] Discoveries made in one place by one culture are rapidly available to everyone. Although there are still differences between what the rich can get and what the poor can get.

Why does this matter to type-1 diabetes research? Because, especially right after diagnosis, many people become interested in type-1 diabetes research because they believe that somewhere, someone has already cured type-1 diabetes (or is about to), and the news just hasn't reached them yet. They are very hopeful that the future cure for type-1 diabetes is already here, it is just in some amazon jungle tribe's traditional knowledge, or some clinic owner in Germany, or the back of some Ivy League / big pharma research lab, etc. Even years after they realize that it's not so, they continue to hope (and sometimes make poor decisions based on that hope).

Even worse, there are people who actively prey on that line of thinking. They say "I know how to cure it, and the only reason you haven't heard of it is because of some grand conspiracy or simple lack of communications, but in any case, if you give me your money, I already know how to cure you." These people are using other people's belief in the "not distributed evenly" idea to create a false hope.

In my opinion, the truth is that the first quote used to be true. Knowledge has been unevenly distributed for all of humanity's existence, except the very last few years. This belief forms the foundation to almost everyone's thought process. Many people believe it very deeply without even thinking about it. But today, the second quote is almost always true, and shortly the second quote will always be true [d2]. People will make better decisions if they understand how untrue that first quote is, when it describes knowledge, right now.

Today, with the internet, and English as a common language of both science and engineering, knowledge spreads more quickly and more evenly than at any time in the past. So it is now almost impossible to have knowledge available in one part of the world, that is not available in all the rest as well.

Extra Discussion and References

[d1] Dualities are not choices between right and wrong answers. They are inherent trade-offs without a single correct answer that force us to learn about the underlying situation, in order to make the best decision about a situation. Wikipedia puts it this way: "a single conceptual unit that is formed by two inseparable and mutually constitutive elements whose inherent tensions and complementarity give the concept richness and dynamism" http://en.wikipedia.org/wiki/Duality_%28CoPs%29

[d2] The only exception is cost. The rich will always be able to afford things that the poor can not. However, especially in the context of a cure for type-1 diabetes, this is not likely to be a huge issue. See my previous post: http://cureresearch4type1diabetes.blogspot.com/2011/11/future-cost-of-type-1-cures.html for more discussion of a cost of a cure

References

[r1] William Gibson, author of the most forward thinking book of the 20th century: Neuromancer.

[r2] This quote, with this meaning, is attributed to Nandan Nilekani and made famous by Thomas Friedman (Pulitzer prize winning journalist) who wrote a book: The World is Flat, commenting on the lack of barriers to goods, services, and knowledge moving around the modern world.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com

Artficial Pancreas Updates

2011-12-08T17:50:00.000-08:00

Here are a couple of recent updates on Artificial Pancreas testing and development. Remember that not everyone considers an AP a cure, but here is an update no matter if you consider it a better treatment or a cure. Also there are a couple of "odds and ends" on other topics at the end of the posting:

Medtronic Starts Testing Veo technology in the US

Veo is a "stage 1" artificial pancreas, meaning it is an integrated pump, CGM device which has one small piece of intelligence in it: it will automatically turn off basil insulin if the BG numbers have been too low for too long. It is the very first baby step to a commercial artificial pancreas. They've been selling it commercially in Europe for years, and just got permission to start testing it in the US.

I could not find the clinical trial record for this study, so I'm basing my information off the press release.
First, the study will be "pivotal" which usually means phase-III.
Second, it will be an at home study, which is another sign that they are close to FDA approval.
But I do not know how large this test will be, how long it will run, or when results will be expected. Although device tests are often much quicker than drug tests, so these tests might only run for a few months, but they will still need to recruit a lot of people, which takes time in itself.

Press release: http://wwwp.medtronic.com/Newsroom/NewsReleaseDetails.do?itemId=1319745760295&lang=en_US
News coverage: http://medgadget.com/2011/11/medtronics-low-glucose-suspend-technology-brings-insulin-pump-closer-to-artificial-pancreas-functionality.html

Artificial Pancreas Operating on Cellphone Tests Successfully
Type-1? These guys got an app for that! :-)

This is a university research group at the University of Virgina, which is running an aggressive artificial pancreas project. They have completed four clinical trials, and are recruiting for six more:
http://www.clinicaltrials.gov/ct2/results?term=Kovatchev

This specific trial involves 15 people (5 each Virgina USA, Padua Italy, Montpellier France), who will spend two nights in a hotel and the day between at the hospital. This is a pilot study to see if it feasible to run a larger study. I would consider this a phase-I trial. The software uses standard CGM and pumps, but the thinking part of the artificial pancreas runs on a Android phone.

I like this approach for a number of reasons. First, I think it will make it easy to make incremental improvements to the AP software. It is much easier to download a new app, than to get a new pump. Second, the easier it is to develop AP software, the more people will do it, and the faster development will move forward. Third, my gut feeling is that anything that runs on a computer now (such as the Sansum software being tested in the next two trials) will be able to run on a smart phone in a few years. Fourth, pumps tend to have crummy screens, buttons, and user interfaces in general, because the companies focus on the "functional" parts, such as the pump. However, smart phones have great screens, buttons and user interfaces because those are very important for their success. So any AP software running on a smart phone will get a better user interface "for free", as compared to anything running on a pump like device. Fifth, smart phones are naturally networked which I think can lead to improved quality of care.   I look forward to a time when your smart phone will power your AP, and maybe once a week it will upload a week's data to a central computer ("in the cloud") which will run lots of data analysis on it, and then download some improvements to your AP.

Note: In real life (when not writing this blog) I'm a software engineer (actually a "technical lead") and the software I'm working on right now is an app for a smart phone, so I do know something about app development. The software I develop is not part of the medical industry.

They expect this study to be completed by September 2012. (Remember: device studies are often quicker than drug trials.)

Clinical trial records (one per site, I don't know why):
http://www.clinicaltrials.gov/ct2/show/NCT01447979
http://www.clinicaltrials.gov/ct2/show/NCT01447992
http://www.clinicaltrials.gov/ct2/show/NCT01470807

News coverage: http://www.nbc29.com/story/16105702/artificial-pancreas-operating-on-cellphone-tests-succesfully
http://www.healthcanal.com/medical-breakthroughs/23649-Artificial-pancreas-real-world-success-for-diabetes-patients.html

Phillip Artificial Pancreas Trial

This artificial pancreas is called MD-logic and this it it's second test on people (that I know of). This trial is 18 teenagers, and is being done in a camp like setting in Isreal, for at least 24 hours.   The MD-Logic device comes in two types, but the one being tested here is the "SC" system which tests sugar levels just under the skin, and doses insulin just under the skin. So it is like a current CGM system and a current pump system, connected via a laptop computer. (For this trial the laptop is being carried around by the patient, all the time.) This "SC" system has been previously tested on 4 adults, in 8 hour sessions in a hospital. The results of the previous trial was BG levels between 92 and 150, which in my opinion is very good.

MD-Logic also comes in an "IV" system, which measures sugar levels directly in the blood stream, and also doses insulin directly in the blood. In theory this should lead to more accurate BG readings and faster insulin effectiveness. This version has only been tested on pigs, for 1 hour at a time. However, during those experiments it kept BG levels between 80 and 130, which I believe is the same levels as found naturally in a non-type-1 diabetic.

I think this is the clinical trial record for this study (if not it is for a closely related trial):
http://www.clinicaltrials.gov/ct2/show/NCT01308164

Note that some articles have claimed that this is the first trial outside of a hospital, but I don't think that is correct. I think there have been two or more previous trials outside of hospitals, including the one right above.

Abstract of earlier research: http://www.ies.org.il/abstracts09/Stem%20cell%20in%20Diabetes%20Mellitus%20symposia-HW103-106.pdf
News coverage: http://asweetlife.org/a-sweet-life-staff/featured/the-loop-has-closed-the-artificial-pancreas-program-comes-to-life-in-israel/21042/

I'm not 100% sure, but I think that these guys are using the same Sansum Diabetes Research Institute software as the Beck group below. I believe this team is also participating in the Beck trial below.

Beck In-patient Evaluation of an Artificial Pancreas

This is a 50 person study, which should be completed by March 2012, so quite soon. (It started back in March 2011, and I'm sorry that I did not blog on it back then.) It uses a DexCom CGM, an Omnipod pump and a laptop.

For those in the bay area: Drs. Buckingham and Wilson at Stanford are involved. There are also sites in Virgina, Denver, Padova Italy, Montpellier, France, and Israel.

I believe that the "Phillip" trial listed above, is using the same basic software, but in a more aggressive setting. The "Phillip" trial is camp like, while "Beck" is in a hospital. On the other hand, "Beck" is larger and multi-site, while "Phillip" is smaller and only one site. "Phillip" is on children, "Beck" on adults. Finally, "Beck" is over half way done, while "Phillip" is just starting.

The FDA's New Guidance for Artificial Pancreas Testing

Last Thursday the FDA issued new guidance for artificial pancreas testing, and several readers have asked my thoughts on it. As you read my opinions, remember that I'm not an expert in understanding FDA technical documents, and it is a very specialized field with much specific knowledge needed to do a good job.

My general opinion is that FDA guidelines don't matter. What matters is how they are interpreted in actual use. So reading a guideline is nice, but the important thing is what happens when the FDA actually uses that guideline to approve or delay a medical device. So my basic reaction to this news (that the guidelines have been released) is to shrug and wait for them to be used, and see what happens then. The guidelines are a necessary step forward, but can't be evaluated on their own merits. Not issuing them delays the process, and now that delay has ended, and that's a very good thing, but it says nothing about the quality of the guidelines.

I did read parts of the guidelines, and skim other parts. It's tough going, but I have the following comments based on my understanding of the guidelines. These are all improvements over the current rules, and point 2 especially would be a huge improvement:
1. There need to be three phases of testing (much like new drugs), and the first is usually in a hospital, the second usually in a camp or similar controlled environment, and the third in the real world.
2. There seem to be two alternate paths to approval, one being testing that the device is better than current methods ("Superiority"), and the other is that the device is not worse than current methods ("Non-Inferiority"). Either path would lead to device approval, but with different marketing claims being allowed. Proving superiority would allow marketing literature saying that the device was better, and so on. If A1c is used as the primary end point for the phase-III study, then showing a 0.4 improvement would be proof of superiority.
3. Computer simulations (referred to a "in silico" testing), may be used to replace some animal testing, but is not a replacement for human testing.
4. A1c data or BG data from a CGM may be used as primary end point data, although the FDA recommends A1c data.
5. There is a lot (my opinion) of flexibility in the secondary data that an applicant may choose to collect in their study.
6. In some cases, trials from other countries can be considered in approving devices.

FDA: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/HomeHealthandConsumer/ConsumerProducts/ArtificialPancreas/default.htm
News coverage: http://www.cbsnews.com/8301-500368_162-57335258/new-fda-guidelines-for-testing-artificial-pancreas/
http://yourlife.usatoday.com/health/story/2011-12-02/FDA-speeds-development-of-artificial-pancreas-systems/51579288/1
JDRF's PR: http://www.sacbee.com/2011/12/01/4093655/jdrf-encouraged-by-draft-fda-artificial.html

Unrelated News Items, Which I Found Interesting

Measuring Pre-Type-1 Diabetes

Quote from the press release:

[Lead researcher Kevan C. Herold and team] at Yale University have developed a method to detect and measure the destruction of beta cells that occurs in the pancreas by measuring DNA expression in the blood. The destruction of beta cells leads, over time, to type 1 diabetes.

If this research pans out, it is likely to have two large and quick effects on research aimed at curing type-1 diabetes. First, it will make it easier to test treatments aimed at preserving or regrowing beta cells. Right now, it is hard to tell if these work, because we generally measure them indirectly (via C-peptide production). This might allow us to measure it directly, and see if the treatments are working a little, a lot, or not at all. Second, it might make it easier to prevent type-1 diabetes, by agressively treating type-1s right when the beta cell destruction starts. Right now, we know when it is about 80% complete (that's when type-1 is diagnosed), and we can see when antibodies start to be generated (but that might be too early). This gives us another way to intervene early for purposes of prevention, if not cure.

Press release: http://media-newswire.com/release_1162305.html

Overview Article on Status of a Cure

The following article is worth a read. It discusses the recent failures of CD3 based clinical trials, and the general state of research into a cure:
http://www.endocrinemetabolic.com/blog/reset_clock_on_type_1.pdf

More Evidence that "Dead in Bed" is Slow

In my previous post on "Dead in Bed", one of the points I made, very briefly, was that type-1 diabetics who died in their sleep did not "spike low". They did not have really low BG for a really short period of time before dying. Quite the opposite, in the one case history presented there [r13], the person was low for many hours before dying. The study below is a similar one, but it covers four people who had seizures. These people did not die.

The take home point, is that three of them had low BG levels for four hours before their seizure, and the forth for over two hours. That suggests to me that a low BG cut off feature would have plenty of time to work and prevent seizures (and eventual death).

Full paper: http://care.diabetesjournals.org/content/31/11/2110.full

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com

Dead in Bed: What is the Chance?

2011-12-02T17:57:00.000-08:00

Note: this posting was edited for clarity on Dec-24 .
Warning: this posting deals entirely with the worst side effect of type-1 diabetes: death.
Please do not read this posting if discussion of death upsets you.
Also, if you are a brittle type-1 diabetic or the relative of one, then [r12] will be particularly shocking. Please read the entire discussion with that reference, if you read any at all.
Some people may find [r13] particularly upsetting, as it deals with a specific death, rather than statistical deaths in general.

The r-numbers in square brackets [r1] refer to references which are discussed throughout the post, the d-numbers [d1] to extra discussion at the bottom of the post.

Recently, there was a lot of shock and horror when JDRF published an ad which said that for a type-1 diabetic the chance of dying of low blood sugar was about 5% over a lifetime. So in this blog posting I'll examine the data on "dead in bed" to see if 5% is the correct rate. Obviously, this posting is not about my regular topic: clinical trials aimed at curing type-1 diabetes. But it is a subject important to everyone near to type-1 diabetes, and I wanted to see if that 5% number is true.

I don't know if anyone has said this before, but if not, I'm saying it now:

"There is never enough data to convince someone of something that they don't want to believe."

My one paragraph summary: there is no doubt that for type-1 diabetics who die young (ie under about 40 years old), over 5% of these deaths are due to hypoglycemia (low BG). All the recent studies show this. I could not find any data at all to come to a conclusion about the death rate for type-1 diabetics older than that. Since the data we do have is over 5%, I think 5% is a conservative estimate, although the lack of data for older diabetics does leave room for speculation that it is lower, there is no data to suggest that it is lower.

This posting is in four sections:
1. Some background information and discussion about how to measure death.
2. A review of the studies that JDRF referred to in their follow-up email as supporting the 5% number.
3. A review of other available studies, from my own research.
4. Some discussion on the social and political importance of this data.

Background Information

Measuring Death is Harder than you Think

Measuring how type-1 diabetics die is a lot harder than you might think, with unconnected medical records, like the US [d1]. The obvious thing to do, is to select a group of people, wait for them to die, and record how they died. However, you need to wait for them to die, so the data is available an entire generation after you selected the people. You could also do this "in reverse", research everyone who dies in a given place, and find out which ones have type-1 diabetes, and then record how they die. To do this for 300 type-1 diabetics, you'll need to research about 90,000 people who die just to find the 300 who have type-1 (remember only 1 in 300 will have type-1). That's a problem, too. A third way to do it is to follow many people of different ages, and then splice the data together grouped by age, to get a chance of death over an entire lifespan. But that requires following a lot of people, in several different groups, and it's not easy, either.

But none of these techniques are going to give you quick, up-to-date, and easy-to-get information on how type-1 diabetics die.

To make matters worse, not all "dead in bed" cases are hypoglycemia[d2,r10], and in many cases, especially in the past, these were tracked as sudden, unexplained death (or similar) but not generally considered a side effect of diabetes.

Many of the studies done in the past reported on "chronic complications" of type-1 diabetes (things like heart attack, loss of limbs, etc.) and "acute complications" (either low BG or high BG / ketoacidosis). But they did not provide data on the number of low BG related deaths, just on all acute complications combined.

Finally, and perhaps most horribly, some researchers have referred to "dead in bed" or hypoglycemia as "insulin overdoses" or "drug misuse". This has the effect of blaming the type-1 diabetic for their own death, or maybe blaming their doctor for prescribing too much insulin. In any case, if a researcher had the choice of listing death as "insulin overdose" or "unknown cause of death" which did you think they did? But then the true cause of death is lost from later analysis.

These issues have in the past lead to an under counting of deaths caused by hypoglycemia, but they provide little help in determining what the rate actually is.

A Review of JDRF's Sources

A quick summary of the data is as follows: two of JDRFs sources were very similar, and written by the same person, and used a total of 5 studies to estimate the 5% number. See the quote under [r2] below. Basically they showed that older studies had 2%-4% numbers and newer studies had 6%-10% numbers. For reasons described above, I agree with JDRF that the new studies should be given more weight.

Another study that JDRF cited was the DCCT trial. This is a large, recent study on the complications of type-1 diabetes. This well respected study is commonly cited when researchers need data on rates of complications. I suspect it has been used dozens, if not hundreds of times in the years since it was published. It found a rate of 6%.

Below are listed the 9 sources that JDRF referred to in their email as supporting their 5% number:

[r1] Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes 2008;57(12):3169?76.
full paper: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2584119/
This paper came to very similar conclusions to the one below, based on the same underlying research, and done by the same person, so see [r2] for details.

[r2] Cryer, PE. Hypoglycemia in Type 1 Diabetes Mellitus. Endocrinol Metab Clin North Am. 2010. 39(3): 641-654.
full paper: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923455/?tool=pubmed

Early reports suggested that 2% to 4% of deaths of people with diabetes are the result of hypoglycemia [r1][r16]. More recent reports indicate that 6% to 10% of deaths of people with T1DM are caused by hypoglycemia [r7][r8][r9]. Regardless of the exact rates, the existence of iatrogenic mortality is alarming.

[r3] Cryer PE. Death during Intensive Glycemic Therapy of Diabetes: Mechanisms and Implications. Am J Med 2011 124(11):993-996.
No abstract or paper available, still in process of being printed.

[r4] Deckert T, Poulsen JE, Larsen M. Prognosis of diabetics with diabetes onset before the age of thirty-one. I. Survival, causes of death, and complications. Diabetologia. 1978;14:363-370.
No abstract or paper available to me.

[r5] Tunbridge WMG. Factors contributing to deaths of diabetics under fifty years of age. Lancet. 1981;2:569-572.
No abstract or paper available to me.

[r6] Laing SP, Swerdlow AJ, Slater SD, et al. The British Diabetic Association Cohort Study, I: all-cause mortality in patients with insulin treated diabetes mellitus. Diabet Med. 1999;16:459-465.
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/10391392
Neither abstract had data on low BG deaths, and paper was not available to me.

[r7] Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group. Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med 2007;356(18):1842?52.
Full paper: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701294/

A total of 1144 patients with type 1 diabetes enrolled in the Diabetes Control and Complications Trial (DCCT) and its follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study were examined on entry to the DCCT (at mean age 27 years) and a mean of 18 years later with the same comprehensive battery of cognitive tests.

Of the 53 deaths during the DCCT and the EDIC study, 3 were attributed to hypoglycemia ...[So a 6% rate.]

[r8] Feltbower RG, Bodansky HJ, Patterson CC, et al. Acute complications and drug misuse are important causes of death for children and young adults with type 1 diabetes: results from the Yorkshire Register of diabetes in children and young adults. Diabetes Care 2008;31(5):922?6.
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/18285550

A total of 4,246 individuals were followed up, providing 50,471 person-years of follow-up. Mean follow-up length was 12.8 years for individuals aged 0-14 years and 8.3 for those aged 15-29 years. ... A total of 47 of 108 deaths (44%) occurred from diabetes complications, 32 of which were acute and 15 chronic. [

The [r9] study below found that about 30% were acute and about 10% were low BG, so if that ratio is true for this study as well, then this study would also find about 10% death rate from low BG.

[r9] Skrivarhaug T, Bangstad HJ, Stene LC, et al. Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway. Diabetologia 2006;49(2):298?305.
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/16365724
Full paper: http://www.springerlink.com/content/f932481234766352/fulltext.pdf

All Norwegian type 1 diabetic patients who were diagnosed between 1973 and 1982 and were under 15 years of age at diagnosis were included [1,906 people]. Mortality was recorded from diabetes onset until 31 December 2002 and represented 46,147 person-years. The greatest age attained among deceased subjects was 40 years and the maximum diabetes duration was 30 years.

This paper found that about 10% of the people who died, died of low BG.

A Review of Other Sources

When summarizing research papers, the biggest single source of bias is to only include papers which support your position in the list of papers summarized. So, to see if that happened, I did my own search of the literature, using Pubmed, ClinicalTrials.gov and Google Scholar as my primary sources.
My summary of these other sources, is that most of them do not provide directly useful data, but that the data they do provide does not conflict with the 5% number from the JDRF ad.

[r10] Abstract: http://www.ncbi.nlm.nih.gov/pubmed/16186267
Diabetes Care. 2005 Oct;28(10):2384-7.
Mortality in childhood-onset type 1 diabetes: a population-based study.
Dahlquist G, Källén B.
Mean age at death was 15.2 years (range 1.2-27.3) and mean duration 8.2 years (0-20.7).

Seventeen diabetic case subjects were found deceased in bed without any cause of death found at forensic autopsy. Only two of the control subjects died of similar unexplained deaths. In my opinion, this shows two things: first, that most "dead-in-bed" cases are acute complications of type-1 diabetes, but also that a few are not. This makes the accounting harder to do.

[r11] Full paper: http://www.ncbi.nlm.nih.gov/pubmed/21903695
BMJ. 2011 Sep 8;343:d5364. doi: 10.1136/bmj.d5364.
Time trends in mortality in patients with type 1 diabetes: nationwide population based cohort study.
Harjutsalo V, Forsblom C, Groop PH.
Key table: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169676/table/tbl4/

This paper found about 19% (very roughly) died of acute complications. If the same 1/3 ratio seen in [r9] is also true here, that would result in about 6% of deaths caused by low BG. However, this paper separated alcohol/drug related acute events and those unrelated. About 40% of the acute deaths were related to alcohol or drugs. I think that is important to remember.

[r12] http://www.ncbi.nlm.nih.gov/pubmed/21285231
The outcome of brittle type 1 diabetes--a 20 year study.
Cartwright A, Wallymahmed M, Macfarlane IA, Wallymahmed A, Williams G, Gill GV.
Department of Diabetes/Endocrinology, University of Liverpool, Liverpool L9 1AE, UK.

This was the most emotionally horrifying paper I came across. It was a small (33 person) study focused on brittle diabetics, the ones most likely to die from low BG. They found that 20% of the deaths were caused by low BG, and that the type-1 diabetics who started out brittle (by their definition) had a death rate of 50% (!) over a 20 year period. At the end of the 20 year study, none of the surviving patients remained brittle. A very depressing result, but I don't think the data applies to most diabetics. But it certainly makes me understand why brittle diabetics would be willing to have transplantation surgery including rest-of-their life drug treatments. According to this study, the alternative is a 50% chance of death, and many chronic complications.

However, I later came across this follow on paper:
http://onlinelibrary.wiley.com/doi/10.1002/pdi.1630/abstract
which suggested that some of the type-1 diabetics in the previous study were brittle because of psychological issues or a lack of training. The exact quote was this:

Most [surviving type-1 diabetics from the previous study] attributed their previous instability to life stresses and/or inadequate diabetes-related education. Two (20%) admitted to inducing dysglycaemia by therapeutic interference. ... None of the survivors was actively brittle, and most attributed resolution of brittleness to positive life changes.

[r13] Abstract: http://www.ncbi.nlm.nih.gov/pubmed/19833577
Confirmation of hypoglycemia in the "dead-in-bed" syndrome, as captured by a retrospective continuous glucose monitoring system.
Endocr Pract. 2010 Mar-Apr;16(2):244-8.
Tanenberg RJ, Newton CA, Drake AJ.

These researchers were recording CGM data (not monitoring it in real time!), from a patient who died of hypoglycemia with the monitor attached. They were able to provide absolute proof that, at least some, "dead in bed" cases were directly caused by low BG.

For me, the most interesting data from this case, was that this person did not "spike low". It is not that he suddenly dropped to a very low BG, and then died. Nor is it that he dropped low, and then quickly died. He was low for hours before death. I suspect that his body was doing everything it could (glucagon, etc.) to try to keep the BG up. The CGM was alarming repeatedly. But after hours of keeping BG levels above fatal levels, the body simply could not do this any more, and the person died.

[r14] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1060170/?tool=pubmed
Abstract did not mention % of deaths caused by low BG, but more than 90% of the people in this study were type-2 diabetics who were treated with insulin.

[r15] http://diabetes.niddk.nih.gov/dm/pubs/america/pdf/chapter13.pdf
H. Fishbein and P. Palumbo, "Acute Metabolic Complications in Diabetes," in Diabetes in America (Bethesda, Maryland: National Diabetes Data Group, 2nd ed. (1995) ch. 13, p. 283

Chapter in a book, but no specific information on prevalence of low BG as cause of death.

[r16] Cryer PE. Pathophysiology, Prevalence and Prevention. American Diabetes Association; Alexandria, VA: 2009. Hypoglycemia in Diabetes.

Some Discussion

JDRF seems to have relied on several papers published by Dr. Cryer to develop their 5%. His published record of research on the causes of death of type-1 diabetics goes back at least as far as 1990, and he has published a wide range of papers on this subject.

Why Publicize the 5% Number?

To be blunt, because it is the only way to get the FDA to do their job. As I describe the situation, please remember that I'm speaking only for myself, and these are my opinions based on the (indirect) information available to me: The FDA is supposed to approve devices because they are scientifically shown to be safe and effective. However, in this case they are simply refusing to do so [d4]. Insulin pumps with automatic shut offs for low BG conditions were approved in Europe years ago, and have been actively used there (by large numbers of people!) for at least two years. There is no question about the safety or effectiveness of these systems. Never the less, the FDA refuses to approve them here. Luckily, the FDA, being a political agency, is subject to political pressure, and I assume that is why JDRF is publicly pointing out that the result of the FDA's lack of approval is death. I very much wish that the FDA would do it's job based on the scientific data showing safety and effectiveness, but they aren't. So this sort of pressure is the only other option available.

BTW: If anyone who works for the FDA or has first hand knowledge of the approval process for automatic shut off insulin pumps: I would very much like to talk to you about what IS happening. Send me email, and I'll send you my phone number.

And remember, refusing to approve a safety cut off for low BG levels in a pump, has the effect (at least short term) of stopping all movement on a commercial artificial pancreas in the US. Every pump manufacturer in the world knows that if the FDA won't approve a low BG cut off, they surely won't approve anything more advanced either. So the best treatment likely to be available in the next decade or so, is being held hostage by FDA unreasonableness. There is a lot at stake here.

Late breaking news: in the last day or two, the FDA has announced new guidelines for testing closed loop / artificial pancreas systems. I'll see if I can put together a blog on that news in the near future. Better late then never, I guess. Hopefully better guidelines rather than worse ones.

Non-Data Based Arguments That the 5% Number is Wrong

I was a little surprised (but I shouldn't have been) about some of the arguments that people made that the 5% number was wrong, that was not based on data at all. I discuss two of those arguments -- very briefly! -- below.

I never heard that number before, so it must be wrong. [d5] Many people are uneasy with discussion about the possible death of themselves or their children. There is a lot of pressure not to talk about death as a side effect of type-1 diabetes. So it is not at all surprising that there is not as much talk about it as it deserves, and hence, many people have not heard about it before. But that is no reason to assume, when it is talked about, that the data is wrong.

Also, as long as doctors thought of low BG as insulin overdose or as drug misuse, then they also may choose not to talk about it, since they will end up blaming the dead, or the dead person's doctor. So, both doctors and patients (including relatives of patients) had good reasons not to talk about "dead in bed", so some people are a little surprised to hear about something they are not used to hearing about.

That number only applies to relatively young type-1 diabetes (under 40, for example), and doesn't apply to all because most die when they are older than that. This is not a groundless argument, because the data we have is for people younger than 40, but most people die when they are over 40. However, it requires a lot of speculation. We have data for people under 40 and the more recent data shows a higher rate than 5%. We have no data for people older than 40, so some people hope that the over 40 number death rate might be very different from the under 40 death rate, and therefore that the entire-life chance of dying from low BG might be lower than 5%. For me, that's not reasonable doubt, that's just speculation. Maybe "wishful thinking" is a better phrase to describe it. I do think that running a study focusing on older type-1 diabetics would be a good thing, and would fill an important hole in the data. But I do not think it is reasonable to speculate that the data we don't have is different from the data we do have.

Why Talk about Scary Data? / Why Present the Data so Strongly?

When this data was presented several people felt it should be muted or toned down. I think that is largely a matter of personal taste. Do you get more from being quiet and polite or being loud and scary? Different people will disagree and this is reasonable. For my part, I think the JDRF and the the pump/CGM industry has been taking the quiet and polite tack for years, and it doesn't seem to be working. So I'm cool with the loud and scary tactic at this point.

Obviously death is the worst possible side effect of type-1 diabetes. If we are not prepared to get loud and scary about that, then what? There is no question in my mind that we are looking at the cause of about 10% of the type-1 diabetics who die young (under 40). That's huge all by itself, without even starting to discuss 5% over a lifetime.

More Discussion and References

[d1] I mean records which are scattered and hard to review or use for large scale studies. In the US, we have death records, but no way to link them to health records. If a patient changes doctors or health plans, their records become separated, and so on. There is no place to look for a person's entire health history.

[d2] In the 1990s co-worker of mine (in his 20s) was found dead-in-bed, and he did not have type-1 diabetes. It was very mysterious and ominous. See [r10] for a little more data.

[d4] I don't follow FDA process closely myself, but my understanding is that the FDA started out saying that in order to be approved, an automatic cut-off system had to show that it reduced low BG events by 10% compared to MDI. Obviously, this is NOT showing safe and effective, this is showing better than the competition, so already a groundless requirement for the FDA to make. However, when the company actually presented the studies to the FDA, to get them reviewed prior to starting, the FDA changed it's mind, and decided that the company had to show 30% decrease!

The European safety agency actually did what the FDA was supposed to do, they required tests that the shut off feature did not cause any problems (safety), and that it worked at least as well as current pump technology (effectiveness) in terms of low BG issues.

[d5] The speaker thinks that because they themselves have never heard something, then therefore it must be false. Or the speaker thinks that something doesn't make sense to them, so therefore it must be false. The first is very dangerous because it assume a person is all-knowledgeable, so if they haven't heard it, it's not true. The second is dangerous because it assumes that the truth always makes sense (or is logical), and it doesn't.

The soundtrack for this blog entry is Juke Box Hero (Any Live Version) by Foreigner as found on YouTube.com: http://www.youtube.com/watch?v=EAUOx4lpt24

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com

Andromeda's DiaPep277 Succeeds In Phase-III Trial

2011-11-27T16:56:00.000-08:00

... but what does that mean?

Good News First

This was a big (450+ people) study, and phase-III, so late in the processes of commercialization. The treatment was DiaPep277, which is a peptide (a short protein) which is related to a naturally occurring protein called "heat shock protein 60" or hsp60. The treatment is one under-skin injection every 3 months. People were followed for 2 years. The study was blind, random assignment; half got the treatment, half the placebo.

DiaPep277 works by increasing the activity of regulatory T cells (especially Th2 cells), which serve to control the autoimmune attack on beta cells in the pancreas. Earlier research described the mechanism this way: hsp60 is a protein found in the pancreas and very similar to hsp65, which is found in microorganisms. Your autoimmune system gets mixed up between hsp65 (sign of foreign invasion) and hsp60 (naturally there), and attacks the beta cells in your pancreas. DiaPep277 is part of the larger hsp60 molecule and teaches your immune system not to attack. The idea is similar to giving people tiny amounts of peanut protein to wean them off of peanut allergies. [r3,r4]

The important pieces of news from this study are:

The primary outcome for this was C-peptide production. Measuring C-peptide is the same as measuring the body's production of insulin[d1]. The people who got the treatment generated (on average) 0.949 nmol/L/20 minutes more, which is 23.4% more than the untreated group. That was statistically significant. But remember that type-1 diabetics generate very little insulin, so even a tiny bit more will cause a big percentage change.
Untreated honeymoon diabetics loose their ability to generate insulin as the disease progresses. People treated with DiaPep277 also lost this ability, but it happened more slowly, so that at each point in time, the treated group generated more of their own insulin as compared to the untreated group. Some of the news coverage refers to "preserving insulin production" but it is important to remember that insulin production was not preserved at the same level as when treatment started. Instead, production was higher in treated people then in untreated people. It's a big difference.
A secondary outcome was lower A1c numbers in the treated group. The company did not report average A1c numbers [d2], but they did say that 45.5% of the treated group was below 7, but only 35.7% of the untreated group was that low. This suggests that the extra insulin produced was useful, and was lowering A1c, and was having a positive effect on the body.
The "initial safety data also indicate that DiaPep277 was well tolerated", which means no serious side effects, which is always a good thing, and consistent with earlier testing. This drug never had a hint of safety issues, that I know of.
Shlomo Dagan, CEO of Andromeda (the developer of the drug) said "I estimate that that the drug will be on the shelf by the end of 2014" (but this was quoted in Hebrew, which I don't understand, so I'm relying on a translation into English). But I think he's wrong about that. To get approved, a drug needs two trials. The second phase-III trial is supposed to finish enrollment in 2012, and it's a 2 year treatment program, so that study finishes in 2014. Then there is a year or two for marketing approval, so I'd estimate approval in 2015 or 2016, assuming further analysis of this trial is successful, and the second phase-III trial is also successful.

You can read more about Andromeda here: http://www.andromedabio.com/

Now the Bad News

This is not a cure, in it's current form. This drug has only been tested on honeymoon diabetics and only been found to extend the honeymoon duration.
I'm not sure how big the effect really is, in terms of how much it would improve the life of a type-1 diabetic [d3].

However, right now we have nothing that effects the body's immune system to help a type-1 diabetic. Nothing at all. If this treatment gets approved, then we will have one thing. And we must start somewhere, so I do think getting this approved and available is a big step forward no matter what it's limitations.

Comparison with Other Results

Dr. Faustman's BCG results showed spikes of .004 to .005 nmols of C-peptide [d4], so the DiaPep277 results are about 200 times bigger an effect than her results [d5], although her results were in established type-1 diabetics, not honeymooners.

Dr. Orban's Abatacept (Orencia) results showed improvements of 60% in C-peptide production, as compared to 23.4% seen in DiaPep277 [d5]. However, Abatacept was in a phase-II trial, so it was smaller, and farther away from approval for type-1 diabetes. But it is already approved for use for another disease.

Dr. Pescovitz's Rituximab results showed improvements of about 20% in C-peptide production as compare to 23.4% seen in DiaPep277 [d5]. However, Rituximab was in a phase-II trial, so it was smaller, and farther away from approval for type-1 diabetes. But it is already approved for use for another disease.

More Data; Future Results
There were a couple of data points that I wish were in the press release, but aren't. I'll certainly be looking for them in the published paper. First, a comparison of A1c numbers in treated vs. untreated. See [d2] for details of what I'd like to see. Second, a time based comparison: if an untreated type-1 reaches the end of their honeymoon N months after diagnosis (on average), how many months will it take someone with this treatment to get to the end of their honeymoon? Third, some details on safety. It's great to say "well tolerated", but I'd like to see the details.

In terms of future work: obviously, these guys need to complete their analysis of this trial, complete their second phase-III trial, and get marketing approval from the FDA and EMEA. That's just to get it widely available in the market.

In addition there are several expansion paths which I hope they will take now, but might need to wait until after the treatment get approval. (Once a drug is approved for any use, it is a lot easier to run a trial for other uses.) Interesting lines of research would include:

Trying it on patients before they were diagnosed with type-1 diabetes. Many believe that anything that works in honeymooners will work better in people who have not yet been diagnosed at all. Even a few years ago, however, we could not find those "not yet diagnosed" people, so we could not design a trial around them. Now however, thanks to the "natural history" trial run by TrialNet [r2], we can find people who have not yet been diagnosed, and recruit them for pre-diagnosis trials. So running a trial on people more likely to be diagnosed in the future, but not yet diagnosed, is an obvious thing to do.
Combining it with other drugs. Testing multiple drugs is becoming a common technique when there is no one drug that is completely effective. For this drug, there are two ways to attack the problem. One is try a combination of drugs all aimed at extending the honeymoon. See if all of them together can actually stop the beta cell destruction and permanently preserve the beta cell function which is present at diagnosis. Another track is to combine this drug with another drug which grows beta cells.
Trying it on established type-1 diabetes. Majority consensus is that stopping type-1 diabetes when in starts (during the honeymoon) is easier than stopping it later (once established). However, I'm still in favor of trying a drug that works on honeymooners, on established type-1 diabetics as well, especially when the side effects are very small or nonexistent. Especially researchers who believe that beta cells continue to grow back slowly throughout a person's life, they might be particularly interested in a drug that lowers the autoimmune attack, even if given late in life. Also, to put it bluntly, at this point established type-1 diabetics have little to loose, and few good options to try.

Press release:
http://www.andromedabio.com/page.php?pageID=69

News coverage:
http://www.marketwatch.com/story/andromeda-announces-phase-iii-clinical-study-with-diapep277r-a-novel-immunotherapeutic-agent-for-type-1-diabetes-met-primary-endpoint-2011-11-22
http://www.globes.co.il/serveen/globes/docview.asp?did=1000699926&fid=1725
http://www.rttnews.com/Content/BiotechStory.aspx?Id=1766892&Category=ClinicalTrial

Extra Discussion and References

[d1] Researchers can not measure insulin directly, because that would just measure how much insulin was being injected. Measuring C-peptide tells them how much insulin the body is producing itself. C-peptide is the official (by FDA) marker for approval of drugs to help type-1 diabetes, so it is the right thing to look at for trials like this.

[d2] My personal requirement, is that changing A1c numbers by 0.5 is interesting and worth looking at, but that changing them by 1 is important, and obviously good without any further discussion. My understanding is that most diabetes researchers are happy with 0.5, and consider even smaller changes interesting.

[d3] Primarily, I'm not sure how much improvement there would be in terms of fewer side effects, less dangerous lows, etc. I think the most important point here is duration of effect. If the effect is long lasting, then it is reasonable to assume fewer long term side effects, but I have not seen any duration information. Separately, there is also some debate about the benefit of having a longer, stronger honeymoon. Some people hold that this just makes it tougher to treat type-1 diabetes: easier to have hypoglycemic events and harder to control BG and A1c numbers. From a cure point of view, however, generating more of your own insulin is clearly the path to a cure, so I consider a longer, stronger honeymoon to be a good thing.

[d4] Different research report C-peptide results in different units. Dr. Faustman reports [r1] her results in terms of pmols / liter, and a pmol is 1/1000th of an nmol, so 5 pmols is the same as .005 nmols / liter. On the other hand, Dr. Pescovitz reports in pmol / milliliter (which happens to be the same as nmol / liter).

[d5] Because there are several different ways to measure C-peptide production, I don't think this is a direct "apples to apples" comparison. However, it is the closest to a direct comparison that I can make. C-peptides can be measured in response to a meal, or while fasting. The exact mechanism of measurement can vary as well.

[r1] http://www.solvingdiabetes.org/2011/07/04/highlights-of-ada-scientific-sessions-i-bgc-trial/
[r2] http://www.diabetestrialnet.org/studies/natural-history.htm
[r3] How it works in NOD mice: http://www.ncbi.nlm.nih.gov/pubmed/9133541
[r4] How it works in BB rats: http://www.diabetes-mellitus.org/p277_idf.htm

Thanks to Abush at CWD for posting the first news of this, including the English translation.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com

Results from Trucco's Phase-I Dendritic Trial

2011-11-10T19:57:00.000-08:00

This is another "is the glass half full or half empty" kind of result.

This experiment was started in 2007. People who had type-1 diabetes for more than 5 years were treated by removing dentric cells, treating those cells, and then reinjecting them. This was done 4 times (2 weeks apart). About 10 people were treated, but there was no placebo group. This study was a phase-I trial, very clearly aimed at safety, not effectiveness. As far as I know, this is the first clinical trial aimed at type-1 diabetes, which used this basic method (of reinjecting a patient's specially treated dendric cells). So there were new and unique safety issues to be tested. Just recently a second study using this same basic technique has started which you can read about here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Polyclonal%20Tregs

This is from the abstract:

CONCLUSIONS Treatment with autologous dendritic cells, in a native state or directed ex vivo toward a tolerogenic immunosuppressive state, is safe and well tolerated. Dendritic cells up regulated the frequency of a potentially beneficial B220+ CD11c− B-cell population, at least in type 1 diabetes autoimmunity.

My translation is is this:
First, there were no safety issues. The treatment's safety was good.
Second, there were some effects (which they think are good) on a particular type of B-cell.
Third, there were no other effects seen (so no changes in C-peptide levels, A1c, or T-cells, for example).

What does this mean?

The most important results, is that the treatment is undoubtedly safe enough to continue into phase-II trials. (In the presentation below there is a letter from the FDA saying that.)

But after that, did it work? Very hard to tell, but it did not work as measured in the obvious ways by raising C-peptide levels, for example, or lowering antibody levels. The researchers hope that the change in B cells is a good sign, but I'm not sure that it is.

It is important to remember that B-cells and T-cells come in all different types. So when these researchers say B220+ CD11c− B-cells they are referring to one type specifically. They hope that more B-cells of that specific type are a good thing, but this trial alone does not show that is so. For comparison, the most talked-about type of B cell is called CD20. T cells that are researched as part of type-1 research include CD4 and CD8 (and many more). I know of no other clinical trials working with this type of B-cell.

Abstract: http://care.diabetesjournals.org/content/34/9/2026.short
Presentation: http://www.ucdenver.edu/academics/colleges/medicalschool/centers/BarbaraDavis/OnlineBooks/Documents/Keystone2011/Keystone%202011%20Trucco%20Cellular%20Therapies.pdf
Clinical Trial Record: http://clinicaltrials.gov/show/NCT00445913

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

The Future Cost of Type-1 Cures

2011-11-01T18:32:00.000-07:00

Every now and then, someone will ask me how much I think a cure will cost, or they will complain that a cure that I take seriously will be too expensive (whatever that means), even if successful. I have three thoughts that I always try to keep in my head when people talk about the cost of a cure:

First, it is a total waste of time, to discuss the cost of something that you can not buy. No one really knows how much something will cost, if they can not sell it, and you can not buy it. It's like discussing ghosts or fantasy football.

Second, "demand creates it's own supply" which is an economics phrase, that basically means that if people want something badly enough, then other people will find a way to make those things cheaper, which will change the basic economics of availability. An example has to do with transplanting beta cells recovered from cadavers. Right now, that doesn't result in a cure. Some people say that could never result in a general cure, because there are not enough donated cadaver pancreases. So such a cure is impossible, because even if it worked scientifically, there would not be enough cadaver pancreases. But I don't agree with that logic. For one thing, if cadaver pancreases could be used to cure type-1 diabetes, there would be a huge increase donated pancreases. Groups like ADA and JDRF would launch public relations campaigns. There would be scores of "feel good" local news articles about people cured with donated pancreases. Suddenly, there would be many more pancreases donated. At a minimum, every grandparent of a type-1 diabetic would be signing those forms. Furthermore, I would expect the technology to improve over time. So if the first cure takes beta cells from three pancreases to cure one person, over time, it might take 2.5 and then 2, and maybe eventually 1.5 or even just 1. That means that even thought the number of pancreases doesn't change, how many people they cure would change. These are two examples of how "demand can create it's own supply".

Third, technology makes everything (high tech) cheaper. Computers that cost over $100,000 dollars in 1970, cost $2000 in 1980, and so on. My daughter has a $400 iPad, which probably has a lot more computing power than an entire Apollo moon launch from the 1960s, and so on. Many of the possible type-1 cures that people are afraid will be "too expensive" are very high tech, and we can expect them to get cheaper over time as we learn how to build them, and the general level of technology improves.

So my policy when thinking about cures myself, is not to worry about cost. I know others do, and so I include that information when I have it. But for myself: I only worry about availability, not cost. Right now we have nothing. So having a cure, even a really expensive cure, would be such a huge step forward, that I just can't bring myself to worry about the price. I am sure that even if a cure starts out "too expensive" it will not stay that way for long.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Atorvastatin (Lipitor), One down, one to go

2011-10-27T21:17:00.000-07:00

In the mid-2000s, two different groups started clinical trials which gave honeymoon type-1 diabetics Atorvastatin (Lipitor®). One of these trials was at Children's Hospital of Philadelphia (fondly known as "CHOP") and the other in Germany. Lipitor is one of the most prescribed drugs in the world, and is used for long periods of time, so safety should not be an issue. On the other hand, I could never understand exactly why anyone thought it would help cure type-1 diabetes. Earlier this year, the German group posted their results. Here is their conclusion:

Atorvastatin [Lipitor] treatment did not significantly preserve beta cell function although there may have been a slower decline of beta-cell function which merits further study.

Which I translate to "It didn't work."

The CHOP study is a little overdue as well. They were expected to finish collecting data in July 2010, so they've had about 15+ months to publish, but have not as yet. Since that is the last Lipitor clinical trial that I know of, when we get the results from it, Lipitor is done.

My Previous Blogging: http://cureresearch4type1diabetes.blogspot.com/search/label/Lipitor
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/21412424?dopt=Abstract
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT00529191
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT00974740

A Little Discussion: What was the FDA's Orphan Products group thinking?

One question you might have is do researchers think it would work? After all, Lipitor is aimed a lowering cholesterol, which doesn't have any obvious connection to type-1 diabetes. The basic answer is two fold. First Lipitor is a immune modulator, so it might stop the immune system's attack on self. Also, studies have shown that atorvastatin (Lipitor), and other statins, preserve beta cell function in a mouse model of type 1 diabetes. But other studies have show that it did not work on NOD mice specifically. So it was a known immune modulator, with conflicting results in animals.

But it has two things going for it, separate from the question of "does it work". First, it is known safe and widely used. So that makes it very easy to work with and get approvals for. The second thing is that it has a big company behind it. (And for that company, it's a big deal drug.) So they have a strong interest in finding new markets to sell it to, especially if they can somehow get patent coverage over a new use. Anyway, that was good enough to get two clinical trials started.

But there was one humorous note about this research: The funders of the two trials. The first trial was funded by Pfizer, which is just as you would expect. They are the big pharma company that makes the drug. But the second trial was funded by the FDA's Office of Orphan Products Development. So here you have the biggest selling drug, from a huge drug company, and research is being funded by the office of orphan productions. Both groups are funding research at about the same time, while the drug was still under patent. It makes no sense to me.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Two Summaries of Clinical Trials Aimed at Curing Type-1 Diabetes

2011-10-16T19:56:00.000-07:00

I keep two different summaries of the status of clinical trials aimed at curing type-1 diabetes, and I've just updated both of them. So if you want a summary of the whole field, you might try looking at one or both of these:

Summary Table
This is a PDF file (so you can view it on the web), which is a table of all clinical trials aimed at curing type-1 diabetes. From left to right it is organized by phase of clinical trial, so phase-I is on the left, and phase-III on the right. Within each phase are three milestones: Has the trial started? Is it fully enrolled? And have results been reported? From top to bottom are different rows representing different techniques being tried to cure type-1. So there is a row for immunology, a row for encapsulation, a row for inflammation, etc.

This table contains one entry for each treatment which is currently being tested, and is designed to be printed out in black and white on a 3 foot by 4 foot poster. It is very plain, with no graphics at all.

This file is stored on www.box.com, but anyone should be able to see it, here:
http://www.box.net/shared/3i4hl9o2iuoqde3h1vup
or look here:
http://www.box.net/shared/4dlxsj9vshd2ghn9zil4
for the whole directory of material.

Next Expected Milestone
This is a list of all clinical trials currently or recently running aimed at curing type-1 diabetes. My goal with this page is to make it easy, for each clinical trial, to see what research milestones are expected to be completed and when. It can also serve as an TLOD ("too long over due") list of research that isn't reporting the expected results. It also contains the last milestone that a trial reached, so you can see where everyone last was.

This list contains one entry for each clinical trial which is currently underway, or recently was underway. If many trials are being run on the same treatment, then there will be several entries in this list. It is designed to be viewed on a computer monitor, so color is important.

This file is part of my blog, and you can see it here:
http://cureresearch4type1diabetes.blogspot.com/p/next-expected-milestone.html

I update these files at least once a year. (I try to do it once a quarter.) If you see a mistake or something is missing, please tell me. Thanks.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Antibiotics and Type-1 Diabetes

2011-10-08T09:49:00.000-07:00

I occasionally get asked about a link between antibiotics and type-1 diabetes. Basically, people want to know if our expanding use of antibiotics is causing cases of type-1 diabetes.

The following study looked at this issue specifically (use of antibiotics causing type-1 diabetes) and found that it did not happen:

http://aje.oxfordjournals.org/cgi/content/abstract/kwp038v1

Denmark has a centralized records medical system, so it is possible to do studies where you look at all children in the country, and compare their antibiotics usage to their type-1 diabetes status. We could never do something like that here in the USA, but we can benefit from the studies done in other countries. This study was based on about 600,000 patients, and was just published recently (in 2009).

Here is about half of their abstract. I've removed the numbers, so that it reads better:

Use of any antibiotic was not associated with type 1 diabetes. Evaluation of type 1 diabetes risk according to number of courses of any antibiotic yielded no association between antibiotic use and type 1 diabetes. No specific class of antibiotics was associated with type 1 diabetes, no specific age of use was associated with type 1 diabetes, and no specific age at onset of type 1 diabetes was associated with antibiotics. In a large nationwide prospective study, no association between antibiotic use and type 1 diabetes was found among Danish children.

I have not found any controlled clinical (human) studies which show that increased antibiotic use increases the chance of type-1 diabetes.

Joshua Levy

All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

JDRF Funding Research for a Cure 2011

2011-10-01T09:34:00.000-07:00

In the US, we are starting the "Walking Season" when JDRF asks us to walk to raise money for cure. So I'd like to do my part, by reminding you all how important JDRF is to the human trials of potential cures for type-1 diabetes, which I track.

Let me give you the punch line up front: 59% of the treatments currently in human trials have been funded by JDRF. (And the number is 76% for the later phase trials) This is an strong impact; one that any non-profit should be proud of.

As you read the list below, please remember that it is a list of possible treatments, not a list of trials. Some of the treatments below have several different trials on-going right now. Also remember that I give an organization credit for funding a treatment if they funded it any any point in development; I don't limit it to the current trial. For example, JDRF is not funding the current trials for DiaPep277, but they did fund much of the early research into it, which allowed it to grow into human trials.

Cures in Phase-III Human Trials
Summary: there is only one treatment in phase-III right now, and it has been funded by JDRF.

Andromedia's DiaPep227

This treatment has more than one study active right now.

Cures in Phase-II Human Trials
Summary: there are 16, and 12 of them have been funded by JDRF, either directly or indirectly through ITN. Here are the treatments that have been funded by JDRF:

Abatacept by Orban at Joslin Diabetes Center
Diabecell by Living Cell Technologies (Established)
Diamyd's GAD65 and lansoprazole and sitagliptin
Exsulin (previously INGAP) by Exsulin (Established)
Kineret / Anakinra by Mandrup-Poulsen at Steno Diabetes Center
Liraglutide at Hvidovre University Hospital (Established)
PROCHYMAL by Osiris Therapeutics
Rituximab by Pescovitz at Indiana
Sitagliptin and Lansoprazole at Sanford Health
Thymoglobulin (also known as ATG) by Gitelman
Umbilical Cord Blood Infusion by Haller at University of Florida
Xoma 52 by Xoma Corp (Established)

Not funded by JDRF:

Atorvastatin (Lipitor) by Willi at Children's Hospital of Philadelphia
Brod at University of Texas-Health Science Center
Canakinumab by TrialNet
NI-0401 by NovImmune

Cures in Phase-I Human Trials
Summary: there are 20, and 11 of the are funded by JDRF and 9 are not. Here is the list funded by JDRF:

Alefacept by TrialNet
AAT or Alpha-1 antitrypsin by OmniBio and also Kamada
ATG and GCSF by Haller at University of Florida (Established)
BHT 3021 by Bayhill Theraputics (Established)
CGSF by Haller at University of Florida
Trucco at Children’s Hospital of Pittsburgh (Established)
IBC-VS01 by Orban at Joslin Diabetes Center
Leptin by Garg at University of Texas
Polyclonal Tregs
Proleukin and Rapamune by Greenbaum at Benaroya Research Institute (Established)
Lisofylline by DiaKine

Not funded by JDRF:

ATG and autotransplant by Burt at University of Sao Paulo
BCG by Faustman at MGH (Established)
CGSF and autotransplant by Esmatjes at Hospital Clinic of Barcelona (Established)
Encapsulated Islets at University clinical Hospital Saint-Luc (Established)
Etanercept (ENBREL) by Quattrin at University at Buffalo School of Medicine
Monolayer Cellular Device (Established)
Rilonacept by White at University of Texas
The Sydney Project, Encapsulated Stem Cells (Established)
Pioglitazone by Wilson at Stony Brook

This summary does not include Artificial Pancreas research or stem cell trials, which I discuss separately. The list above is a list of treatments, not a list of trials. For example, the "ATG and autotransplant" treatment is actually running two trials (that I know of) one by Burt and another by Snarski, but since they are testing the same treatment, it is only one item in the list. DiaPep277 is running several trials, Rituximab has two, and so on. Each treatment gets one entry in the list, not each trial. Finally, those treatments marked "(Established)" have at least one trial which is open to people who have had type-1 diabetes for over a year. So those are open to non-honeymoon diabetics.

Summary of all Trials
37 in total
22 funded by JDRF
So 59% of the human trials currently underway are funded (either directly or indirectly) by JDRF. Everyone who donates to JDRF should be proud of this huge impact; and everyone who works for JDRF or volunteers for it, should be doubly proud.

Just Looking at Trials on Established Type-1 Diabetics
13 in total (35% of all trials)
8 funded by JDRF (61%)
So 61% of the trials recruiting established type-1 diabetics, are funded by JDRF.

Compared to Last Year
In 2010 there were 33 treatments in clinical trials, in 2011 there are 37 (growth of 12%)
In 2010 there were 4 treatments in Phase-III trials, in 2011 there is 1 (major drop: -75%).
In 2010 there were 16 treatments in Phase-II trials, in 2011 there are still 16 (no change).
In 2010 there were 13 treatments in Phase-I trials, in 2010 there are 20 (big growth: 54%).

The big change this year is that 3 out of 4 phase-III trials have ended in failure. That big, bad news. The other side of the coin is that there are 7 new phase-I trials, but it's still a loosing trade off. The basic trade off is that -- on average -- starting 4.5 phase-I trials will eventually result in 1 phase-III trial. So we gained the equivalent of about 1.5 phase-III studies, but lost 3.

The following two drugs might turn out to be treatments rather that cures, but right now it's not know how they will turn out, so I'm still tracking them as possible cures:

Liraglutide at Hvidovre University Hospital
Sitagliptin and Lansoprazole at Sanford Health

And finally, the Sitagliptin-only trial which I was covering as a possible cure last year, I now think is a treatment, so I'm removing it from the list of possible cures.

How I Count Trials for This Comparison

I give an organization credit for funding a cure if it funded that cure at any point in it's development cycle.
I mark the start of a research trial when the researchers start recruiting patients (and if there is any uncertainty, when the first patient is dosed). Some researchers talk about starting a trial when they submit the paper work, which is usually months earlier.
For trials which use combinations of two or more different treatments, I give funding credit, if the organization in the past funded any component of a combination treatment, or if they are funding the current combined treatment. Also, I list experiments separately if they use at least one different drug.
The ITN (Immune Tolerance Network) has JDRF as a major funder, so I count ITN as indirect JDRF funding.
I have made no attempt to find out how much funding different organizations gave to different research. This would be next to impossible for long research programs, anyway.
Funding of research is not my primary interest, so I don't spend a lot of time tracking down details in this area. I might be wrong on details.
I use the term "US Gov" for all the different branches and organizations within the United States of America's federal govenment (so includes NIDDK, NIAID, NICHD, etc.)
I don't work for the US Gov, JDRF, or any of the other organizations discussed here. I'm an adviser to JDCA. I also own stock in several of the companies discussed here.

This is an update and extension to blog postings that I've made for the last three years:
http://cureresearch4type1diabetes.blogspot.com/2010/09/jdrf-funding-research-for-cure-2010.html
http://cureresearch4type1diabetes.blogspot.com/2009/09/jdrf-funding-research-for-cure.html
http://cureresearch4type1diabetes.blogspot.com/2008/10/jdrf-funding-of-cure-research-phases-ii.html

Please think of this posting as being my personal "thank you" note to all the JDRF staff, volunteers, and everyone who donates money to research a cure for type-1 diabetes:

Thank You!

Finally, if you see any mistakes or oversights in this posting, please tell me! There is a lot of information packed into this small posting, and I've made mistakes in the past.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Stem Cell Research Checklist (and recent uterine stem cell news)

2011-09-16T18:43:00.000-07:00

Whenever I see stem cell research published, I always ask myself the following questions, in order to evaluate it's importance:

What animal was used in the research?

Humans are the best animals to use, obviously.
NOD mice, and other animals that have autoimmune diabetes are good to use.
Animals that have artificially produced diabetes are not so good.
Animals that don't have diabetes at all are the least promising.

Were the cells created true beta cells?

Sometimes people announce that they create "precursor" cells, or some other cell on the way to a beta cell, but not there yet.
Making a complete beta cell is good, but not enough.
The best result, is making a beta cell that generates insulin in response to sugar in the blood. That's what a real beta cell does.

What sort of immune suppression (if any) was used.

Any stem cell from another person (adult or embryonic) may trigger an immune response, so the first question is did they use the animal's own stem cells?
What sort of drugs, treatments, or encapsulations were used to prevent rejection of the stem cells?

Did it work in actual animals?

Some research just measure what the cells do in petri dishes or cell cultures, but the true measure of a beta cell, is what it does in a real animal that needs insulin.
Did the researchers measure C-peptides?
Did they need less insulin, see lower A1c and lower BG (especially after meals)?
The best would be no need for external insulin, and no bad side effects

How long did it work?

Obviously, longer is better (and remember to scale based on the lifespan of the animal involved).
It's always better if the experiment ended before the effect ended, rather than the other way around.

What's the plan for preventing the autoimmune attack from destroying the new beta cells?

Many stem cell researchers have a "that's someone else's problem" attitude, which I don't think is a good one.
A few stem cell options come with an integrated solution to the autoimmune attack, and those are a lot more interesting to me.

(As I look back over this list, I think most of it could be used for any research which claims to be curing type-1 diabetes. First ask yourself: what animal? And so on.)

Applying the Checklist to a recent headline:

Uterine stem cells used to treat diabetes in mice

A press release is here: http://www.nih.gov/news/health/aug2011/nichd-30.htm

Here are the first few paragraphs (we've all read this stuff many times before):

Researchers funded by the National Institutes of Health have converted stem cells from the human endometrium into insulin-producing cells and transplanted them into mice to control the animals' diabetes.

The endometrium, or uterine lining, is a source of adult stem cells. Normally, these cells generate uterine tissue each month as part of the menstrual cycle. Like other stem cells, however, they can divide to form other kinds of cells.

The study's findings suggest the possibility that endometrial stem cells could be used to develop insulin-producing islet cells. These islet cells could then be used to advance the study of islet cells transplantation as a treatment for people with diabetes. If the transplantation of islet cells derived from endometrial cells is perfected, the study authors write that women with diabetes could provide their own endometrial tissue for such a transplant, sidestepping the chance of rejection posed by tissue from another person. Endometrial stem cells are readily available and can be collected easily during a simple outpatient procedure. Endometrial tissue could also be collected after hysterectomy, the surgical removal of the uterus.

How do I apply my checklist/questionnaire to that research?   Like this:

What animal was used in the research?
Two quotes from the abstract: "mice having a laboratory-induced form of diabetes" and "mice had few working beta cells. But the paper and in email from the author, things were a little more explicit: SCID mice were used, and their diabetes was triggered by giving them SZ toxin, which kills their beta cells. SCID are "Severe Combined ImmunoDeficiency" mice. These mice did not have autoimmune diabetes. This creates some complexities, which I discuss below.

Were the cells created true beta cells?
Two quotes from the abstract: "The researchers found that some of these cells also produced insulin." and "the researchers exposed the mature stem cells to glucose and found that, like typical beta cells, the cultured cells responded by producing insulin." And the paper makes it crystal clear that the new beta cells did generate insulin in response to BG, and worked the way real beta cells are supposed to work.

What sort of immune suppression (if any) was used?
Nothing is mentioned in the abstract or paper. SCID mice were used and they don't have a fully functioning immune system anyway. In email, Dr. Taylor (lead author) said that he expects that a biopsy from one person would create enough stem cells to treat one person. Discussion below about why that is important in terms of immune suppression, or lack of it.

Did it work in actual animals?
Pretty well, but not perfectly. The paper says that the mice had BG levels between 250-300, and were not given insulin. This stayed pretty constant (my eye-balling of the data) during the weeks that the mice were followed. Obviously, the current standard of care is closer to 140, but remember that until the 1980s, BG levels around 300-400 were pretty standard. So in this very first mouse experiment, they achieved better standard of care than the first 70+ years of human treatment. And I expect they can refine their procedures to do much better.

How long did it work?
The abstract says "the animals continued to produce some insulin for six weeks, until the researchers ended the study." And the paper has more details on this. The fact that they ended the study before the effect ended is promising as well. It suggests that the effect will last longer.

What's the plan for preventing the autoimmune attack from destroying the new beta cells?
So far, there isn't one. Since the mice in the experiment did not have autoimmune diabetes, the researchers didn't learn anything about what a type-1 diabetic's immune system would do to the new beta cells. (Type-2 diabetics would not have this problem, of course.) See below for some discussion about this.

What does all this mean?

My one sentence summary is: this is good research; very promising that it might be available in people in 15-20 years.

I know that a lot of people are staring at their screens right now screaming silently "how can it be good research yet still so far from general availability? Good research should give me a cure, quickly!" And the answer is that if it were not good research, it would be even farther away. Just because we want a cure quickly, does not mean we are going to get it that quickly. Human research takes 10-12 years to make it from start to general availability, so I'm assuming that this research starts human trials in 3-10 years. Because this research was done in severely immune compromised mice, I would expect that they would need to do some experiments in NOD mice or similar before trying it in type-1 diabetic people.

(Although the 10-12 year approval process is for drugs and devices, not surgical procedures, but this difference is too complex for me to describe here. The much oversimplified version is: this research might take slightly less than the normal 10-12 years, but don't bet on it.)

Why is this research good?
Mostly because they made true beta cells that generated insulin in response to blood sugar and actually worked in real animals. That's huge. Even better, it continued to work for the length of the experiment.

What about this research needs more work?
It needs to run longer, for the whole life of the mouse.   It needs to be done on animals or people who have natural autoimmune diabetes. Finally, it needs to be done in people.

What about this research is complex?
The type of mouse used combined with the lack of immunsuppression is the complex part of this research. The mice used were SCID and these mice have seriously broken immune systems. That's why they are used in transplant studies; they can't really reject foreign cells they way normal animal could. So the researchers didn't have to give the mice an immunsuppresive drugs, because the mice were already immunsuppressed. That all sounds pretty bad, in terms of applying this to people.

But maybe not. Dr. Taylor has told me that he is hopeful that a single biopsy would provide enough uterine stem cells to treat one person.   If so, perhaps a person's own uterine stem cells could be used to treat themselves. In that case, no immunespressives would be needed, because it would not be a foreign transplant. Finding doners would not be a problem, either. At least not for female diabetics.

The only issue remaining, and it is a big one, is this: would the body's own autoimmune attack kill of the new beta cells same as the old ones? I would think they would.   However, the stem cell harvest / implanting process is simple (could be done in a clinic), so even if the new beta cells were attacked by the autoimmune process, maybe they could be replenished at every endo visit? Or maybe every couple of endo visits? That is why the researchers chose these particular stem cells to use: they are plentiful relatively easy to get, and are naturally replenished every month in women.

I'd like to thank Dr. Hugh Taylor (lead author), for his information., and for giving me a copy of the paper.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Results from a Phase-II Trial of Abatacept (Orencia)

2011-09-11T14:33:00.000-07:00

Results from a Phase-II Trial of Abatacept (Orencia)

Abatacept is a treatment that prevents T-cells from becoming activated. Presumably, for type-1 diabetes, it works by blocking the "bad" killer T-cells from activating. This drug is already approved for use in rheumatoid arthritis when other treatments have failed, and is marketed as Orencia. It was just recently approved for home use via under skin injections (similar to insulin). Previously it required an infusion, and this study used the infused form. It regulates (or modulates) T-cells, rather than depleting them, so the hope is that it will have less side effects than other immunosuppressives.

This study attempts to preserve beta cells during the honeymoon phase by giving newly diagnosed patients Abatacept. This was a placebo controlled, double blind trial with 112 patients. About 2/3s (77 people) got the treatment and 1/3 (35 people) did not. Three infusions the first month, and monthly thereafter for two years. C-peptide production in response to a meal was the measured after two years. The results where clearly better in the treated group. Basically they produced 60% more of their own insulin at each point in the trial. (Remember: C-peptide is a marker for insulin production.) Also, the treated group had better A1c numbers. The researchers estimate that this is similar to a 6-9 month delay in beta cell loss of type-1 diabetics at diagnosis.

Since Abatacept blocks some T-cell activation, infection was a worry, but the infection rates were the same in treated and placebo groups, as were injection site issues. There were more mild side effects (things like headaches and nausea) in the treated group.

The researchers are going to continue to follow the patients to see what happens in the months after they stop getting regular doses of the drug. They will see if the dosed patients stay ahead of the placebo group or not.

Next Steps

I'm not exactly sure what the next steps are in this line of research. Are these results "good enough" so that you'd just move the same dosing into phase-III trials and then into the market? Would you change the dose to try to get a better result? (It looks like the researchers used the standard rheumatoid arthritis dosing for the trial.) Would collecting data for a longer period of time, help planning the next move? Belatacept is a follow on drug to Abatacept which was just approved in June 2011 (but not for type-1 diabetes), so would you move forward with Abatacept, Belatacept, or both?

Another whole set of options involves combining Abatacept with another treatment. The study chair for this trial is Dr. Tihamer Orban, who is also working on a B-chain insulin treatment (which already completed a phase-I trial, and which I've blogged on in the past), and he is interested in combining these two approaches.

Abstract: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60886-6/abstract
News: http://www.medpagetoday.com/MeetingCoverage/ADA/27312
Previous blogging: http://cureresearch4type1diabetes.blogspot.com/search/label/Abatacept
Clinical trial record: http://clinicaltrials.gov/ct2/show/NCT00505375
More News: http://www.marketwire.com/press-release/new-hope-immune-therapy-children-young-adults-with-type-1-diabetes-founder-orban-biotechs-1546447.htm
Related news: http://www.medicalnewstoday.com/articles/232194.php
Wikipedia: http://en.wikipedia.org/wiki/Abatacept

This study was run by TrialNet. Thanks to Dr. Tihamer Orban for providing me we a pre-print of the Lancet article. And thanks to everyone who provided help and information for this posting.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Possible Cures for Type-1 in the News (August)

2011-08-26T21:27:00.000-07:00

More News on Rituximab

Background on the drug: Rituximab targets the CD20 part of the immune system's B cells (different from the pancreas's beta cells) to try to prevent the autoimmune attack. B cells are part of the body's immune system and communicate with the T cells, which actually attack the body's beta cells in the pancreas. By targeting the B cells, it is hoped this treatment will stop or lower the attack of the T cells. Rituximab showed some effectiveness in preserving the beta cell function of honeymoon type-1 diabetes in a phase-II trial, and there is a second trial underway. Rituximab is a monoclonal antibody, a product of Genetech (now a division of Roche), and already approved by the US FDA for rheumatoid arthritis and several cancers (and used off label for several other diseases).

Background on antibodies: Type-1 diabetes is triggered when the body's own immune system attacks it's own beta cells in the pancreas, which create insulin. Autoantibodies are part of the process of this self-attack. In type-1 diabetes four different types of autoantibodies have been measured: GAD, Insulin, IA2, and ZnT8. There might be a few more autoantibodies that we don't yet know about. People with type-1 diabetes usually have one or more autoantibodies in their system, and this starts before they are diagnosed. I think that GAD is the most common, and IAA is second, but I'm not up on the details.

For this study, 49 patients where given four doses of Rituximab, while 29 got the placebo. For all patients, measurements were made for each different type of autoantibody. What they found was that Rituximab was very good at lowering IAA autoantibodies, but much less effective on the other three known types of autoantibodies. This was the biggest finding:

A total of 40% (19 of 48) of rituximab-treated patients who were IAA positive became IAA negative versus 0 of 29 placebo-treated patients.

So that means that Rituximab was highly selective as to what antibodies it shut down. This is a very interesting finding, at least for me. In terms of impact on patients, we need to see the C-peptide numbers, which were not in the abstract.

Next Steps?

In light of these results, one obvious clinical trial to run would be to treat honeymoon type-1 diabetics, who only have autoantibodies to IAA, with Rituximab, and see what happens. The results above imply that over a third of these patients would end up having no autoantibodies remaining, and it would be very interesting to see what happens to these patients. What effect will it have on their insulin production? Will they still have type-1 diabetes? Will their pancreases regrow? If so, how quickly? These are critical questions.

Another interesting clinical trial to run would involve patients that did not have type-1 diabetes, but were being tracked by TrialNet's Natural History Study, and are known to only have IAA autoantibodies. Basically, does treating these specific people with Rituximab delay or reduce the onset of type-1 diabetes?

And finally, there is a potential study for established type-1 diabetics who only have IAA antibodies. Would giving them this drug have good effects?

I have no idea if any studies like these are feasible, or are being planned, but I hope so!

Abstract: http://diabetes.diabetesjournals.org/content/early/2011/08/05/db11-0674.abstract
News article: http://www.doctorslounge.com/index.php/news/pb/22439
Wikipedia: http://en.wikipedia.org/wiki/Rituximab
More on Autoantibodies: http://www.msdlatinamerica.com/diabetes/sid683880.html

News about News on DiaPep277

DiaPep277 is the longest running phase-III study aimed at curing type-1 diabetes. It is a honeymoon only treatment. Results from the phase-II study were (in my opinion) "mixed". (I know that doesn't sound very definitive and I really should go back and review their phase-II results in more depth, but I haven't had time.) My most detailed discussion of their phase-II results is here, but it's not much:
http://cureresearch4type1diabetes.blogspot.com/2009/11/possible-cures-for-type-1-in-news-nov.html
and all of my blogging on DiaPep277 (hsp60) is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/DiaPep%20277

The following quote is from a news article on them, and is the most recent news I have heard about when they might have some phase-III results. The key news is that the study should be done late this year, which is not very far away. With a little luck, we'll see results in 2012.

In the first Phase III studies being conducted at 40 medical centers in Europe, South Africa and Israel, diabetes patients aged 16 to 45 have been receiving DiaPep277 injections once every three months. The study began in 2005 and is ending late this year.

They have a second phase-III study already underway, and expected to finish in 2014. (Remember, you need two in order to get FDA or EU approval.)

News coverage: http://www.shalomlife.com/health/15810/promising-treatment-for-diabetes/

Rilonacept is Recruiting for a Phase-I Trial

I know there is a lot of frustration about studies that are targeted at "honeymoon" diabetics. And it is certainly true that most current trials are aimed at honeymooners. However, "most" does not mean "all". Dr. White is running a study on Rilonacept that is open to people within 5 years of diagnosis. Also, this study has no placebo group, so if you are in the study, you know you are getting the treatment.

I have previously blogged on this clinical trial, which you can read here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Rilonacept

This drug is already approved in the US under the trade name "Arcalyst", but not for type-1 diabetes. In addition to this approval, it is currently being used in about 12 other clinical trials for a variety of inflammation related diseases. Dr. White has told me (via email) that there have been "no untoward effects thus far". The trial is being run in Dallas, Texas. Contact information is in my previous blogging (link above).

Trial web site: http://www.childrens.com/specialties/endocrinology/rilonacept-study/
Clinical Trial Site: http://www.clinicaltrials.gov/ct2/show/NCT00962026

Some Background Reading

Below is a link to a short interview with Dr. Arthur Caplan, a bioethicist at University of Pennsylvania, which makes for some interesting reading. It is about the ethics of overseas medical research. Something that we are seeing a lot of in type-1 diabetes research. Dr. Caplan is an interesting guy and a good speaker. UPenn is my alma mater:
http://www.pbs.org/newshour/rundown/2011/08/sending-us-drug-research-overseas.html

The following Wikipedia article covers accuracy of home glucose monitors. Many people are shocked to learn that they are only accurate to within 20%. So you might get 310, 340, or even 360 at the same time: http://en.wikipedia.org/wiki/Clarke_Error_Grid
Thanks to swellman at CWD for pointing this out to me and many others.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Dr. Faustman's Phase-I Results

2011-08-08T22:34:00.000-07:00

For over 10 years, Dr. Faustman has been researching the theory that BCG (Bacillus Calmette-Guérin, used as vaccine for tuberculosis) could be an important part of a cure for type-1 diabetes. She published animal research to support this theory in 2001 and 2002, research in human cells in 2008, and started a human trial in 2008. In late June, as part of the ADA convention, she published two abstracts, which are her first results in human trials.

You can read the abstracts here:
http://ww2.aievolution.com/ada1101/index.cfm?do=abs.viewAbs&abs=12326
http://ww2.aievolution.com/ada1101/index.cfm?do=abs.viewAbs&abs=12141
This posting is more about the first one. The second one is interesting enough for it's own posting, but that will have to wait until another blog.

Here is a supplemental FAQ on the trial from Dr. Faustman's lab:
http://www.faustmanlab.org/docs/clinicalt/Phase%20I%20Trial%20FAQ.pdf

Here is the original clinical trial paperwork (for comparison) from the FDA:
http://www.clinicaltrials.gov/ct2/show/NCT00607230

Some news coverage (there is a lot more):
http://online.wsj.com/article/SB10001424052702304231204576406011708905314.html?mod=googlenews_wsj
(note the WSJ reporter describes 6 treated patients, when the abstract is clear that there were only 3)
http://articles.latimes.com/2011/jun/25/health/la-he-bcg-diabetes-20110625

Scott King's blog on this research. (He is more optimistic than I am):
http://www.solvingdiabetes.org/2011/07/04/highlights-of-ada-scientific-sessions-i-bgc-trial/

Everyone wants a one sentence summary of results. Unfortunately, this research as described in the abstracts, doesn't have a good one sentence summary. But I've provided three to choose from:

An optimistic summary: A low dose of BCG shows some effect on people with long established type-1 diabetes, and that is so unusual that it is a good result, worthy of follow up.
A neutral summary: A tiny study was done, but the information in the abstract is so limited that it can not be evaluated, so we must wait for the paper and the additional information it contains.
A pessimistic summary: The data that was supposed to be the primary results of the trial were not included in the abstract. The results that were reported are so small and so vague that nothing good can be concluded from them. More worrisome, the study reported in many ways is a step backwards from the study that was discussed at it's start.

Here is my attempt of a one paragraph summary:

Dr. Faustman's research theory is that raised TNF levels would cure or help to cure type-1 diabetes. No data presented in the abstract supports that idea, because no TNF data was presented. Dr. Faustman's clinical theory is that giving people BCG would cure or help to cure type-1 diabetes (by raising TNF levels). The very tiny amount of data presented here is unclear because the effect was seen in 2 of 3 treated patients, but also in 1 of 3 untreated patients (who came down with "mono"), and at the tiny numbers of patients involved, it's hard to interpret those results. No data on the size or duration of the effect was presented in the abstract. The study reported now is much smaller than the study described at it's start (in FDA paperwork). An interesting reaction was seen in one patient who came down with Epstein-Barr virus infectious mononucleosis (commonly known as "mono" or EBV). That data is the focus of a separate abstract.

Please read below for lots of details and specifics. Marks like this: [d0] refer to extra discussion at the end of the posting.

Before Discussing the Study
Before even discussing the results of this study is is necessary to discuss two very important points. In light of these two points, I think the best thing to do, might be to just wait for the paper. (On the other hand, the rest of this post is my attempt to analyze the abstract, so I'm not really following my own advice. :-)

First, I only have access to the abstract, a few short conversions with various people, a few short emails with Dr. Faustman, and a "FAQ" document that she sent me. Abstracts are required to be very short (often only a few hundred words), so can not contain all the important details. Also, Dr. Faustman doesn't have time to reply to every question that comes up (especially since a short abstract leaves many questions unanswered). Even if she did have time to answer every question; all those answers together would basically be the paper, and the paper is not yet published. So the bottom line, is that there are several critical unanswered questions, and we will all just need to wait for the paper. I expect a major update to this posting when the related paper is published.

Second, because this study only involved giving 3 patients BCG, even with the extra information from a paper, the results are likely to be almost meaningless, because of the tiny size of the study. In my opinion, only in extremely rare cases where the results are extraordinarily obvious will 3 treated patients yield a useful result. (Obviously, Dr. Faustman has a different opinion, and that is discussed very briefly below.)

The Study and What Was Reported

Patients were randomly assigned into two groups: 3 people were dosed with BCG, and 3 people were given a placebo. These were all people who had type-1 diabetes for a long time (average 15 years). The treated group were given two small doses of BCG, one month apart. They were followed for a total of 20 weeks. In addition, there were also 6 "clinical controls" (who did not have type-1 diabetes), and two other patient "reference" groups: 58 people who had type-1 diabetes and 17 who did not [d1]. These two reference groups were not given anything, but were monitored. The patients were monitored for this data: autoreactive T-cells, regulatory T-cells, GAD autoantibodies, and C-peptide.

There were two results reported:
1. Transient increases in the number of circulating dead autoreactive T cells against insulin. (The abstract did not say if these increases were statistically significant, or which group of patients they were compared to. For this discussion I will assume the most positive possible interpretation: that the increase was statistically significant and that it was in comparison to the placebo group.)
2. C-peptide levels rose transiently above baseline levels. (In this case the abstract says specifically that the rise was statistically significant and in email Dr. Faustman said the comparison was in the same patient: before vs. after treatment and that it was true of two patients in the BCG group and also the patient who came down with EBV in the placebo group.)

Some terminology:
"Autoreactive" refers to T-cells which attack the body's own beta cells. In other posts, I refer to these as "bad killer T-cells", because they attack the wrong cells causing type-1 diabetes.
"C-peptide" is a chemical that your body makes only when it also makes insulin. So measuring that is really measuring your body's ability to make it's own insulin. Also, C-peptide is an FDA approved marker for progress towards a cure of type-1 diabetes.
"Statistically significant" means the change was unlikely to be due to chance or luck. In general, only statistically significant findings are taken seriously by the scientific community.
"Clinically significant" means different enough so that the patient would notice or gain some benefit from the difference. Phase-I trials are often not clinically significant; that often comes later.

Discussion
There are several large areas of discussion on this study:

First, Why was the study size so small?
Except in a few very rare situations (such as complete cures in all cases), a study that only treats three people is very unlikely to provide unambiguous results. When you are looking for slight improvements, or even medium improvements, three people just isn't enough to rule out random chance. All the people who work with statistics, who gave me opinions on this research, commented on this point. The abstract acknowledges the tiny size of the study, by calling it a "proof-in-principle" study. But no matter what it is called: it is the smallest phase-I clinical trial that I have ever seen. For comparison, phase-I trials of already approved drugs (similar to BCG) include: Anakinra dosed 15, Etanercept dosed 18, AAT dosed 15, etc. So a 3 person study really stands out as being much smaller than the others.

Why were there so few people in the study? Remember: the published plan for the study at it's start was for dosing about 12 people, not 3. There are three common reasons a study is small: 1. money, 2. recruiting, and 3. safety. But this study was well financed with about 10 million US dollars (and using an inexpensive, unpatented drug, too), had many volunteers lining up, and there were never any safety issues. So why not enroll 25 people, like they planned to? What happened?

Obviously, Dr. Faustman does believe that 3 people is enough to lead to significant results, and felt that the small number of people was offset by the large number of blood tests given to each person. The FAQ document and Dr. Faustman herself suggest that by doing a lot of tests on a very small number of people, they can attain significant results. The FAQ document makes several mentions of the number of blood tests done as part of this study (1012), as evidence that the study was large enough. However, standard practice is to measure studies by number of patients involved, not number of blood tests. Especially in this trial, where it looks like 3 patients were given BCG, but approximately 84 (58+17+3+6) were not, that suggests that over 96% of the blood tests were run on people who didn't get the drug being tested. So the large number of blood tests does not accurately reflect the size of the study.

Second, why was a new "reference group" added to the study? And more generally, why was the study design so complex with so many different groups of patients?
The abstract refers to reference patients. These were patients that either had type-1 or did not, but they were not treated. This group was not mentioned in the original description of the trial. The second reported result (the C-peptide change) compared the treated group to this reference group. The original design compared the treated group to a placebo group, and this is a common comparison to make. So there are obvious questions about why it was added, and why not just compare the treated patients to the placebo patients.

More generally, the study included 5 different groups (treated, placebo, comparison, reference with type-1 diabetes and reference without type-1 diabetes). That's a lot of different groups, and it is not clear to me why they were all needed. It is also unusual. The common thing is to compare the treated group to the placebo group, and that was the original design of this study.

Finally, there are the issues with the size of the various groups. If you start out with a 3 person group treated with BCG, then it makes perfect sense to have 3 or maybe even 6 people in the placebo group, (they had 3) but it's not clear from the abstract what the data from those patients was used for. On the other hand, a 58 patient "reference" group seems unusually large. There was a 17 person group that didn't have type-1 diabetes, in addition to a separate 6 person "comparison" group that also didn't have type-1? I am looking forward to reading the paper to learn why all this was done, rather than do the simple thing.

Third, what were the size of the effects seen?
This abstract did not contain either the size of any effect, nor their durations, so I can not comment on how big the results were or how long they lasted. We will all need to wait for the paper for that. The size of the effects seen (especially the TNF, C-peptide, and autoreactive T-cell levels) are critical to understanding these results. [d2]

Fourth, why were TNF levels not reported in the abstract?
The essence of Dr. Faustman theory is this:

BCG causes the body to generate TNF and TNF causes fewer autoreactive T-cells

(and fewer autoreactive T-cells results in more insulin generation)

So the most important data in her experiment was the TNF levels as compared to the autoreactive T-cell levels. This was why the levels of autoreactive T-cells were designated as the primary outcome. However, in the published abstract, the TNF levels are not mentioned. This weakens the abstract in at least two ways. First, it is impossible to see correlation between TNF levels and autoreactive T-cells, which is exactly the confirmation Dr. Faustman is looking for. Showing this correlation would be direct evidence that Dr. Faustman's theory is correct. Second, it is impossible to see if the BCG and EBV patients had similar TNF profiles and therefore should have the similar results that were seen.

Fifth, what was the result of the primary outcome measure? Why were dead T-cells reported on, but not live ones?
The first goal of a trial is to report it's primary outcome measure. For this study, the researchers clearly specified "concentration of autoreactive t-cells" as the primary outcome in their FDA paperwork. The published abstract says that this data was gathered, but does not report it. Obviously, I hope that this data will be published in the paper or poster (and is statistically significant). But right now: nothing is nothing.

If this was a commercial company, the failure to report on the primary outcome would be a clear signal that the trial had failed. End of story; end of discussion.

Levels of dead autoreactive T-cells are listed as being statistically significant, and this is an interesting finding, but it is not a replacement for data on live autoreactive T-cells. It is the live ones that matter; they cause type-1 diabetes. The implication from the dead T-cell data is that the bad cells are being killed off. If true, this is great news. But dead T-cells are an indirect measurement, while reporting a drop in live T-cells would be a direct measurement, and it was what the original design described.

Sixth, discussions of dosing.
This study apparently used the low (vaccine dose) of BCG, and Dr. Faustman is talking about using larger doses to get better results in the future. And I agree that if small doses lead to small results, then it makes sense to try larger doses. So we'll all need to wait for the paper what the current results are. Remember: the abstract had no results numbers.

Seventh, the difference between a Phased Clinical Trial and a Case Report.
Dr. Faustman has two abstracts in ADA (links above), and it is important to remember the differences between them, and not mix them up or combine them. The first is a report on a Clinical Trial. Clinical trials are structured programs where people are given treatments and the results are measured. The second abstract is a Case Report, which is a report from a doctor on an unusual occurrence in a patient. In this case, it is an unusual occurrence in someone enrolled in a clinical trial. Phased trials are part of a path to find out if a treatment works and get it approved. Case reports are basic research which can start a line of research. Phased trials are at the end of a research program, case reports usually at the start. The difference is often 5 or 10 years of work.

Eight, why is this study so much different (and in many ways worse) than the study first registered and started 3 years ago?
The study (as completed and reported) is very different than the study (as registered on the FDA's clinical trials site). In particular:

The reported study was much smaller (6 vs. 25 people).
The reported study included two groups of patients which were not included in the original description at all, and these new groups were roughly 12 times bigger than the placebo/treated groups described in the original filing (75 vs. 6).
TNF was one of the secondary outcomes of the planned trial, but was not reported in the abstract.

These are all steps backwards in trial design and implementation. None of them had to happen, but they did. The smaller size in particular leads to many of the uncertainties in the current results.

Ninth, what about the money?
I don't want to talk too much about money. After all, a cure (or even much improved treatment) would be worth every penny no matter what the cost. The funding goal for this phase-I study was US$ 10 million. That would make this the most expensive phase-I clinical trial aimed at curing type-1 diabetes that I have ever encountered. At the same time, with 3 dosed patients, it is also the absolute smallest phase-I trial that I have ever encountered. Even if you divide it by the 1012 blood tests, that's almost $10,000 per test.

Rumors

The following information are rumors which I picked up from people who were at ADA in San Diego or associated with Dr. Faustman's lab. None of them are in the published abstracts, so I don't know if they are accurate or not:

The effects described as "temporary" in the abstracts actually lasted two weeks.
The effects that were described as statistically significant, were not clinically significant.
A paper is in process to be published in a well known and respected scientific journal. (I have not gotten an OK to include the journal's name, so I'm not).
TNF data was collected as part of the trial, even though it is not included in the abstract (and I asked specifically about the EBV patient).
There was a poster for the second abstract (the case study of EBV), but not for the first abstract (the more general BCG trial). Or maybe this poster covered both abstracts, because there was plenty of BCG data on it? (And I've tried to get a PDF of that poster. No luck yet. If you were there, and got the thumb drive with all the posters on it, and this poster is there, please email it to me. Thanks!)
Autoreactive T-cell data was on the poster.

Opinions (and some Ranting)

When I realized that this entire abstract was based on giving 3 people BCG, I was dumbfounded. In the final analysis, we -- the people who funded Dr. Faustman -- paid about 10 million US dollars, waited 3 years, and now we get results based on three people? Three people! It's completely shocking. Even more so when you realize that part of the reason BCG was chosen was because it was known to be both safe and inexpensive!

For me, one of the most worrisome things about this clinical trial, is how much it has changed since it started years ago, and all for the worse. It started out being a straight forward clinical trial, much like any other test of an already approved drug: about 12 people would get the drug, about 12 would not, results could be compared. Somewhere along the way the study included 5 different groups. And the size of the treatment group and the placebo group actually shrank! (And not just a little bit: to one forth their original size). The resulting trial has some size oddities that I've never seen before. Two simple examples (which I've already touched on):

First, they followed and ran tests on a total of 84 patients, and ran a lot of tests on each one. Yet only 3 people actually got BCG. That's a huge imbalance. Normally clinical trials are either 50/50 or 2/3s 1/3. Meaning either half the people get the treatment and half don't, or 2/3s get the treatment and 1/3 don't. Occasionally, you get designs with multiple dosing levels, and even there, the placebo group is the same size as each dose. This study is wildly different.

Second, the study involved a total of 23 people who did not have type-1 diabetes at all. That group is about 4 times larger than the total number of type-1 diabetics in the combined treated / placebo groups. Again, that's very unusual. [d3]

Fewer patients means less clarity, and that's exactly what happened here. I'm very much looking forward to the published paper, and whatever discussion it includes on the reason for the small patient count, and the difference between the sample size as the study was registered and the sample size as the study was reported.

The abstract did answer one question, which is why did we never hear of anyone who was part of the study? Participants of other studies are often quoted in newspapers or they post on internet forums, but I never saw anyone who was actually part of the study in any public space. And now it is clear why: with only 3 people getting BCG (and 3 people in the placebo group) this was a truly tiny study.

Previous Work

My previous blogging on Dr. Faustman's research is here:

Many people who follow Dr. Faustman's work assume she is the only person doing BCG research, or the first person. This is completely wrong. In the late 1990s BCG was a topic of research as a possible cure for type-1 diabetes. Three previous placebo controlled studies which gave similar BCG doses to type-1 diabetics showed no good effects. To the best of my knowledge, the only difference in treatment between these studies and the c-peptide part of Dr. Faustman's study, is that these guys were given one dose of BCG, while Dr. Faustman's trial used two. However (according to Dr. King's blog) Dr. Faustman used a much more sensitive C-peptide measurement than the older studies:

http://care.diabetesjournals.org/cgi/content/ab stract/22/10/1703
http://care.diabetesjournals.org/cgi/reprint/22/10/1703
Published in 1999, this study treated honeymoon diabetics with BCG and saw no improvement, compared with an untreated group. From the abstract: "Vaccination with BCG at the time of onset of type 1 diabetes does not increase the remission rate or preserve beta-cell".
http://care.diabetesjournals.org/cgi/content/abstract/21/10/1691
This study was published in 1998: "BCG vaccination in children who have been recently diagnosed with IDDM does not affect the progressive decline in C-peptide levels or alter the clinical course of the disease."
http://210.101.116.102/Diabetes/koreamad/JournalSearch_index.asp?year=2000&page=340&vol=24&iss=3
ftp://210.101.116.17/kiss8/27203283.pdf (in Korean)
Published in 2000. Here is the key sentence from their results section: "During follow-up, there was no significant difference in fasting and postprandial 2 hour C-peptides." They then go on to list various good things they did see, in particular there were slight differences in C-peptide and insulin usages, and temporary remission in two patients, but these were not statistically significant. (And remember: this study was of honeymoon diabetics.) Their paper is in Korean, which I cannot read, however the tables are presented in English, and each table says very clearly "The differences between the two groups were not significant."

In addition, three earlier studies compared type-1 rates in people given BCG as a TB vaccine to those who did not. They showed no difference in rates of diabetes:

http://cat.inist.fr/?aModele=afficheN&cpsidt=11111587
In English the article is entitled "THE CUMULATIVE INCIDENCE OF CHILDHOOD DIABETES MELLITUS IN SWEDEN UNAFFECTED BY BCG-VACCINATION". Published in 1995.
http://care.diabetesjournals.org/cgi/content/abstract/20/5/767?ijkey=de477936685fbc95cfd98bc52cb120be655acd09&keytype2=tf_ipsecsha
Retrospective study on people who had been vaccinated with BCG. Published in 1997. "However, as a whole, results from these analyses fail to support a protective role of BCG vaccination against juvenile-onset IDDM."
http://care.diabetesjournals.org/cgi/content/full/28/5/1204
Published in 2005. Neonatal vaccination with BCG has no good effect on type-1 diabetes rates: "The cumulative risks for developing islet autoantibodies by age 2 or 5 years were unaffected by BCG vaccination in the first 3 months of life" and "Progression to type 1 diabetes in BCG-vaccinated autoantibody-positive children was significantly faster than in nonvaccinated children" and "No evidence was found that BCG vaccination could prevent against ß-cell–damaging processes leading to type 1 diabetes in genetically at-risk children. The findings do not suggest that BCG vaccination will affect the overall incidence of type 1 diabetes"

Where are We, Where are We Going, How do We Get There?

The first thing to do is to wait for the paper to be published.

After that, one way to move forward is to change the dose. And Dr. Faustman is already talking about doing that. In a sense, this is the easiest change to make. However, right now, there is no published evidence that it would help. In order to see if this is worthwhile, we will need to see the data comparing TNF to C-peptide data (for all three groups: BCG, EBV, and placebo). If higher TNF leads to higher C-peptide, then it is worthwhile to try higher BCG doses (and other methods, as suggested by EBV) to try to achieve higher TNF results. Hopefully all this will be in the paper.

Another way is to focus on the single EBV patient. This was a very interesting occurrence. One of the patients in the placebo group came down with mono during the trial. That patient apparently had high levels of dead bad killer T-cells and also elevated C-peptide counts. (Although keep in mind the caveats above, especially the lack of actual numbers.) If that one patient had high TNF levels, and high levels of dead bad killer T-cells, and high levels of C-peptide (and that is three very large "ifs"!), and it is not just random luck with one patient (a fourth huge "if"!), and then it could mean that Dr. Faustman is right about TNF helping to cure or treat type-1 diabetes, and suggests that there are things besides BCG that can get us there. So there might be some interesting research to be done there. Of course, with one person, it might just be just some random weirdness.

Some Personal Notes

I have put more hours into this posting than any previous blog entry. One thing that I learned, is that I should not write blog postings based on abstracts alone, when those abstracts don't contain any results data.

I know this will not be a popular posting. However, in the final analysis: if a commercial company, indeed, if any other researcher, had published results that did not include their own primary outcome measurement, everyone would immediately agree that the clinical trial was a failure. And if any other researcher had added (after design) a "reference" group with more than 12 times as many patients as the treated/placebo groups, then again, everyone would immediately clamor for an explanation. And finally, if any other researcher had designed such a tiny experiment, they would be called out for an explanation. Dr. Faustman did all of these things and so I treat her the same way that I would treat any other researcher.

Also, I have spent a lot of time comparing the clinical trial as described in the abstract at the end of the trial, to the clinical trial as described in the FDA paperwork which was submitted at the start of the trial. I know many supporters hate that whole attitude. They think that what Dr. Faustman said three or more years ago, is irrelevant to the results she reports today. They don't want past promises compared to current realities. For me, that attitude ("what is said before doesn't matter to what is given now") is not merely wrong, it is dangerous.

For me, this comparison between what is promised and what is delivered is important information. If someone promises a piece of bread, but gives you a crumb, should you thank them for the crumb, or complain about not getting the bread? Does your opinion change if you were charged for the bread in advance? If the person is, even now, asking for even more money for future loaves? Does possession of a crumb now mean that the bread will be available in the future? Does not delivering the slice of bread now, mean that future loaves will not be delivered as well? The future is always uncertain, and research is all about the future.

I'd like to thank everyone who helped with this posting, either by giving me information, reviewing it, or motivating it by asking insightful questions. All mistakes here are my own, just as all opinions are mine.

I grant permission to anyone to republish this article anywhere they wish, as long as it is not edited (except to fix spelling and grammar). If you wish to republish parts of it, rather than the whole thing, please email me.

Extra Discussion

[d1] I don't know exactly how the 6 "simultaneously studied clinical trial controls" (who according to the abstract did not have type-1 diabetes) were different from the 17 "reference patients" (who also did not have type-1 diabetes).

[d2] Dr. King's blog talks about C-peptide changes measured in pmol/l, which is a very small change, indeed.

[d3] On a few rare occasions I've seen studies that involved people who didn't have the disease being studied, but I've never seen a study with 4x as many people who didn't have the disease, as had the disease and were in the combined treated/placebo groups. Or any other studies that mixed people with the disease and people without it as this study does.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Longer Lifespans (non-cure news)

2011-07-13T20:27:00.000-07:00

The American Diabetes Association meeting (ADA 2011) just finished, and as with every year there has been a lot of news. Normally, I only cover cure related research, but this is such important news (even if non-cure) that I'm going to give it a blog.

I know that many people are interested in Dr. Faustman's results. I have worked on a posting on those for eight evenings, and it is still not ready. I have not been able to get a copy of the poster they presented, and I'm spending more than the usual amount of time reviewing my posting. So I'm expecting it to go out approximately July 21. After that, I'm hoping for several more postings with news from ADA.

Increased Lifespan for People with Type-1 Diabetes

This is the single best news that I got from ADA 2011: the "lifespan gap" in the USA between people who have type-1 diabetes and people who don't is getting much smaller. When my daughter was diagnosed, we were told that, on average, people with type-1 diabetes had a lifespan 15 years shorter than other people. That information weighed heavily on my mind. And this paper shows that type-1 diabetics born between 1950 and 1964 did have a lifespan 18 years shorter than others born at that time. However, this study also shows that for type-1 diabetics born between 1965-1980, the gap has dropped to about 4 years. That is very strong progress.

It is important to remember that this study uses a lot of estimations (after all, most people they studied are still alive). However, they used standard techniques to do these estimations, and there is a large body of research on life expectancy, so I don't see any reason to doubt them. In particular, I think the same techniques were used for the 18 year gap as for the 4 year gap, so I'm totally comfortable with the trend: it is getting much better.

As an optimist, I'm hopeful that things are going to be even better from the 1980-1995 cohort, and continue to improve in the 1995-2010 cohort and onward. I think that with pumps, quarterly A1C measurements, and now CGMs, I think we can expect continued improvement.

Abstract: http://ww2.aievolution.com/ada1101/index.cfm?do=abs.viewAbs&abs=10077
News: http://seattletimes.nwsource.com/html/health/2015472674_diab04.html

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Introduction to the The Juvenile Diabetes Cure Alliance

2011-06-20T22:22:00.000-07:00

At the bottom of my posts is the phrase "nothing here is official JDRF or JDCA news, views, policies or opinions". Everyone knows what the JDRF is, but I do occasionally get asked what JDCA is. In the past JDCA was in "start up, stealth mode" meaning they were deliberately staying out of view. But they are now taking a more public stance, so I thought I'd say a few words about them:

Introduction to the JDCA: The Juvenile Diabetes Cure Alliance

JDCA is a relatively new organization, which I think is unique in the world of type-1 diabetes charities (and maybe unique in all of philanthropy). I think of it as a hybrid of Consumer Reports and a Lobbying Organization, but focused on type-1 charities. The Consumer Reports part of their goal is to shine a light into what various type-1 charities are spending money on. The Lobbying part of their goal is to focus more of that money into projects directly aimed a curing type-1 diabetes in the next 15 years. They want to lobby the charities to focus on this goal, and also help doners channel their money into this goal.

Their tag line is "The Voice Of The Donor for a Cure" and their mission is to "direct donor contributions to the research opportunities that provide the best chance of curing Type 1 diabetes by 2025".

Obviously there are some strong synergies between what they want, and what I research. We are both focused on the cure end of the process. I look at human trials, which gives me a 10 year view. They are looking at a slightly longer 15 year view. But even 15 years is not very long in the world of research.

Culturally, they have a strong business / financial ethic. The founder and the senior guys he's hired have business backgrounds. They use the terminology, methodology, and mind set of business analysis. It is my understanding that the key movers in the organization are parents of children with type-1 diabetes (at least right now).

They also feel that measurable progress and deadlines for results are critical to ensuring that funded research will lead to a cure, quickly.

As far as I know they don't accept donations for themselves, rather they are funded by one wealthy family which is recently effected by type-1 diabetes, and which thinks that this project is the most productive work they can do to cure type-1 diabetes.

Their web site is here: www.thejdca.com
Their first report is here: http://www.thejdca.org/uploads/JDCA_initial_report_2011.pdf
Their definition of a cure is here: http://www.thejdca.org/uploads/Defining_a_Practical_Cure.pdf
(Their "practical" cure is very similar to my "functional" cure.)

Non-conflict of interest statement: I don't work for the JDCA nor am I a member. They've never paid me or given me any kind of gift or freebie. They do read my blog and use the research they find there. We discuss specific issues that they care about and they sometimes ask my opinions on research into cures. Some of the information and opinions we discuss have not yet made their way into my blog.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Possible Cures for Type-1 in the News (June)

2011-06-01T17:45:00.000-07:00

LCT Starts A Phase-II Trial in Argentina

LCT is developing an encapsulated pig islet cell product. The hope is by implanting these cells, people with type-1 diabetes will not need to measure their BG level or inject insulin, and the cells will keep their BG levels in normal range without an external help.

LCT has gotten government permission to start a phase-II trial in Argentina. They expect to dose 8 people in the second half of 2011. Each person will get to implants about 3 months apart. LCT has already run a phase-I trial in Russia, and a phase-II trial in New Zealand. But together, those trials have treated only 20 people. This trial will bring the number up to 28. Previous results were that one patient was did not need external insulin for a few months, and another was insulin free for a few weeks. Several other patients used less insulin after the implantation, for weeks or months. From my point of view, that's a long way from a cure, but LCT has been working to improve their encapsulation technology and their islet cell processing technology, and research is always about doing better in the future.

http://www.lctglobal.com/html/blob.php/974605%20(2).pdf?attach=0&documentCode=3453&elementId=20084

Are Pharma Companies Paying Your Doctor?

The guys over at Pro Publica have gotten a hold of several databases of doctors who are being paid by pharmaceutical companies, for various reasons. The companies provided this information to the government, but Pro Publica has also taken it and made an easy to search database. See if your doctor is getting paid for speaking, or for meals, or for any other reason. (Look up names like "Smith" and "Jones" to get a feel for how much money is involved.) I never thought a lunch or two really mattered, but some of these guys are getting more than $35,000 in one year, and that's enough to make you wonder. Or at least make me wonder.

http://projects.propublica.org/docdollars/

Xcell (Adult Stem Cell Clinic) Shut Down in Germany

Every few months, I get asked about for-profit clinics that offer to cure various aliments (including type-1 diabetes) by injecting people with their own adult stem cells. I'm working on a detailed posting about these clinics, but in the meantime, there is one less clinic to worry about: Xcell, with two locations in Germany, has been shut down.

I definitely got more questions about Xcell then about similar clinics in Mexico, Argentina, Thailand, the Ukraine China or anywhere else. I think being located in Europe gave them an aura of respectability missing from other clinics. Years ago, they announced that they were going to start a clinical trial on type-1 diabetes. I searched diligently, but never found any evidence that the actually had started the study, and certainly no results. But they always had great on-line testimonials from people with type-1 diabetes (and many other illnesses) who they had "helped".

News coverage:
http://www.bionews.org.uk/page_95103.asp
http://www.telegraph.co.uk/news/worldnews/europe/germany/8500233/Europes-largest-stem-cell-clinic-shut-down-after-death-of-baby.html

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Diamyd Fails in Phase-III Trial

2011-05-15T12:29:00.000-07:00

Diamyd Fails in Phase-III Trial

Diamyd's European phase-III trial has failed. The official quote is "did not meet the primary efficacy endpoint". Basically, the the people who got the drug did not do better than those who did not, in the the most important measurement of success. The primary endpoint for this experiment was C-peptide generation, which is a marker for natural insulin production. Basically, they were hoping that giving this drug would help honeymoon type-1 diabetics generate more of their own insulin, but it did not.

(By the way: if that paragraph sounds familiar, it's because its the exact same paragraph that I used to describe Tolerx's Otelixizumab failure a few weeks ago, and could have been used to describe MacroGenics's Teplizumab failure a few weeks before that. It applies pretty much the same to all three. They all failed in about the same way and at almost the same point in their development cycle. They were all in phase-III clinical trials.)

This is a vaccine like treatment designed to teach the body's own immune system to stop attacking it's own beta cells. You can think of it like the anti-alergy injections that people sometimes get. They give a little of the allergen so that the body slowly becomes used to it. The company's description is this: "with Diamyd® is thought to induce tolerance to GAD, thereby intervening in the autoimmune attack and preserving the capacity to produce insulin in patients with autoimmune diabetes".

Where is Diamyd Now?

The situation for Diamyd is a little more complex than for ToleRx or MacroGenics, because there are more different studies being done with Diamyd's drug than for ToleRx's or MacroGenics's drugs, and those studies are being done by more different people. Diamyd is planning to continue their large phase-III trial in the US, which is basically a twin of this trial that failed. And they are also going to continue following the patients in this trial, just in case there are good results after a longer period of time. I don't hold out much hope for either of those studies being successful.

Additionally, there is at least one study which is using Diamyd to try to prevent type-1 diabetes by giving it to people who have not yet been diagnosed. There is at least one phase-II study being done by academics in the US (so not run by Diamyd). Finally, there is a very small "combo" study being done at the NIH where Diamyd is being combined with two other drugs to try to either regrow beta cells, or get more insulin out of the existing beta cells. The hope is the combination of all three drugs might impact type-1 diabetes. I expect all three of these trials to continue, and they are all a little different from the one that failed, so there still is some hope.

So Where are We Now?

I think everyone needs to understand that these last six months have been disastrous in for human trials designed to lead to a cure for type-1 diabetes. We've gone from having 4 drugs in phase-III trials -- the last phase before market approval -- to having just 1. The remaining one is DiaPep277. On average, a drug which enters phase-III trials should successfully move to the next stage (market approval) about 55% of the time. In fact, for type-1 diabetes we are currently somewhere between 0% and 25% (the higher number only if DiaPep277 eventually gets approved).

Also, it is disturbing to note that no new drugs have started phase-III trials in the last two years. We have gotten new phase-I and phase-II drugs, but nothing has entered phase-III trials to take the place of the three that have dropped out. That's a bad sign as well.

I'm not sure the proper musical background for this blog entry, but definitely something by Nine Inch Nails, maybe "Something I Can Never Have".

You Won't Hear It Here, First
I was talking on the phone to a research analyst months ago, and he as me "how do you know all this research news before anyone else". I was so shocked, I almost dropped the phone. Because it's not true. Almost never am I the first person to publish something in my blog. Why not? First, because I'm in California. That means if something happens in Europe or the East Coast, local bloggers will be posting about it hours before me. But the big reason is that I'm not trying to to be quick; I'm trying to provide context and thoughtful reflection on the news. I'm not trying to be news clipping service. My own goal, is to blog on important events within a week of when they occur, and more minor events within a month. But I don't always succeed even at that.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Orban's Phase-I Results

2011-05-04T19:55:00.000-07:00

I'm a little embarrassed that it has taken me so long to blog about Dr. Orban's results. They were announced almost a year ago.

Data from Orban's Phase-I Trial

This research is a vaccine-like attempt to teach the body's immune system to stop attacking it's own beta cells. A molecule (insulin B chain) similar to insulin was given along with IFA (an adjuvant, a chemical that makes the immune system react more strongly to a vaccine) to try to train the immune system not to attack beta cells. This was a single injection during the honeymoon phase and patients were then followed for two years.

In terms of safety, the results were fine: nothing bad happened, and this is a new treatment, so safety was an important question. But in terms of effectiveness, the results are mixed. The vaccine did result in a specific immune system change that looks promising. The exact quote was:

The induction of a lasting, robust immune response generating autoantigen-specific regulatory T cells provides strong justification for further testing of this therapy in type 1 diabetes.

But no effectiveness was seen during the trial. Their was no improvement in C-peptide generation of the treated group compared to the non-treated group. They were checked every six months. Dr. Orban works at the Joslin center.

Opinions

In my mind how you view these results says a lot more about your personality, than the results themselves. If you are an optimist, then you say "they proved safety, and they proved the treatment induced the change in the immune system the researchers were looking for so this is a success, and they should move on to phase-II testing to find a dose that will have a good effect on the person". If you are a pessimist, then you say "it did not effect the patient's C-peptide numbers, so there is no reason to think it will end up curing (or even improving) type-1 diabetes". The American phrase for this dichotomy is "Is the glass half empty or half full?"

But the truth is, that my opinion doesn't matter, and neither does your's. (Unless you happen to be funding Dr. Orban, of course!) If Dr. Orban gets funded for the next phase, then this study is a success on a path that might lead to a cure. If not, then it is a failure. That's not a very scientific view of success, but it is very pragmatic.

In the past, I know that ITN has discussed the possibility of doing a phase-II trial, but nothing ever came of it. I don't know why. Also, Dr. Orban has started his own company, specifically to bring this cure to market. Their web page is here: http://www.orbanbiotech.com/

The most recent news I have have from them is that in Nov 2010 they got a grant from the US Government: http://www.marketwire.com/press-release/orban-biotech-awarded-244000-qualifying-therapeutic-discovery-grant-from-us-government-1354039.htm
"Orban Biotech Awarded $244,000 Qualifying Therapeutic Discovery Grant From U.S. Government"
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/19931408
Summary: http://www.immunetolerance.org/studies/autoantigen-vaccination-newly-diagnosed-type-1-diabetes-mellitus
Full Paper: http://www.immunetolerance.org/sites/files/2010.04_Orban_JAutoimmunity.pdf
(Thank you Immune Tolerance Network! For making this available on your web site.)
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT00057499

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

Possible Cures for Type-1 in the News (late April)

2011-04-29T20:06:00.000-07:00

Alefacept Starts a phase-II Clinical Trial
This study is also called "T1DAL", which I'm sure is pronounced "tidal".

This drug targets the immune system's T cells, and is already approved for treating "plaque psoriasis" which is an autoimmune disease similar to type-1 diabetes. It has a good safety profile there. The hope is that by giving it to honeymoon type-1 diabetics, beta cells will be preserved.

Because this is an ITN trial, there is a long list of sites where you can participate. For the locals: UCSF is the only California location. They expect enrollment to take 2 years, but (of course) I hope it fills up sooner than that. The sooner they finish recruiting, the sooner we learn the results. The trial is for people within 100 days of diagnosis, and requires weekly injections for 12 weeks, followed by 12 weeks "off", followed by another 12 weeks of injections.

Estimated Enrollment: 66

Study Start Date: March 2011

Estimated Study Completion Date: August 2014

Estimated Primary Completion Date: August 2013 (Final data collection date primary outcome)

Web page: http://www.immunetolerance.org/news/2011/04/itn-announces-enrollment-first-participant-t1dal-trial-people-recently-diagnosed-type-1
Recruiting web site: http://www.t1dal.org/
Clinical Trial: http://www.clinicaltrials.gov/ct2/show/study/NCT00965458

Artificial Pancreas Trial Handles Dinner and Night

Hovorka's team at Cambridge University continues to make progress on testing their AP. These most recent results are aimed at showing that their AP can deal with dinner and the night after dinner. They tested with both a simulated "at home" dinner (fewer carbs, earlier in the evening) and an "out" dinner (more carbs, alcohol, and later in the evening). The study was small (12 people) and "cross over" meaning that half used a pump and half used an AP for the "eat in" dinner, and then they switch (previously pumpers do AP, previous AP use their pumps), and have another "eat in" dinner, and then do again for the "eat out" dinner. Each person was in the test group once, and in the untreated group once, for each meal scenario.

"For the eating-in scenario, overnight closed loop delivery increased the time plasma glucose levels were in target by a median 15 percent," said Hovorka. For the eating out scenario, the average time good blood sugar control was increased was 28 percent on average. And, when combined, the average increase in blood sugar control was 22 percent, according to the study.

Remember, the goal for FDA approval for something like this is as good control as a pump, so 22% better than a pump is more than good enough. Now, to get insurance to pay for it, it will need to do better than a pump, but this trial shows that it is. My reading of the study, is that they did tell the pump the number of carbs eaten at the meal, so this is what the JDRF would call a stage 4 AP. (A stage 5 AP would not need to be told ahead of time about carbs in food.) You can read my general background for AP research (including stages) here:
http://cureresearch4type1diabetes.blogspot.com/2009/09/background-for-artifical-pancreas.html

I know there has been some interest in how accurate CGMs really are. This is what the study found:

The accuracy of the sensor, evaluated as the median relative absolute difference between sensor glucose levels and paired plasma glucose levels divided by plasma glucose levels, was 8.0% (4.5-19.3%) in the eating in scenario and 12.0% (6.8-17.2%) in the eating out scenario.

News coverage: http://www.businessweek.com/lifestyle/content/healthday/651955.html
Full paper: http://www.bmj.com/content/342/bmj.d1855.full (Thank you BMJ!)

Team Brazil Rolls
In the past, I have blogged about what I call the "Burt" research, which you can read here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Burt
but it was done in Brazil, so maybe that is a better term for it. This research uses the patient's own hematopoietic stem cells. (remember that)

In any case, it is by far the most successful research aimed at curing honeymoon type-1 diabetics. Most of the people treated were insulin free for months, many for years. Some for five years or longer. These are much better results than anyone else. But those results came at a cost of safety. Although no one died or suffered serious side effects, the treatment involves significant risk. At least one researcher (not part of this team) has estimated that the chance of dying would be "less than 1%" (personal communications with me), but that is way too high for most people to accept.

So the question is, how does this research move forward? There have been several different answers, as you might expect:

Haller's CSGF+ATG studies are trying a similar treatment, but without the most dangerous drug.
Snarski is replicating the Brazilian trial, and getting similar results (and no serious side effects so far).
Now in this paper: a Chinese group is replicating their work. University of Naijing (2006) found that of 5 patients treated within 3 months of dx, 4 of them used no injected insulin for a time. However, of 11 patients treated after 3 months of diagnosis, none became free of injected insulin. So the good news here is that the replicated the results. The bad news is that it looks very honeymoon dependent. In the past, I had hoped that this treatment might also work for established type-1 diabetics, but this trial shows that isn't true.
And also in this paper: the original group is trying to use mesenchymal stem cells (a different type of stem cell than used previously. This protocol is significantly safer than the current one. The following paragraph from the paper describes the new protocol:

The protocol includes bone marrow biopsy under general anesthesia in first-degree relatives for the collection of mesenchymal cells. These cells are sent to a laboratory to be stimulated to proliferate for a month and are later infused into the patient ...; there is no need for chemotherapy. The patient is hospitalized for 1 day but only as a precaution. After 1 month, the patient receives another infusion. ... Inclusion criteria are age 12 to 35 years, diagnosis of T1DM less than 4 weeks prior to treatment without ketoacidosis and positive serum levels of anti-GAD. So far [in 2008] , two patients have been included in this protocol and, as soon as we have a proper follow-up, the results will be published.

The paper below is an overview written by this research team. It describes the background for their original research, the results they got, and continue to get, and (new to me) extentions of their work (items 3 and 4 above).

Full paper: http://www.springerlink.com/content/hq7882r31162332t/fulltext.pdf (Thank you Diabetology & Metabolic Syndrome!)

Another Overview Paper

This is a readable overview paper by Jay S. Skyler and Camillo Ricordi, both very big names in type-1 diabetes research. The title is "Stopping Type 1 Diabetes: Attempts to Prevent or Cure Type 1 Diabetes in Man". Thanks to Ellen at CWD for pointing out this paper to me.
http://diabetes.diabetesjournals.org/content/60/1/1.long

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Roadmap To Curing Type-1 Diabetes

2011-04-23T09:38:00.000-07:00

This posting is a draft. But I've been working on it for so long that I decided to publish what I have while continuing to refine it. It's not perfect as-is, but I've decided that it is good enough to publish.

I've been posting a lot of narrow updates recently. By narrow, I mean "treatment X passed milestone Y" kind of thing: a lot of detail on a very specific treatment. This posting is the opposite, it is my attempt to put all those narrow postings into context. It is an overview of how we can cure type-1 diabetes using the research that is going on right now. That cure is still a long way off, but this posting describes the possible paths between here and there.

Please remember that this is a posting about possibilities! By listing a line of research here, I'm not saying that I think it will work. All I'm saying is that researchers are actively working on it. I'm sure that in the end most of the research listed here will fail. That doesn't matter. If one succeeds, then it doesn't matter how many fail. Also, I fully understand that not everyone thinks that all the "cures" listed below are legitimate cures for type-1 diabetes. Feel free to ignore the ones that you don't consider cures.

First, A little terminology:
Pancreas is the organ that contains specific structures called islets. Islets contain beta cells, which are the exact cells that generate insulin.

When the immune system mistakenly attacks cells of it's own body, that is called autoimmunity. If the attacked cells are beta cells, that creates a disease called type-1 diabetes. Autoimmunity can target other cells, in which case the disease will have different names and different symptoms.

The immune system attacks beta cells with killer T-cells. Those specific killer T-cells which attack beta cells are often called "bad" killer T-cells or autoreactive killer T-cells. Killer T-cells in general are held in check by regulatory T-cells, which are often called T-regs. Also within the immune system are B-cells (not to be confused with beta cells, which are in the pancreas), and those cells communicate between T cells to encourage them to attack certain cells.

There are many different types of T-cells and B-cells, and they are often identified by CD numbers. So a T-cells might be described as a CD3 T-cell or a CD8 T-cell. B-cells might be CD20. A cell is not limited to one CD number, you could have CD4+CD25+ T regulatory cells (for example).

How to Cure Type-1: Overview

Type-1 diabetes is caused by the body's own immune system mistakenly destroying beta cells in the pancreas. These beta cells would normally create the insulin the body needs. Current research is following five basic paths to try to cure it (labeled A-F below) and many of those basic paths have different sub-paths, which I've numbered.

A. Replace the Beta Cells
Replace the patient's beta cells with ones that can not be attacked by the immune system, so the are not effected by autoimmunity. Simply replacing beta cells is not likely to be a cure, since the autoimmune attack will destroy the new ones same as the old ones.

Encapsulated islet cells. Wrap the cells in a membrane which allows nourishment and sugars in, waste products and insulin out, and also prevents immune cells from attacking the beta cells on the inside. LCT is in phase-II trials and has permission to sell this in Russia but the current results are not a cure, and there are separate phase-I trials in Belgium and Australia.
Elecro-mechanical pancreas (Artificial Pancreas). Build a pump and sensor replacement pancreas that can measure blood glucose and dose insulin. The term "Artificial Pancreas" usually refers to using current pump and current CGM sensor technology, so both of these things use external hardware, and the sensors measure BG levels just below the skin, not in blood veins. There are at least three groups in phase-I or phase-II trials.
Sertoli cells. There are cells in a human body which are not genetically the same as the rest of the cells, and yet are not attacked by the body's immune system. An example are sperm cells; which only contain half the genetic material as regular body cells. They are quite different than regular cells, yet are not attacked as foreign by the immune system. This is because there are special cells, called Sertoli cells, which block the immune system. A possible cure for type-1 diabetes it to combine beta cells and Sertoli cells in a transplant that would not need immune suppressive drugs. Not in clinical trials, although has been in the past. Sernova is doing animal trials in Canada.
Implanted elecro-mechanical. Similar to the artificial pancreas described above, except that implantation means that the blood glucose sensor can be put directly into a blood vein, and resupplying with insulin and new batteries is more of a problem. Also, this is internal, so not visible outside of a person. At least one was in phase-I trials in the past; not sure if any are now. (Dr. Rennard's work in France is with an implanted pump, not an implanted artificial pancreas. So is headed in this direction, but not quite here, yet.)
Non-pancreatic beta cells. In the last decade we have learned a little bit on how to take adult stem cells and program them to become other types of cells. So a possible cure for type-1 diabetes would be to take adult stem cells or even just normal cells from the liver, and program them to produce insulin in response to glucose. The hope is that since they started out as liver cells, the autoimmune attack would not target them, but they would still generate insulin in response to blood glucose. Not in clinical trials.
No Moving Parts Artificial Pancreas. This is similar to "self dosing insulin" (described below), except that there is a chemical barrier that is sugar sensitive, and the insulin is stored behind the barrier. If the sugar level in the blood is too high, the barrier becomes more permeable and more insulin leaves the reservoir. Conversely, if the sugar level goes low, the barrier becomes less permeable and less insulin gets out. Not in human trials; may not even be in animal trials.

I don't consider a classic pancreas transplant or beta cell transplant a cure, because they will require a lifetime of immune suppressive drugs and related complications and side effects. But there is a lot of research going on to improve these procedures.

B. Stop the Autoimmune Attack
Stopping the body's immune attack on it's own pancreas is another way to cure diabetes. Some refer to this as curing the underlying cause of type-1 diabetes, as opposed to replacing the pancreas which they view as curing the symptoms.

I divide this research into different groups based on how they attempt to stop the autoimmune attack. Since the immune system is very complex, there are many ways to try to get it to stop, and so many different ways to categorize this research. The division below is my personal taste. Different researchers do it differently.

Any treatment that stops the immune attack on beta cells needs to be focused, so that it does not stop the immune attack on foreign cells. A "cure" that hobbled the immune system's beneficial functions would be worse than than type-1 (in my opinion), and I would not consider it a cure at all.

Antigen specific targeting.

GAD65. GAD65 is one of the proteins on a beta cell which is (mistakenly) attacked by the immune system, and this treatment is an attempt to teach the immune system not to attack that exact protien. In phase-III trials.
Insulin B chain. Finished phase-I trial.
Insulin.

Targeting specific "killer" T-Cells. Modern technology can create monoclonal antibodies which specifically target specific T-cells.

Anti-CD3s. CD3 are a type of immune cells which are involved in the attack on beta cells. These treatments target that cell type. There is currently one (NI-0401) in phase-II trials. (Two more just failed phase-III trials.)

Targeting communications cells. Monoclonal antibodies have also been created to target CD20. Finished phase-II trials.
Heat Shock Protein 60 (HSP60) is a small protein that might help teach the immune system not to attack it's own body. Diapep277 is based on this, and in phase-III trials.
Polyclonals.

ATG. **need more info here** In phase-II trials.

Raising the level of TNF. BCG. TNF is a naturally occurring substance that kills of certain types of cells (especially tumor cells). If TNF kills off "bad" killer T-cells specifically, then raising TNF levels might put type-1 diabetes into remission or even cure it. Since BCG is known to raise TNF levels, it is a possible cure for type-1 diabetes. No results from a phase-I trial.
Reinforcing T regulator cells.

Dendric cells. **need more info here** In phase-I trials.
T-regs. **need more info here** In phase-I trials.

Note that this path may require that we replace the lost beta cells (see section C), or those cells may regrow without outside help, once the autoimmune attack is stopped.

C. Create new beta cells to replace those that were lost.
If the autoimmune attack is stopped by a cure from group B, then it may still be required to regrow, improve, or replace beta cells in order to have a cure.

Drugs that trigger regrowth. There are several drugs which might trigger regrowth of beta cells. These include Human Growth Hormone and Exsulin, which have done some clinical trials, and CureDM, which has not yet. Exsulin is in phase-II trials.
Stem Cells could be used to grow new beta cells. Many different techniques, some you can get in a clinic now, some in phase-I, and others still doing animal experiments.
Temporary beta cell replacement. Any of the cures in group A could also be used to provide new insulin, especially if only needed temporarily while the body's beta cells naturally regrew.
Type-2 drugs. Many of the drugs given to type-2 diabetics work by getting more insulin out of existing beta cells, or having that insulin used more efficiently by cells, so any of them might be helpful here as well. Several in phase-II trials.

D. Stop inflammation to stop type-1.
Most researchers believe that as the immune system attacks the beta cells, it causes inflammation:
Autoimmunity -> Kills Beta Cells -> Causes Inflammation
But some researchers believe that the inflammation itself kills the beta cells.
Autoimmunity -> Causes Inflammation -> Kills Beta Cells
This difference is important because the second group of researchers believe that if you could stop the inflammation, you could stop type-1 diabetes. There are a large number of anti-inflammation drugs out there, and new ones are being worked on all the time, so I'm only listing those that are being tested on type-1 diabetes specifically: Anakinra is in phase-II, Lisofylline and Xoma 052 are in phase-I. **need more info here**

E. Self Dosing Insulin.
Create a substance that contains insulin, but only makes that insulin available when the blood glucose level is too high. SmartInsulin, SIA-II, and BIOD Smart Basal are examples of research into this type of cure. Smart insulin is probably in clinical trials now. (I'm trying to confirm this.) The other two are not. **need more info here**

F. Gut Permeability
Most researchers believe that gut permeability has nothing to do with diabetes. But some researchers believe that heightened gut permeability causes the autoimmune response that causes type-1 diabetes. When more and larger molicules move out of the intestine and into the bloodstream, that over activates the immune system which attacks the cell of the body. These researchers believe that if you could lower gut permeability, you could prevent or stop type-1 diabetes. Right now, there are no drugs based on this theory in clinical trials, although in the past Alba Therapeutics talked about testing their AT-1001 drug on type-1 diabetes. (It is currently only being tested for Celiac disease.)

Combining Therapies

Basically A, D, E, and F cures are "one step" if they work, we're done. But B and C are a little more complex. B might require C to be a cure, or maybe not, or maybe B will work by itself, but take a very long time, so a practicle cure would still require both B and C. In any case, it seems unlikely that C alone could cure type-1. Certainly, we have tried Exsulin, Human Growth Hormone, and many types of beta cell transplants, and none of those have led to a cure.

Please do remember that this posting is a work in progress, and I do hope to improve it over time. Please email me with specific parts that are hard to understand, or need more explanation. This is a case where I think publishing this information now, is better than waiting for perfect, refined information to be ready in the unknown future.

Joshua Levy

All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

History of Exsulin and AAT

2011-04-17T19:27:00.000-07:00

Based on my last couple of posts, I got the two following questions:

How is the phase-II Exsulin study that is currently underway, different from the phase-II Exsulin study that was reported on in 2009?

The first trial gave one day's dose in one injection. In the current trial, one day's dose is spread over three injections over the course of the day. On one hand, the researchers think this will lead to better results, because they think that Exsulin does not stay in the system very long, so putting it in repeatedly over the day should lead to better results. The drug will be more consistently in the system the whole day through. On the other hand, they also think this will lead to fewer "injection site side effects". In the earlier trial, some patients complained about pain, redness, itching, and other problems right around the injection site. Since the second trial will only be injecting 1/3 of the dose at once, they are hoping there will be far fewer of these side effects. They are also changing the exact formulation to try to minimize this discomfort.

Also, the first study lists the doses as 600 and 300, while the second lists them as 200 and 100. I'm assuming that is per injection, and the daily dose was the same for each study. But it is possible that is not true and the second trial is using a much lower dose. If so, this would be another big difference.

The purpose of most phase-II studies is to find the best dose, the best format for that dose, and to test the treatment on a larger population than in phase-I. So this study is testing improvements to the dosing and formulation; just what you would expect in phase-II studies.

What is AAT used for today? Is that disease like type-1 diabetes?

AAT (Alpha 1-antitrypsin) which is also sometimes called A1AT, is approved for treating Alpha 1-antitrypsin deficiency. Makes sense: your body doesn't produce enough AAT, so AAT is approved as a treatment. This disease is not an autoimmune disease, and is nothing like type-1 diabetes. It is genetic, and comes in different severities depending on if you have one or two of the bad genes . It is estimated to affects 1 out every 2,500 people in the US, although only about 10% of the people affected are actually diagnosed. Here is a note on the most common symptoms from the Alpha-1 Association:

The most common indicators of Alpha-1 include shortness of breath, a chronic cough, and abnormal liver test results. If you have any of these symptoms there is a simple blood test that can detect alpha-1 antitrypsin levels. This test is also recommended if you have relatives, especially siblings, who have been diagnosed with alpha-1, or if there is a family history of early emphysema, with or without smoking.

You can read about it here:
http://en.wikipedia.org/wiki/Alpha_1-antitrypsin_deficiency

And here are some support groups:
http://www.alpha1.org
http://www.alpha-1foundation.org

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Possible Cures for Type-1 in the News (mid April)

2011-04-12T21:00:00.000-07:00

Exsulin's Phase-II Trial is Data Complete

The exact update I got on the Exsulin phase-II trial is this: "We have finished recruitment for this trial. We are still in the process of finalizing the results". I interpret this to mean, not only have the finished recruting all their patients, but they have all their data, and are now working on the data analysis / paper writing part of the research. This is great news, because I'm hopeful that we will hear the results in a few months.

Rituximab Starts another Phase-II Trial

Rituximab targets the CD20 part of the immune system's B cells (different from the pancreas's beta cells) to try to prevent the autoimmune attack. B cells are part of the body's immune system and communicate with the T cells, which actually attack the body's beta cells in the pancreas. By targeting the B cells, it is hoped this treatment will stop or lower the attack of the T cells.

Comment: Most treatments aimed at stopping the autoimmune attack are very focused on stopping the "bad" T cells which directly attack the beta cells in the pancreas. This treatment (if successful) opens up a whole 'nother way to stop the attack: by targeting the immune systems communication and support system, the B cells.

The current research (which I consider phase-II, although the researchers list it as phase-IV) is very similar to the a previous trial which I blogged on before (link below). The current trial has already started enrolling 50 people at First Affiliated Hospital, Nanjing Medical University (Nanjing, Jiangsu, China). If you are interested in enrolling, contact Tao Yang, PhD at phone 86-25-83718836 ext 6466 or email yangt@njmu.edu.cn. There is no placebo group in this trial: everyone is treated. They started in July 2010, and hope to complete it by December 2013. This is for people with type-1 diabetes for less than one year.

clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT01280682

A Sad Note to the Previous CD20 Research
The previous Rituximab research was led by Dr. Mark Pescovitz who died in a car crash at the end of last year. That work was published by the prestigious New England Journal of Medicine, and was just one part of a distinguished research career.
http://www.boingboing.net/2010/12/13/mark-pescovitz-1955-.html
http://www.jdrf.org/index.cfm?page_id=114825

My previous blogging on Rituximab is here: http://cureresearch4type1diabetes.blogspot.com/search/label/Rituximab

Sitagliptin Completes Enrollment on a Phase-II Trail (as a Treatment)

This is a large (140 person) trial which started in late 2010 and is the follow on to a trial which I've blogged about before. The goal of this is to lower A1Cs for type-1 diabetics by about 0.3, by lowering BG levels more quickly after a mean than is done now. The 0.3 number is pretty close to what they did in an earlier, smaller trial. Sitagliptin is already approved for type-2 diabetes. It's trade name is Januvia.

They completed enrollment in February 2011, I think. The record is not 100% clear, and it might have been earlier. If they did complete enrollment in February, then they will finish collecting data about June. The clinical record says the trial will complete in July 2011, so I think it is reasonable to see results by the end of this year for this research. This same group published their previous results very quickly after the study was done.

Clinical trial: http://www.clinicaltrials.gov/ct2/show/NCT01227460
Previous trial: http://www.clinicaltrials.gov/ct2/show/NCT00978796
Results from related trial: http://cureresearch4type1diabetes.blogspot.com/2011/02/possible-cures-for-type-1-in-news-late.html (but this was combining this drug with another)

Extra Reading

Dr. Skyler has written a wonderful summary of some of the more interesting clinical trials in type-1 diabetes done between June 2009 and July 2010:
http://onlinelibrary.wiley.com/doi/10.1111/j.1742-1241.2010.02580.x/full
One of the things I particularly liked about this paper, is that for each clinical trial, there is a summary of the abstract and then Dr. Skyler's comments. These comments often put the research into context, discuss next steps, or give his opinions on it. That perspective is missing from the raw scientific papers. (Although he wrote this before the two anti-CD3 treatments had failed in phase-III trials, so those are discussed here, although they are already dead as cures.)

Here is part of his summary of the whole year:

That negative studies continue to dominate the field, and that the positive ones still show decline in β-cell function over time, has led to more calls for combination approaches. When I [Dr. Skyler] have advanced such prospects at meetings of paediatric diabetologists, I hear groans. Yet when I have advanced these prospects at meetings of immunologists and transplant surgeons, I hear cheers.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Possible Cures for Type-1 in the News (early April)

2011-04-02T08:52:00.000-07:00

Canakinumab Completes Enrollment
Canakinumab is a monoclonal antibody, which is designed to lower inflammation. It targets IL-1β (interleukin-1 beta) which causes inflammation. The drug was approved in 2009 (both US FDA and EU EMEA) for a collection of rare autoimmune based inflammatory diseases. (And type-1 is an autoimmune disease which causes inflammation, but it is not clear how important the inflammation is to the symptoms of the disease.) Good results have been seen in people with type-2 diabetes, and it has been used in children as young as 3.

They have completed enrollment of their phase-II clinical trial (66 people) as of March 2011. Because this drug is already FDA approved, there was not a phase-I trial in people with type-1 diabetes. So the results from this trial will be the first type-1 results that we see.

Why is completing enrollment important? For two reasons. First, because it is now possible to predict when they will finish collecting data. This study runs for 2-4 years, so they should have data collected by March 2015 at the absolute latest, and might have some early data by March 2013. Second, because much of the uncertainty that surrounds clinical trials, is involved with recruiting participants. It is often unclear how hard it will be to recruit people, and long it will take. But that this point, all that uncertainty is behind the researchers. From now on, it is just gather data, then analyze data, and then publish data. Researchers have a lot more control over those later stages, then over recruiting people in the first place.

Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT00947427
Wikipedia entry: http://en.wikipedia.org/wiki/Canakinumab

Xoma 052 Fails (Mostly) in Phase-II for Type-2

Xoma 052 is a monoclonal antibody which is a broad anti-inflammatory, and works by blocking the IL-1 inflammation pathway. The news is that Xoma announced that their Xoma 52 phase-II trial for type-2 diabetes had missed it's primary end point (which was better BG control). They are still hopeful that it will lower bad cholesterol and be marketable for that purpose. But that's a big come-down: they were hoping to lower BGs which is a big, sweeping treatment for type-2, but now they are hoping to help one particular symptom. Plus, there are already other drugs that lower bad cholesterol.

Why is this important? Xoma is also testing this drug on type-1 diabetics. That trial is ongoing and results are not expected until around October 2011. But obviously, this is not good news. However, since the mechanisms behind type-1 and type-2 are very different, we really need to wait and see what happens in their type-1 clinical trial.

Reminder About The Blog
This blog generally only covers research results. Occasionally related topics are discussed. However, I generally don't discuss funding issues, stock issues, new hires (such as presidents, new board of director members, etc.) patient issues, mergers and acquisitions ("M&A"), director or C-level resignations, etc. These are all news worthy, but they are not the kind of news that I cover here.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

New Resource: Next Expected Milestone

2011-03-28T19:16:00.000-07:00

I have the first draft of a new on-line resource for tracking research aimed at curing type-1 diabetes. It is not in a "polished" form as yet. I'm releasing it now partly because I think it will be very helpful, and partly so you can give me feedback on it.

I call it the Next Expected Milestone page. It's permanent home is here:
http://cureresearch4type1diabetes.blogspot.com/p/next-expected-milestone.html
But I've included the important part below.

My goal with this page is to make it easy, for each clinical trial, to see what research milestones are expected to be completed in the next month, season, year, etc. On the one hand, this page can serve as an TLOD ("too long over due") list of research that isn't reporting the expected results. On the other hand, it can tell you what announcements to especially look for in the next few months.

In the table below, the the important column is the last one. It contains the next expected milestone the researchers should make. So "Jun-2011 III Results !" means that in June of 2011, that trial should release their results, and the ! means they have publicly said they will do this. "April-2012 II Started" means they will start a phase-II trial in April 2012, and so on. Red dates are long over due. Orange dates are slightly over due. and BoldGreen dates are coming up in the next few months. All the columns in the table, and all the abbreviations and acronyms, are described in a section below the table.

Name          Id/Developer           Notes            Date Last Milestone        Date Next Milestone 

Lisofylline   DiaKine                Inflam           May-2009 I Started         Dec-2009 I Complete
BCG           Faustman               Estab Comm       Jun-2010 I GotData         Oct-2010 I Results
Anakinra      NCT00645840            Inflam (Kineret) Jun-2010 I Completed       Dec-2010 I Results 
Exsulin       Exsulin                Beta             Sep-2009 II Started        Nov-2010 II Complete
Atorvastatin  NCT00529191            (Lipitor)        Feb-2010 II Enrolled       Feb-2011 GotData 
Etanercept    NCT00730392            (ENBREL)         Apr-2009 I Results         Apr-2011 II Start
GAD65*        NCT00723411 - EU                        Nov-2009 III Enrolled      Jun-2011 III Results!
Dendritics    NCT00445913            Estab            Feb-2011 I Enrolled[*]     Jun-2011 Results
Liraglutide   Hvidovre Univ Hosp     Estab            Jan-2011 II Complete       Jul-2011 II Results 

AAT           Kamada                 Inflam           Mar-2011 I Paperwork       Aug-2011 I Starts
Anakinra      AIDA                   Inflam (Kineret) Jan-2009 I Starts          Sep-2011 I Complete 
BHT-3021      NCT00453375            Estab            Nov-2010 I Enrolled        Oct-2011 I Complete?
Xoma 52       Xoma Corp              Estab Inflam     Jul-2010 II Enrolled       Oct-2011 II Results
GAD65         NCT00751842 DIAPREVENT                  Nov-2010 III Enrolled     Oct-2011 III Complete  
DiaPep227*    DIA-AID1 NCT00615264                    Sep-2009 III Enrolled      Dec-2011 III Complete

Rituximab     Pescovitz at Indiana                    Dec-2009 II Publication?   Dec-2011 III Start?

Cord Blood    Haller                                  Mar-2009 II Started        Mar-2012 II Complete?
PROCHYMAL     Osiris                                  Jan-2010 II Enrolled       Apr-2012 II Results
Pioglitazone  NCT00545857                             Oct-2009 I HalfEnrolled    Jun-2012 I Complete
GCSF          NCT01102699            Estab            May-2010 I Started         Jun-2012 I Complete  
IBC-VS01      NCT00057499 Orban                       Jun-2010 I Published       Jun-2012 II Start

GAD65 [1]     NCT00837759            Estab            Jan-2011 II Enrolled       Oct-2012 II Complete 
GAD           NCT00529399                             Apr-2010 II Enrolled       Dec-2012 II Complete  
Sitagliptin   Garg                   Estab            Feb-2011 I Results         Feb-2013 II Start
GCSF          Haller                                  Apr-2008 I Start           Apr-2013 I Complete 
ATG GCSF      Haller                 Estab            Apr-2010 I Started ?Aug    Apr-2013 I Complete 
AAT           NCT01319331            Estab Inflam     Mar-2011 I Started         Sep-2013 II Complete  

Abatacept     Orban at Joslin                         Feb-2008 II Started        Sep-2013 Results
Proleukin Rapamune  NCT00525889      Estab            Nov-2010 I Enrolled        Sep-2013 I Complete?

NI-0401       NovImmune                               Aug-2010 II Started        Aug-2013 II Results ?
Rituximab     NCT01280682                             July-2010 II Started       Dec-2013 II Completed
DiaPep 277    DIA-AID2 NCT01103284                    May-2010 III Started       Mar-2014 III Complete 
AAT*          RETAIN-1 NCT01183468   Inflam           Oct-2010 II FirstDose      Nov-2014 II Complete
Canakinumab   TrialNet               Inflam           Mar-2011 I Enrolled        Dec-2014 I Complete 
ATG           START NCT00515099                       Aug-2007 II Started        June-2015 II Results

Poly Tregs    Gitelman               Estab            Jan-2011 I Started         2016 I Results

[1] Combo trial including GAD65, lansoprazole, and sitagliptin

Understanding The Table

Each line is a separate clinical trial (so drugs/treatments with more than one trial active may have more than one line).

Name

The most common name of the drug or treatment. Only one is included. For drugs that have trade names and generic names, I usually use the generic name if there is space for it. A * means this is the leading (farthest along) clinical trial for this drug or treatment in type-1 diabetes, for treatments with many studies going on at the same time.

Id/Developer
Should be an identifying number or trial name, or both. However, I started out putting the name of the researcher here, and I'm only slowly replacing that with the US government's clinical trial number, or a similar number from another governmental organization. Developer is the organization creating the treatment or testing it. Only one is included.

Notes

Here are the notations in this field:

Appr: Drug or treatment already approved in the US or EU or both.
Beta: Drug or treatment aimed at increasing beta cell mass or efficiency.
Comm: A commonly used drug, so widely prescribed or not prescription at all.
Estab: A trial on established (non-honeymoon) type-1 diabetics. Generally over 1 year.
Inflam: A drug or treatment based on preventing or lowering inflammation.
Prev: A trial aimed at preventing type-1, not curing it.
Treat: A drug aimed at treating type-1, not curing it.
(...): A trade name of the drug in the trial, these drugs are usually "Appr".

Milestone Columns
The last two columns in the table are both milestones, and are very similar. Here are the types of milestones listed in these columns:

Paperwork: Filed the paperwork required to start a trial. Usually either the clinical trial record, or the IND application, if in the USA.
Start: Started trying to enrolling patients in the trial. Recruitment has started.
First Dose: The first patient actually enrolled and dosed.
Enrolled: Finished enrolling patients in the trial. Trial is full.
Complete: The completion date from the clinical trial record.
GotData: Finished gathering data.
Results: Important results published in some form (paper, symposia, abstract,etc.)
Published: Important Results published in a peer reviewed journal.

Also, these marks are used in both milestone columns:

"I", "II", and "III" refers to phases of clinical trials, and trials which the researchers consider phase-IV, are considered phase-II here.
A "?" means I need to recheck that date.
A "!" means the researcher or organization has publicly listed that date.

Last Milestone
This column contains the date and content of this research's last milestone.

Next Milestone
This column contains the date and content of this research's next expected milestone.

Possible Cures for Type-1 in the News (March)

2011-03-22T17:11:00.000-07:00

The first two lines of research discussed below involve treating inflammation, so here is a quick introduction to treating inflammation as a cure for type-1 diabetes: Everyone knows that type-1 diabetics have a lot of inflammation in their pancreas and especially around their beta cells. Most researchers believe that inflammation is a result of the body's immune attack on it's own cells. That is, the underlying immune problem causes inflammation and also causes beta cells to die (which causes the symptoms of type-1 diabetes):

            /---> causes --> beta cells to die     

Autoimmunity 

            \---> causes --> inflammation

However, some researchers believe that the underlying immune problem causes inflammation, and that this inflammation kills the beta cells, which then causes the symptoms of type-1:

Autoimmunity -causes-> inflammation -causes-> beta cells to die

The difference is that, in the second model, if you stop the inflammation you can stop the symptoms of type-1 diabetes (the high BG numbers and the low numbers). And that is a big difference. But this second model is still a minority opinion.

OmniBio Starts a Phase-I Trial on Established Type-1 Diabetics and Expands their Honeymoon Phase-I Trial

Alpha-1 Antitrypsin (AAT) is an anti-inflammatory drug, which the body makes naturally, and which is already FDA approved for people who have a rare condition where a person don't make enough of it on their own. OmniBio had already started a phase-I trial for honeymoon diabetics, however they are now expanding in two important ways:

First, they are starting up a non-honeymoon phase-I clinical trial. Obviously, this is very important to the majority of type-1 diabetics who have had the disease for a long time:

The initiation of a late stage Type 1 diabetes trial. Proposed Trial Site: University of Basel, University Hospital-Basel, Basel, Switzerland. Principal Investigator, Dr. Marc Donath, Professor of Endocrinology, Head of Clinic of Endocrinology, Diabetes & Metabolism.

Second, they are expanding their Honeymoon phase-I trial to 50 patients. At that size, it really more of a phase-II trial. Here is that part of the announcement:

The trial ... has seen improvement in the condition of the first enrolled patients. Based on observations of the first enrolled patients..., Omni Bio intends to expand the patient enrollment to 50 patients, which may involve obtaining a second trial site.

That sounds like great news, but I'm very interesting in exactly what those results where. (This is a case where "details matter" and a vague statement of improvement is not good enough by itself.) Hopefully these guys will publish some details, soon.

Press release: http://www.prnewswire.com/news-releases/omni-bio-pharmaceutical-intends-to-expand-type-1-diabetes-trial-to-50-patients-117053528.html
clinical trials: http://www.clinicaltrials.gov/ct2/show/NCT01183468 http://www.clinicaltrials.gov/ct2/show/NCT01183455

Thanks to Cameron Donahue (who works with OmniBio) for providing some of the information used here.

Kamada Starts Paperwork for a Phase-I Trial of AAT

Kamada is a different pharmaceutical company that makes AAT. They currently make an FDA and EMEA approved formulation which is used for people who naturally don't produced enough AAT of their own. They are also working on an inhaled version of AAT, since the current product is intravenous, but that is still in clinical trials. They are planning to test a different brand name of AAT (Glassia®), than Omni's (Aralast NP), but I don't think that is important.

The trial they are planning includes 24 people and will be completed around December 2012. There will be no control (or "placebo") group, but three groups will each get different Glassia doses. The primary outcome for this study is general safety, and the secondary outcomes are efficacy as measured by injected insulin and A1c numbers. (There is also a mention of testing for "Pancreatic beta cell function" which I hope means C-peptide measurements, but the paperwork is not specific.)

This clinical trial is being done at two sites in Israel: Schneider Children's Medical Center (Petach Tikva) and Assaf Haroffeh Medical Center (Zerifin). Contact is Mariana Rachmiel and her phone number is +972-8-9542007.

clinical trial: http://www.clinicaltrials.gov/ct2/show/NCT01304537
corporate site: http://www.kamada.com/

Personal Opinions on the Impact of this Research on Dr. Faustman's Research

The Alpha-1 Antitrypsin (AAT) research described above may also have huge impact on Dr. Faustman's research. It could provide strong evidence that her theory is right or wrong. Dr. Faustman's theory is that BCG will cause the body to generate more TNF which in turn will kill the autoreactive ("bad") T-cells and result in the body generating more of it's own insulin. She announced that her phase-I trial had finished almost a year ago, but has not published results as yet. (A very bad sign in itself.) However, taking AAT lowers the amount of TNF in a person. This is the opposite of BCG. Especially for a honeymoon diabetic, this means that if Dr. Faustman's theory is correct, then giving AAT will cause a shorter honeymoon, and will generally result in a quicker onset and the body to generate less insulin.

So, if AAT results in a longer, stronger honeymoon, that suggests that Dr. Faustman's theory is wrong, even if she never publishes the results of her own clinical trail. Conversely, if AAT results in a shorter, weaker honeymoon, that supports her theory. Again, independent of her own results.

Teplizumab Starts Phase-II to Prevent Type 1 Diabetes

Teplizumab was being developed by MacroGenics until late last year, when it failed it's phase-III clinical trials for honeymoon type 1 diabetics. It is similar to Tolerx's Otelixizumab which also failed it's phase-III clinical trials. Both target a specific type of cell in the immune system, called a CD3. However, months before the phase-III trial failed, the paperwork had started on a clinical trial to give this drug to people at high risk for type-1 diabetes, but who had not yet come down with the disease. These patients would be identified by having two or more auto-antibodies, a first degree relative with type-1, and already having an abnormal glucose tolerance test. The idea would be to give these guys Teplizumab to see if it prevented or delayed or lessened the impact of type-1 diabetes. TrialNet is moving forward with this clinical trial.

It is easier to have a good effect on type-1 diabetics during the honeymoon phase than later on, after the disease is long established, so it makes sense that it should be easier still to prevent type-1 entirely than to treat it in the honeymoon phase. So even though this drug did not improve honeymoon diabetics, there is still hope that it might still prevent the disease.

The study will enroll about 170 people, from many different clinical sites all over the US (for the locals: UCSF and Stanford are recruiting, but nothing in Sacramento). Results in January 2016 if all goes according to plan. Since the drug has already been through phase-I and II trials for honeymooners, they can start off at phase-II for their prevention trial. If you're interested there is a recruiting web site and a lot of contact information in the clinical trial record (links below).

News: http://www.popsci.com/science/article/2011-03/experimental-drug-may-prevent-diabetes
Recruiting web site: http://www.diabetestrialnet.org/studies/ACD3.htm
Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT01030861
Note that the news article uses the term "Body Reboot" in it's title. I think this is a poor choice of words. The drug being tested does not reboot anything (in my opinion). I think the term "reboot" is properly used to describe the cure being researched by Burt (and collaborators) in Brazil and Snarski in Poland.

(If this had been nearer to Halloween or nearer to April 1st, my lead paragraph would have been something like this:

Zombie Drug, Left for Dead, Walks Again!

Teplizumab which was last seen buried in a shallow grave, after having failed phase-III testing in honeymoon diabetics, has risen from the grave and is shambling towards a different use: preventing type-1 diabetes when given to at-risk people who have not yet been diagnosed with the disease. It was heard mumbling to itself "Hungry for Ceeee Deeee Threees. Must have Ceeee Deeeee Threees. Give meeeee Ceee Deeee Threeees...... :-)

A Little Commentary

In addition to seeing if Teplizumab can prevent or minimize type-1 diabetes, this trial will also have a synergistic effect with TrialNet’s Natural History Study trial. That trial tests relatives of type-1 diabetics for antibodies to help gather pre-diagnosis data on the disease. I know some people don't participate, because even if they turn up positive for one or more antibodies, nothing can be done. And they'd rather not know, if nothing can be done. But now, something can be done: they can enroll in this Teplizumab trial, and maybe (emphasis on "maybe") get a benefit if the trial is successful. So I think the very existence of this Teplizumab trial will help populate the Natural History Study trial. And if you have not participated in TrialNet’s Natural History Study, because you didn't think you could use what you learned, well now maybe you can.

Also, this trial simply could not be run without something like TrialNet’s Natural History Study trial. The Teplizumab study is dependent on identifying a large group of people who don't yet have type-1, but have a high chance of having the initial onset in the next few years. That's exactly the type of data that the Natural History Study produces. Without a trial like Natural History Study it is almost impossible to even test a type-1 preventative drug, because you would need to give it to thousands of people, to even see even 10 or 20 people who would eventually become type-1 diabetic. By starting with the Natural History Study data, you can run reasonably sized preventative trials, like the 170 for this one.

So this trial helps TrialNet’s Natural History Study, and TrialNet’s Natural History Study helps this trial. I would expect that as we get more and more data from the Natural History Study these sorts of follow on, prevention studies will be come easier and easy to run (and cheaper), and therefor more common.

Obviously, this trial is not research aimed at curing type-1 diabetes; it is aimed at preventing it. So I'm not sure I will continue to follow this in the future. I do include honeymoon trials. Should I include prevention trials?

Non-Type-1 Diabetes News (Learning from Other's Mistakes)
One of the major points I try to make in this blog, is that you can not make your medical decisions based on one study. No matter how good, how important, how famous, or how much you like the results. You must look at the whole area of research, and especially follow up studies, before you make a decision. The Chronic Fatigue Syndrome community is learning this lesson the hard way, as a purported connection between a retrovirus (XMRV) and their disease is coming apart in a very painful and political way:

Editorial: http://newsblogs.chicagotribune.com/tribnation/2011/03/xmrv-chronic-fatigue-syndrome-and-a-fuller-picture-of-their-dubious-connections.html
News: http://www.chicagotribune.com/health/ct-met-chronic-fatigue-xmrv-20110317,0,6116823.story

This quote is from the editorial:

Our story today is about the danger of putting too much stock in one study and forgetting that scientific knowledge is hard won, proven over time, and borne out through many, many studies -- not just one.

Reminder About The Blog
There three ways you can help with this blog:
First, tell other people about it! Heartfelt testimonials are the best advertising.
Second, tell me about any clinical trials you know about that are not already covered here.
Third, ask me questions that you have. This tells me what I'm not explaining well, and where I need to put more information into my posts.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news
Old Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

Tolerx's Otelixizumab Fails in Phase-III Trial

2011-03-14T17:56:00.000-07:00

Otelixizumab (Tolerx / GlaxoSmithKline) Fails Phase-III Trial

The official quote is "did not meet the primary efficacy endpoint". Basically, the the people who got the drug did not do better than those who did not, in the the most important measurement of success. The primary endpoint for this experiment was C-peptide generation, which is a marker for natural insulin production. Basically, they were hoping that giving this drug would help honeymoon type-1 diabetics generate more of their own insulin, but it did not.

In terms of actions: they have stopped enrollment in their second phase-III trial (DEFEND-2), which shows that they think that there is little to no hope of moving forward with this drug at this time.

So that is about as dead as a phase-III trial can get.

Press release: http://classic.cnbc.com/id/42028160
Tolerx blog: http://tolerx.com/index.php?page=greenchair&entry=committed-to-the-promise-of-our-normalization-immunotherapy-platform
DEFEND-1: http://www.clinicaltrials.gov/ct2/show/NCT00678886
DEFEND-2: http://www.clinicaltrials.gov/ct2/show/NCT01123083

A Little Discussion

This is not completely unexpected, because there was another similar drug (Teplizumab), which was also an anti-CD3 monoclonal antibody which was also in phase-III clinical trials and just a few months ago, it failed as well.   And for the same reason: did not cure/improve people. Neither trial had any safety problems.

There is still one anti-CD3 monoclonal antibody out there. It is NI-0401 by NovImmune, and is in phase-II clinical trials. Unfortunately, I've never been able to find results for their phase-I study, so I don't hold out much hope. If you know anything about NovImmune's NI-0401 results, or where they were published, then please tell me.

Previous blogging on Teplizumab:
http://cureresearch4type1diabetes.blogspot.com/search/label/Teplizumab
Previous blogging on NI-0401:
http://cureresearch4type1diabetes.blogspot.com/search/label/NI-0401

So where are we now?

Years ago, there was only one treatment in phase-III trials: DiaPep277. Last year, there were four. Since then, two have failed and none have entered, so we are down to two: GAD65 and DiaPep277. GAD65 is expected to announce their first phase-III results in the next 3 months, but DiaPep277 results are much farther away.

The official musical accompaniment for this blog entry is "River of No Return" from The Jeff Healey Band's album "See the Light".
      It's a cold hard lesson, that you're gonna learn, on the river of no return....

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

Possible Cures for Type-1 in the News (late Feb)

2011-02-28T17:43:00.000-08:00

Results from a phase-I Clinical Trial

Back in Sept 2009, Dr. Garg started a small pilot trial of Sitagliptin and Lansoprazole. These are two drugs currently used for type-2 diabetes, but this trial is aimed at using them on people who have type-1 diabetes. The study was supposed to last about three months, and now they have published some results.

Summary:

The [treatment] lowered their mean blood glucose by about 12 mg/dL and their A1Cs by 0.27%, and they were able to cut their insulin dose by nearly 10 percent during the treatment period.

They are very happy with the results and plan to start a 120 person study. You can see the government clinical trials registration here, although it hasn't started yet:

http://www.clinicaltrials.gov/ct2/show/NCT01227460

The improvement looks pretty small to me. They are cheering about 12 BG points improvement? A quarter point A1c? 10% less insulin? So, for example, someone who is currently averages a BG of 150 might drop to 138. An A1c might go from 7.5 to 7.25. Instead of using 60 units of insulin a day, they might use 54. I'm underwhelmed, and I hope they get bigger improvements in their phase-II studies. On the other hand, Lansoprazole is a common antacid and is available over the counter, and while Sitagliptin is prescription, it is also very common. I don't know the longest clinical trial run with either one of these drugs however. I'm a little nervous that previous testing of Lansoprazole (the antacid) might just assume you take it once in a while. I'd be real curious if anyone has seen what happened (even in animals) if you took it every day for a month, a year, 10 years, etc. Since that is what is envisioned here. I expect that is what will be learned from the phase-II and phase-III trials.

As far as this blog is concerned, I don't think I will continue following this research, because I think it looks like a treatment for diabetes, not a cure. But I don't want to be too "down" on this research. Up until now, different types of insulin has been the only treatment available for type-1s, so this might be the first step to having an array of drugs that help keep BGs more stable. I know a lot of people would be very happy with a .75 or 1 unit change in A1c, and as a first test, this got 1/3 to 1/4 of the way there. So maybe further development will get there.

Sources:

http://www.diabeteshealth.com/read/2011/01/07/7004/sitagliptin-januvia-lowers-blood-sugar-in-people-with-type-1-diabetes/

http://www.jdrftalk.org/2011/01/19/pilot-study-shows-popular-type-2-diabetes-drug-lowers-blood-sugar-levels-in-people-with-type-1-diabetes/

http://www.renalandurologynews.com/type-2-diabetes-drug-shows-promise-for-type-1/article/193749/

http://www.clinicaltrials.gov/ct2/show/NCT00978796

DiaPep277 Fully Enrolls a Small Phase-III Trial

DiaPep277 is a protein design to help train the body's immune system not to attack it's own beta cells. It was the first treatment that I know of that started phase-III clinical trials, and has been in them for years. There were two different phase-III studies underway, both about 300 people. (Remember that for US or EU approval new treatments generally require two phase-III studies of about this size.) However, the news story below is about a smaller "follow on" phase-III study with 40 people. This study will follow people for 2 years after they were already part of the phase-II study. It is looking at longer term safety/effectiveness issues. Since it is fully enrolled, we "just" need to wait 2+ years for the results. Of course the results from their mainline phase-III trials matter much more.

News: http://www.globes.co.il/serveen/globes/docview.asp?did=1000624744&fid=1725
Clinical trial: http://www.clinicaltrials.gov/ct2/show/NCT01281072

One Scam Cure and One Fringe Theory
Note that both of these guys cite Dr. Faustman's work, but are totally separate from it. One of the "tricks" of scientific scams, is that it helps to cite real research, as part of your fraud. So the fact that Drs. Arnim and Broxmeyer are citing Dr. Faustman says nothing about Dr. Faustman's work.

Ulrich von Arnim
If you ever wanted to know what a type-1 diabetes cure fraud would look like. Here is your chance:
http://bva-tec.com/studien_en.php
And here is the news coverage.
http://www.theage.com.au/national/health-conman-strikes-again-20110209-1an2v.html
I'm not worried that this guy might have really cured type-1 diabetes: he's been in jail for two years for fraud, and has an arrest warrant waiting for him in Germany. But it is interesting to look at his web site. If that was your only source of information, you would think it was real. The only tip-offs that I saw were these:

If you look at the "clinical trial registration" number column, I can see that those are not European clinical trial numbers. Nor are they American numbers. I think they are European patent numbers (and patents are not the same as clinical trials!) Also the first row that says "(pre-study)" so has no clinical trial number. That's wrong: if they used people, they gotta have a clinical trial. There are ethical and legal issues if they don't. (It's possible that things were different in 1990-1992, but I don't think they were that different.)
The second issue was the number of people "cured". He claims to have cured about 14,000 people. Now, there are about 1.5 million people with type-1 diabetes in the EU, so he has cured about 1% of them. Already. And we've never heard from even one of his patients. Sounds nuts to me. (And he claims to have cured 1000s of people as long as 20 years ago, and no one has talked about this?)

Lawrence Broxmeyer
This guy has a fringe theory, or maybe a quack theory, that diabetes is caused by Tuberculosis (TB). Actually, he has a lot of theories that a lot of different diseases are caused by TB.
http://lawrencebroxmeyer.wordpress.com/2011/01/26/diabetes-mellitus-tuberculosis-and-the-science-of-denial-by-dr-lawrence-broxmeyer/
If you believe this stuff, then it's obvious why a TB vaccine (like BCG) would cure type-1 diabetes. He conveniently ignores the fact that giving BCG to people with type-1 diabetes does not cure them. Nor does it prevent type-1 diabetes. (In five or six previously completed studies.)

Random Reading / Listening

If you have a CD player in your car, I recommend a recorded lecture called "What is Wrong with Cloning?" by Dr. Arthur Caplan. (The Sunnyvale, California, USA library has a copy.) It is 1/3 a discussion of ethics, 1/3 the science of cloning and stem cells, and 1/3 stand-up comedy. I have never laughed so hard while learning so much. It's published by The Great Lecture Library.

This University PR piece:
http://www.ucsf.edu/news/2011/02/9428/type-1-diabetes-clinical-trials-aim-save-beta-cells-immunotherapies
describes three different clinical trials all being run out of UCSF by Dr. Steve Gitelman.
You can search my blog site for "Gitelman" to see previous coverage of these trials.

You might want to also look at this data, about longer life spans for type-1 diabetics dx recently vs. dx in the 1950s:
http://www.t1diabetes.nih.gov/Research_Accomp.pdf

Reminder About The Blog

This blog generally only covers research results. Occasionally related topics are discussed. However, I generally don't discuss funding issues, stock issues, new hires (such as presidents, new board of director members, etc.) patient issues, etc. These are all news worthy, but they are not the kind of news that I cover here.

Chance of FDA Approval

2011-02-23T19:38:00.000-08:00

Long ago, one of my first blog postings described the "research funnel". How a drug went from animal tests through three phases of clinical trials and was eventually approved (and how drugs could fail at each step in the process). If you haven't read that posting, it contains a lot of useful background information on how drugs get approved in the USA:
http://cureresearch4type1diabetes.blogspot.com/2008/06/understanding-research-funnel.html

I used the best data I could find for that post, but I'm very happy to say that Biotechnology Industry Organization (an industry trade group) and BioMedTracker (a company which collects data on drugs in development) have published some much better data on success rates for US FDA approvals. Their data set is much larger than what I had back then. And it is interesting! At least to me :-)

The study was conducted from 2004 through 2010 reviewed more than 4,000 drugs from companies large and small and both publicly traded and private. But NOT university or non-profit research.

Major findings about the process right now:

The overall success rate (all the way through successful FDA approval) for drugs moving from early stage Phase I clinical trials is about 9%. For phase-II it is 15%, for phase-III it is 44%.
63% of drugs in Phase I testing advanced to Phase II
33% of Phase II drugs made it to Phase III
55% of the drugs that made it to Phase III testing filed for approval applications.
80% of the drugs that filed for approval gained eventual approval (only about half were approved on their initial FDA review)
Biologics had a 15% chance of going from Phase I through to FDA approval, compared with a 7% success rate for traditional small molecule chemical drugs. A biologic is more complex than a simple drug. It is generally something derived from a living organism. For example, a purified microorganism or specially treated or processed blood or tissue would be a biologic. BCG, cord blood, and ATG are biologics that are being tested on type-1 diabetics.
The highest overall success rate from Phase 1 through likelihood of approval was for infectious diseases, such as hepatitis and HIV drugs, at 12%. Next was endocrine system drugs, featuring [type-2] diabetes treatments, at 10.4%. And then autoimmune diseases, such as rheumatoid arthritis, at 9.4%.
Overall success rates from Phase I to FDA approval is nearly 9%. This number is comprised of lead and secondary indications. When separated, lead indications have close to a one in seven rate of approval and secondary indications have a rate of one in 30. This was seen in all phases of clinical development as well as in all disease areas.
The study also shows that large molecule drugs are twice as successful in gaining approval than small molecule drugs.

Major findings about changes in the process:

Overall success rate for drugs moving from early stage Phase I clinical trials to FDA approval is about 9%, down from one in five to one in six seen in reports involving earlier years.
The 80% approval rate (for drugs that submitted applications), is down from 93% seen in early studies.

Commentary

Here are some very rough calculations:
There are currently about 15 phase-I trials with a 9% chance of eventual approval (1.35 total)
There are currently about 10 phase-II trials with a 15% chance of eventual approval (1.50 total)
There are currently about 3 phase-III trials with a 44% chance of eventual approval (1.35 total)
So, a reasonable estimate is that out of the current crop, 4 drugs will eventually be approved. It will be very interesting to see how this plays out over the next few years.

But with two serious limitations:

First, The study above only included commercial company's drugs. it did not include drugs being researched at universities. I would assume that university research is far less likely to eventually be approved than commercial research. (There are at least two reasons for this: first, universities should be more experimental and less worried about practicle applications, and second, they don't have the resources to push treatments and commercial companies do.) Since several of the current clinical trials are university research, they are less likely to end up being approved.

Second, most of the current crop of treatments in clinical trials are not cures. Indeed, only one (Burt) has kept people free of external insulin for 4 years. That is a phase-I trial, so I think it is reasonable that we are going to need about 10 more treatments in phase-I that actually cure people (or get close) before such a cure will become generally available.

I know that many people want to spend a lot of time and resources investigating drugs that are already approved, for some other purpose, in the hopes that they will cure type-1. This study shows the dangers of such a focus, since those are the secondary indications that have the much lower success rate. It turns out that most treatments only work on one thing, so if you try to use them for something else, you chance of success goes way down. (Even if it is cheaper and quicker.)

Also, it is interesting to me that more complex treatments have higher chances of eventual approval. Biologics are more complex than drugs, but have a greater chance of approval. More complex molecules are more likely to be approved than simple ones. My guess is that because these are more expensive to develop, companies only push the very best of them. Or maybe all the simple cures have already been productized, and only the more complex ones remain.

Handouts:
If you work in the pharma industry, or if it is important to you, I strongly suggest that you look at this PDF file. It is thick with information:
http://insidebioia.files.wordpress.com/2011/02/bio-ceo-biomedtracker-bio-study-handout-final-2-15-2011.pdf
News reports:
http://news.yahoo.com/s/nm/20110214/hl_nm/us_pharmaceuticals_success;_ylt=AgsEciuYx.Hb5aUFo.oOX0gPLBIF;_ylu=X3oDMTJ2OGI2aGpzBGFzc2V0A25tLzIwMTEwMjE0L3VzX3BoYXJtYWNldXRpY2Fsc19zdWNjZXNzBHBvcwM4BHNlYwN5bl9hcnRpY2xlX3N1bW1hcnlfbGlzdARzbGsDc3VjY2Vzc3JhdGVz
http://www.bio.org/news/pressreleases/newsitem.asp?id=2011_0214_02

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

Possible Cures for Type-1 in the News (Feb)

2011-02-08T22:36:00.000-08:00

Rilonacept Starts a phase-I Clinical Trial

About six months ago, I blogged about three clinical trials which had not yet started, but were expected to start "soon". Now the Rilonacept study is actually starting.

This drug has not previously been tested on type-1 diabetes, but is already approved for other diseases (since 2008 to treat CAPS) under the name Arcalyst. It is currently in use in about 12 phase-II and phase-III clinical trials for several different inflammation based diseases, especially Gout. It is an IL-1 inhibitor, and IL-1 is known to be involved in the destruction of beta cells in people with type-1 diabetes. The hope is that this treatment will result in a longer, stronger honeymoon, and may result in long term improvements in A1c (such improvements might lead to fewer serious complications years or decades down the road). This is the third treatment targeting IL-1 that I'm following. Others include Anakinra and Canakinumab.

The study will enroll 15 patients, all of who will be treated with Rilonacept (no placebo group). To enroll you must be over 16 years old, within 5 years of diagnosis, and still producing some C-peptides (> 0.2 nmol/L) in response to food. These people will be followed for six months, involving five clinic visits, and it is hoped the trial will be complete by June 2012. The treatment is weekly injections (under the skin, like insulin). They will be looking for general safety issues, as well as effectiveness (A1c, C-peptides, and insulin dose). This is NOT a honeymoon only trial, by my definition.

This is being run out of Children's Medical Center (Dallas, Texas, USA):
Principal Investigator: Perrin C White, MD perrin.white@utsouthwestern.edu

If you are interested in participating, send Dr. White some email. Don't worry about your C-peptide production. If you meet the other criteria, they will test for that.

It is interesting to me how much the design of this clinical trial has changed in the last six months. You can compare what I'm writing now, to what I wrote back then:
http://cureresearch4type1diabetes.blogspot.com/2010/06/three-new-treatments-preparing-to-enter.html
to see the differences.

Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT00962026

Thanks very much to Dr. White for providing information about this trial.

News on the Animas Artificial Pancreas

News article on Animas's Artificial Pancreas. Obviously, I'll be a lot more interested when it actually starts a clinical trial:
http://www.bizjournals.com/philadelphia/print-edition/2011/01/21/artificial-pancreas-awaits-fda.html

Background reading on Artificial Pancreases in General

This paper is a little dry and a little dense, but it gives a good summary update of where we are, and the lead author (Hovorka) is actively involved in AP research:
http://www.touchendocrinology.com/articles/progress-closed-loop-systems-type-1-diabetes-0?page=0%2C0

Reminder About The Blog

I'm not a doctor or research professional of any kind. I can not provide medical advice, because I lack the knowledge. I don't recommend one clinical trial or another. I think that any discussion about participating in a clinical trial must be held between you and your medical team. I know not everyone has a doctor they trust, and I'm sorry about that, but I can't give you advice on which clinical trial you should be part of, or avoid.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Glucagon / Leptin type-1 "Cure" in the News

2011-01-30T16:31:00.000-08:00

This posting discusses research which has mostly been done on mice. Please remember that anything that cures type-1 diabetes in mice is always years away from general availability in people. I'm posting about this because it is making a big splash in the news, so I expect to get questions about this from friends and relations. I've already gotten questions from BBs. Here is an example of one the better news articles:
http://www.sciencedaily.com/releases/2011/01/110126161835.htm

This research is quite different from other research aimed at curing type-1.

Drs. Unger and Lee Publish a Mouse Study Explaining Why Leptin Might Cure Type-1 Diabetes (or make it asymptomatic)

History

Several months ago, these researchers published a paper showing that giving Leptin to NOD mice was in some ways better than giving them Insulin. Mice given Leptin had much better BG control than mice given Insulin, and that many mice given Leptin did not need to take Insulin at all.
Abstract: http://www.pnas.org/content/107/11/4813.abstract
Previous blog: http://cureresearch4type1diabetes.blogspot.com/2008/09/discussion-of-recent-press-reports-of.html
Related research: http://www.pnas.org/content/107/40/17391

Just recently, these researchers also started a clinical trial of Leptin, to see if people would have the same benefit seen in NOD mice, which I've covered a little bit. But I did not cover it aggressively, because it was not clear if it was a cure for type-1 diabetes, or just a better treatment:
http://cureresearch4type1diabetes.blogspot.com/2010/12/possible-cures-for-type-1-in-news-late.html
http://www.clinicaltrials.gov/ct2/show/NCT01268644

Now, they have published another mouse study, which describes why they think Leptin helps type-1 mice so much. And it is clear that they think they are on to a cure mechanism for type-1 diabetes.
Abstract: http://diabetes.diabetesjournals.org/content/60/2/391
Extract of commentary: http://diabetes.diabetesjournals.org/content/60/2/377.extract

What The Current Paper Means

This paper suggests a much different mechanism for type-1 diabetes than previously believed.
First, it suggests that mice can utilize the carbs in food without producing their own insulin. That even animals with no beta-cells to produce insulin and no injected insulin, will still live long, happy lives if they are injected with Leptin. Insulin is not the "key that lets sugars into cells" that we have been told that it is.
Second, The high blood glucose levels that are seen in type-1 diabetics who do not take insulin are actually caused by glucagon. And these researchers believe that glucagon (in type-1 diabetics) is incorrectly over generated by the body, triggered by a lack of insulin.

Obviously, this suggests that type-1 diabetes can be treated by preventing (or lowering) the generation of glucagon. In fact, from a functional point of view, it may be that preventing (or restricting) the body from making glucagon results in a "cure" where the person does not need to measure carbs, inject insulin, or suffer the long term side effects of type-1 diabetes. This could "kick off" a long discussion of what is a cure, what is not a cure, and so on. Different people have fundamentally different definitions of a cure, and this can lead to huge arguments. My definition of a cure (which is on my blog) is "functional". Others think you must stop the autoimmune attack for a real cure. I don't think it is a worthwhile argument to have now, but do remember: even in the absolute best case, this research is aimed at a functional cure.

Leptin is an example of a treatment which is known to restrict glucagon generation, but there may be others. Some research showing Leptin's impact on glucagon:
http://www.ionchannels.org/showabstract.php?pmid=19401420

As this research progresses, it will be interesting to see if Leptin used in this way effects the use of emergency glucagon injections. My guess is that it would not, there would be so much glucagon in the injection that a Leptin dose earlier in the day would make little to no impact. But testing would be needed to make sure of this.

Some General Discussion

One comment I got about this research is this: "They cured mice. So what. Happens all the time, why care about these guys." And that's true. When someone announces a mouse cure, they are usually 2 years away from the start of a human trial, and often never get even that far. But these researchers are in a different situation. They are NOT announcing a mouse cure. They announced the mouse cure a year ago. They have already started the human trial (3 out of 15 people already have started the treatment). What they are announcing now is research into the mechanism that is curing these mice.

But notice how many times I used the word "mouse" in the previous paragraph. One thing to keep in the front of your mind throughout this discussion, is that people are not mice, and mice are not people. We know that type-1 diabetes is not the same in mice as in people. We get mice cures at a rate of several per year. We get people cures at a rate of zero so far. Over 100 mouse cures have NOT worked in people. One of my serious worries about this research is that it won't work on people at all. That it is based on something in mice that is not there in people. The only way to allay that fear is human trials, and that is why I'm excited that these guys have already started such a trial.

Also, it is important to remember that there were two studies, with two types of mice. The first study, which used Leptin to cure type-1 diabetes used NOD mice. The mice in the second ("mechanism") study were not NOD mice, and did not have autoimmunity. They were given a drug that killed their beta-cells, which induces diabetes, but not the autoimmunity part. In theory, for this research, that should not matter, but I'm always nervous about researching type-1 diabetes in mice that don't have autoimmunity.

One obvious issue is that this theory assumes that insulin is NOT actually needed to get the energy from carbs. It assumes that if glucagon is removed, a type-1 diabetic will still be able to use all the energy in the carbs eaten. However, this goes against mainstream medical theory that has lasted for decades. It seems a little unlikely that no one has noticed -- even after decades of research -- that type-1 diabetics can process carbs without insulin.

Another issue is that some people have had their entire pancreases removed, and those people would not generate any insulin or glucagon. However, they do have the classic symptoms of type-1 diabetes. That doesn't fit in with this theory. (Thanks to CWD's LantusFiend for pointing this out.)

I sometimes get asked "do you think it will work" (about a lot of research, not just this research). I know that question is in the back of many people's minds. But the question is meaningless. It doesn't matter if I think it will work, for me or anyone else. It only matters if it actually works, and that means data from clinical trials. Not opinions.

How do we get from here to a cure?

I don't think we can replicate the recently announced mouse experiments in people. These experiments used specially bred "glucagon knockout" mice. These are mice which are a specific genetic defect that turns off their glucagon system. I don't think there are people like that walking around. Even if there were, we would need to find people who didn't have a glucagon system and did have type-1 diabetes. And even if such people existed, according to these researchers, their type-1 diabetes might be asymptomatic. They wouldn't even know they had it! So they couldn't be recruited for a study.

So back in reality, the only way to test this in people is to find a safe way to turn down the glucagon system of someone who already has type-1 diabetes. If this theory is right, their type-1 diabetes would become asymptomatic (or maybe they would require far less insulin than they do now). But turning off a major hormone is not something done lightly. Hormones are very important, and a little tricky: we often don't know all the functions that one hormone has. Researchers are often surprised that a hormone that they thought just did X, also does Y, or stops Z from happening. So shutting it down to help with X might cause problems in Y or Z.

So, with all that as background, these researchers know that Leptin lowers glucagon generation, so giving Leptin to type-1 diabetics is an obvious clinical trial to run, and they have already started such a trial. However, there may be other ways to limit, control, or stop glucagon generation, and it might be interesting to run other clinical trials that use other method to turn down a type-1 diabetic's glucagon system (carefully).

An obvious question is: how safe is Leptin? The current phase-I study in type-1 diabetics is not the first trial for Leptin. It has already completed some phase-I studies in people who have type-2 diabetes and in people who are over weight. However, the real question is, how safe is it when used on type-1 diabetics in the dose needed for them to get the good effects we want? And also, do any safety issues surface in the larger phase-II and phase-III studies (for any indication)? And those issues can only be resolved by going through the clinical trial process.

Finally, Amylin is a commercial company that is researching Leptin, and they are a collaborator in the clinical trial. Amylin is a big name in the treatment of type-2 diabetes, but as far as I know, they do not have a drug aimed at type-1 (so no "conflict of revenue"). They are interested in Leptin as a combination weight loss treatment. But obviously, good results in treating type-1 could open up a whole new market for them.

One Last Point

If these guys are right about glucagon and Leptin in people, and their study uses the right dose, then they are going to find out quickly. Their current study is NOT blinded, and they believe the effect is not honeymoon dependent. So even though their experiment is supposed to last until early-2013 (and may last longer), the researchers involved (and the patients involved) may know sooner.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

Possible Cures for Type-1 in the News (Jan)

2011-01-19T17:21:00.000-08:00

Polyclonal Tregs Starts a Phase-I Clinical Trail

This one is a little complex. The body's immune system includes T-regulatory cells, which help control the "killer" T-cells which (in type-1 diabetes) mistakenly attack the beta cells. Some researchers have attempted to reduce the number of "killer" T-cells, while other researchers are trying to raise the number of T-regulatory cells. This research is trying to raise the number of T-regulatory cells. The basic technique is as follows: remove some of a patient's own T-regulatory cells, which is the same processes as giving blood. Then separate and purify those T-reg cells, and grow them for about 2 weeks. You can end up with 1000 times as many as you started with. Finally, put them back into the patient. Since these cells naturally regulate (or control) the body's immune system, having more of them may result in the body stopping it's own autoimmune attack. They've had good results in NOD mice. Finally, some researchers believe that the previously seen good results in some other treatments (such as anti-CD3 and ATG) might be caused by these treatments stimulating T-reg production, rather than, or in addition to, lowering "killer" T-cell production.

This study involves 14 people, who have had type-1 diabetes for more than 3 months, but less than 2 years. It is primarily a safety trial (to make sure the procedure is safe), but has secondary measures to also see if the treatment improves type-1 diabetes (for example: higher C-peptides, lower A1Cs, etc.). It is a single site study, being done at UCSF (San Francisco, California, USA). Dr. Gitelman ("Dr. Steve", if you attend Bearskin Meadows camp) is running it.

Unfortunately, this study will not be quick. It is expected to last until 2016.

Clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT01210664
UCSF's web page: http://www.diabetes.ucsf.edu/clinical-care-education/clinical-trials/type-1-diabetes/new-onset-type-1-diabetes-age-6-45-years-wit

Canakinumab Starts a Phase-II Clinical Trial

Canakinumab is a monoclonal antibody, which is designed to lower inflammation. It was approved in 2009 (both US FDA and EU EMEA) for a collection of rare autoimmune based inflammatory diseases. Good results have been seen in people with type-2 diabetes, and it has been used in children as young as 3. Therefore, it is known safe, and can start a phase-II trial for type-1 diabetes. The trial is for 66 people who will be followed for 4 years. It is honeymoon only (100 days from diagnosis). The treatment is monthly injections for a year: 2/3 get treatment, 1/3 get placebo. My general comments on inflammation based cures apply here: http://joshualevy.pbworks.com/w/page/24444346/ConceptsAndBackground#Inflammation

This is a large trial, recruiting in many locations in the US, which are listed in the clinical trial record below. For locals: both UCSF and Stanford are participating.

Clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT00947427
Wikipedia entry: http://en.wikipedia.org/wiki/Canakinumab

Data Published from extended follow up to Diamyd Phase-II Trial

Diamyd as published some extended follow up up data from their phase-II trials, which I have not had time to review, but you can see it here:

Full Paper: http://www.springerlink.com/content/k7051252031r1671/fulltext.html
Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT00435981

Not Yet In Human Trials

There were several new types of artificial pancreas which I heard about in 2010, and this is the latest. It is called a "Bionic Pancreas" and is basically a dual-hormone (insulin and glucagon) AP, but designed as a single, custom computer chip. They hope to start human trials "this year [2011]". These guys know about the dual-hormone work being done at Harvard, and the two groups are using some of the same ideas, but pushing different parts of the technology. The Harvard guys are focused more on exact algorithms, and these guys (at Imperial Collage, in the UK) are focused more on a single chip package.

News report: http://spectrum.ieee.org/biomedical/devices/bionic-pancreas

Not Type-1 Diabetes Related

The following article describes the ethical issues of a chemist who works with brain chemicals in rats, and who's work is often used by black marketeers to create street drugs, which sometimes kill people. It is an interesting read and an interesting moral dilemma.

http://news.yahoo.com/s/ap/20110105/ap_on_sc/us_sci_haunted_scientist;_ylt=Apj8w6un3xq9J8J_t4MMSEAPLBIF;_ylu=X3oDMTJwM2I5NnNlBGFzc2V0A2FwLzIwMTEwMTA1L3VzX3NjaV9oYXVudGVkX3NjaWVudGlzdARjcG9zAzEEcG9zAzIEc2VjA3luX3RvcF9zdG9yeQRzbGsDc2NpZW50aXN0aGF1

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

Symposium on Therapeutic and Preventive Vaccines for Autoimmune Diseases

2011-01-16T21:25:00.000-08:00

I recently attended a Symposium on Therapeutic and Preventive Vaccines for Autoimmune Diseases as a guest of the JDRF. This posting contains some information that I got there, and also some thoughts and opinions that bubbled up while I was there. This is not a summary of the meeting, it's more "bits and pieces" motivated by the meeting.

But before I do that, I want to discuss the word "vaccine". When I talk to parents or people who have type-1 diabetes, and ask them what the word "vaccine" means, they always say something like "something you give to a healthy person to prevent a disease". And they wonder why anyone who already has type-1 diabetes would care about a vaccine. But in the scientific world, the term "vaccine" means something that changes how the body responds to a specific substance (called an "antigen"). As researchers use the term, a vaccine can cause the body to respond more strongly or less strongly. So from this point of view, a vaccine which causes the immune system to stop attacking it's own beta cells would be very important to cure research.

This symposium was jointly sponsored by JDRF and FastForward which is focused on finding a cure for multiple sclerosis. Both of these are autoimmune diseases (ie. diseases caused by the body's immune system mistakenly attacking a working part of the body). So the idea is to jointly research and promote cures for autoimmunity in general.

There was one piece of bad news about why companies do not invest in type-1 diabetes, and two pieces of good news about why they do:

The bad news: If you've got 50 or 100 million dollars to invest in research, are you going to spend it on type-1 diabetes, or type-2 diabetes (which has about 10 times a big a market)? You are going to spend that money to develop a type-2 drug. Bigger market.

The first good news: Curing type-1 is an "unmet need". That means there is no competition. You make more money if there is no competition, so that is motivating people to research type-1 even in the face of the larger type-2 market. If you enter the type-2 market you have lots of competition (and some of it is really cheap, so it is hard for you to charge a lot for a new drug, if an old one is cheap). However, if you enter the type-1 market, you own it.

The second good news: Type-1 is related to other autoimmune diseases (especially: rheumatoid arthritis, multiple sclerosis, and possibly lupus and others.) So that means that money you put into curing type-1 diabetes might also lead to a cure for these other diseases, and that could be very profitable. A sort of three for one deal on cures. This also motivates companies to put more money into type-1 research.

This leads into discussion of the symposium's magic word: "platform". You might think that a platform is a wooden box that you stand on. I'm a software engineer, and we use "platform" to mean a bunch of software that helps develop new software and can be used over and over again for that purpose. The pharma guys use the word in much the same way that software guys do. A pharma "platform" is a way to speed the development of multiple drugs. Everyone who is working on a drug, talks about their platform. They hope that their development can be used again and again to develop multiple different cures for different diseases. The word "platform" represents the unbridled optimism common to researchers; and the funding opportunity that every venture capitalist, pharma company, and non-profit is looking for. They haven't even started a clinical trial, and are already talking about how they will cure multiple diseases in the future. "Platform" is the pot of gold at the end of the rainbow.

To be a little more specific, two types of platforms were discussed. The first was a common collection of ingredients that you can customize to cure different diseases. Consider this bread analogy: you have a recipe for pecan bread. You try replacing the pecans with almonds, now you have almond bread. You replace them with blueberries and now you have blueberry bread. Your bread is what the pharma guys would call a "platform". You drop in one new ingredient to create a new bread. If your bread recipe is good at this sort of flexibility, then a commercial bakery would be very interested in it, as well as all the "specialty" bread recipes.

Bayhills has exactly this kind of platform: it is a ring structure of several chemicals, one of which is specific to type-1 diabetes. That drug is called BHT-3021 and is targeted at type-1 diabetes. But if you take the same basic ring, and replace the type-1 chemical with a different one aimed at multiple sclerosis, then the drug is called BHT-3009 and is aimed at MS. And so on....

Another kind of platform is a method to find drugs, which you can use again and again on different diseases. Again, to use a cooking analogy, let's say you are looking for a dinner recipe and so you grab a can of chicken soup and pour it over chicken meat and bake it. A week later you grab mushroom soup, pour it over beef and bake that. You now have a "platform" for making recipes. The platform is this: pour a can of soup over a meat and bake it. None of the ingredients are reused (as they are above), but the basic technique is reused. There were a couple of different researchers with this kind of platform at the meeting. Including Apitope and Dr. Mannie (neither in clinical trials as yet).

The second most important word at the symposium was "bio-marker". A bio-marker is a way to do an experiment for cheap. For example, lets say you have a drug and you think it cures type-1 diabetes. Running an experiment to see if it does will take years: you need to make sure type-1 doesn't come back. However, if you had some blood test that told you the person no longer had type-1, then you would not need to follow them for years. You would just need to do the blood test. That blood test would be for a "bio-marker". Something that showed you the drug had worked, but was cheaper, quicker, and easier than seeing if it had really worked. Finding a bio-marker for a disease speeds up ALL research aimed at curing that disease, and it attracts research money to that disease, since research there is less risky.

C-peptide is such a bio-marker for type-1 diabetes, but the pharma guys are always wishing that there were more. It makes research, cheaper, quicker, less risky, and less unknown. It is especially important that the government regulators agree to the use of the bio-marker. If they do, then you can get government approval that the drug is useful, based on the bio-marker: quicker, cheaper, less risky, and you know approval will be granted.

Type-1 diabetes is diagnosed in about 78 thousand people per year in the US and the EU. That is your core market for any new, honeymoon treatment. There are about 2.1 million people who have type-1 diabetes in the US and the EU, so that is your market for any new treatment. At the time of diagnosis about 10%-20% of the beta cells are still working.

Since I focus on clinical trials, for me, the most important presenters were those who had clinical trials underway:

Diamyd (makers of GAD-Alum) expects to have results from the Euopean phase-III trial "this Spring, before the Summer". This study has three branches (people who did not get Diamyd, people who got two injections and people who got four injections). It only includes people within three months of diagnosis. Their phase-II study included people from longer after diagnosis, but the results were not so good for those people, so the phase-III study cut off eligibility at 3 months post diagnosis.

There is also have a small prevention trial in Sweden: 50 kids aged 4-7 who already tested positive to 2 or more different antibodies associated with type-1 diabetes, including the GAD antibody. This study will take years, since they need to wait and see how many of the patients actually come down with type-1 diabetes. This is an example of a the type of trial that doesn't have a bio-marker to speed it along, so it takes a long time to do even a small study.

Bayhill is expecting to be ready to start their phase-II study on BHT-3021 "very soon". They expect to publish the full data from their phase-I study "later this year". They have already published interim phase-I results last Summer, and I'm trying to get a copy of that presentation. Although the FDA did not allow them to enroll children in their phase-I trial, they do expect their phase-II trial to be open to patients under 18 years old. Obviously, this make it easier to complete enrollment. It is also a general sign of safety that the FDA will let you include children in your trial.

One of the interesting things about their phase-I trial is that everyone gets treated eventually. When you enroll, half the people get the drug, and half get a placebo. Each group is then followed for a year, and the research is based on this treated vs. untreated comparison. But then, the people who previously got the placebo are given the drug. The advantage to this (I think) is easier recruitment. Because, in the end, everyone gets the drug. In classic trials, some people don't what to participate, because they are afraid that they will be in the placebo group, and go through all the work, and not get the treatment. This design ensures that: everyone gets the treatment.

Finally, ToleRx (makers of Otelixizumab) were there, but my understanding is that their drug is not antigen specific and therefore would not be considered a vaccine. In any case, I did ask, and was told, that they expected to publish results mid this year from their first phase-III trial. I know their second phase-III trial is about a year behind their first, and both need to be done before they can submit to the FDA for market approval.

Most of the research discussed at this meeting had been done on animals, not people, and I discuss some of it (not all of it), below:

I was reminded (yet again) how enticing animal research is. There were at least three or four researchers at this one symposium who had cured type-1 diabetes in NOD mice. Some of them had cured it in several different animals models, and had performed all sources of confirmatory tests to make sure the animals were permanently cured of type-1 diabetes. It would have been so easy to latch one to one of these guys as the one-true-cure that will lead us all to the promised land. Again and again I reminded myself: don't get too excited about animal cures: they are always a long time and an uncertain result away from a human cure.

The most interesting to me was Parvus. They have licensed Dr. Santamaria's research, which is based on attaching proteins to nanomolecules. He published mice research in April 2010, which made quite a splash. The Parvus guys hope to start human trials in 18-24 months. If the FDA requires them to do monkey trials before human trials, then it will be on the longer side of the time frame. If not, then closer to the shorter time. Previous news: http://www.diabetesincontrol.com/articles/did-you-know/9191-

I particularly liked this paragraph:

According to Teodora Staeva, Ph.D., JDRF Program Director of Immune Therapies, a key finding from [this research] is that only the immune cells specifically focused on aggressively destroying beta cells (or, alternatively, regulating these cells) responded to the antigen-specific nanoparticle vaccine. That means the treatment did not compromise the rest of the immune system -- a key consideration for the treatment to be safe and effective in an otherwise healthy person with Type 1 diabetes.

Another interesting piece of animal research was Dr. Daniell, who I've blogged on before:
http://cureresearch4type1diabetes.blogspot.com/search/label/Lettuce
Dr. Daniell is still looking for funding to start a human trial, and his presentation sounded like a funding pitch. Basically, he has genetically modified lettuce to contain proinsulin, and because proinsulin is wrapped in cellulose, it is not digested, but enters the system of whoever ate it. Why is this important? Because giving proinsulin to NOD mice prevents the development of type-1 diabetes. However, previous researchers have tried to slip proinsulin past the digestive system in people, but this has not succeeded in preventing or curing type-1 diabetes. (As I discuss in more detail in my previous blog entry.) I asked Dr. Daniell about this specifically, and his reply was simple. In previous proinsulin clinical trials the methods used to get the proinsulin past the digestive system were not very good, and he believes the experiments failed because they were not good enough. However, generating proinsulin, naturally wrapped in lettuce cellulose is a much better system. This proinsluiln will get past the digestive system, and therefore will be successful even in the face of the previous failures.

A third interesting research area was Dr. Mannie. He has a platform which he used to create an MS drug, which he has successfully tested in animals. He hopes to get IND paperwork (required to start a human trial) done by 2015 for that drug. So far, he has spent $700,000 on the project. He is confidant that his platform will work for type-1 diabetes as well, if someone gave him a few $100,000s for that project. So, think about this: would developing another cure for type-1 diabetes in NOD mice, be worth $500,000? Should JDRF (or anyone else) put in that money now? Or wait about 6-7 years and see what happens to the MS drug in people?

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

LCT Gets Commercial Approval In Russia!

2010-12-12T21:22:00.000-08:00

I had not planned to make another blog entry until Jan-2011, but I felt that the following news was important, so made an exception. Happy Winter Solstice everyone!

The official sound track for this blog entry is The Blur's "Song 2": Woooo-hooooo!
http://www.last.fm/music/Blur/+videos/+1-OSB3SUh3Xd8

LCT Gets Commercial Approval In Russia!

Background: LCT is developing an encapsulated pig beta cell cure for type-1 diabetes.
Called "Diabecell", it has pig beta cells encapsulated in a special coating. The coating allows blood sugar in, and insulin out, but does not allow the body's immune system to attack the beta cells. It also allows nutrients in and waste products out. This allows the beta cells to naturally grow and to react to the body's sugar by generating insulin which goes into the body's blood system. Meanwhile, the body's autoimmune attack can not target these beta cells, and you don't need to take any immunsuppression drugs (as you would for a normal beta cell transplantation). Remember that for decades, diabetics injected pig and cow insulin every day, so the fact that they are transplanting pig beta cells instead of human beta cells should not make anyone nervous. Different researchers have been working on this kind of system for decades, but LCT is the first group to get government approval for this sort of "bio-artificial" pancreas.

I completely understand that not everyone considers a bio-artificial pancreas to be a cure. Some people think it is just a good treatment: a much better treatment that we have now. I've written this blog entry from the point of view of someone who thinks that a bio-artificial pancreas that really works is a cure. If you don't believe that, just replace the word "cure" with "better treatment" in your mind as you read this.

So What Does This News Mean: My understanding is this means LCT has approval to sell their Diabecells as a commercial medical treatment in Russia. LCT already has a commercial presence in Russia, so I would expect that in the next few months we will see actual availability of the treatment there. LCT has said that they are working with two different clinics in Russia. LCT thinks that in the second half of 2011, you will be able to fly to Russia (if you don't live there already) and get this treatment.

What can LCT's Diabecell Do Right Now: In my opinion, the current performance of Diabecell does not make it a cure. They have reported on less than 16 people, and only 2 of them were insulin free for any length of time, and those two were insulin free for only a few months. But don't underestimate LCT's Diabecell just because it is not a cure right now: First, research is about doing more in the future than you are doing right now, and this may grow into a cure over time. Second, this treatment almost eliminates very low blood glucose episodes, and that is a benefit even without being a cure. For "brittle" type-1 diabetics, this might prove reason enough to get this treatment.

Discussion

Just about every one of these discussion points could be expanded to a full blog entry, all by themselves. I'm just trying to "hit the high points" here. As you read this discussion, don't forget the central point: these guys have gotten farther along the path of encapsulated beta cells as a future cure of type-1 diabetes than anyone else. They are the first people to get government approval for something that might, in the future, with some more work, cure type-1 diabetes (at least by my definition of "cure").

Edmunton Protocol vs. Diabecell
In a previous blog I compared Diabecell with Burt's immune system reboot research, but that was unfair because Diabecell works on established diabetics, while the reboot research has only been tested on honeymoon diabetics. However, a better comparison might be to compare the Edmunton protocol (for beta cell transplants) to Diabecell (for encapsulated beta cell transplants). Both work on established type-1 diabetes. Unfortunately, I don't know exactly how successful the Edmunton Protocol is, as used these days, so I can't compare it to Diabecell. But it would be a great project: a useful head to head comparison of cure rates and durations of these two transplant techniques.

My best guess is that right now, the Edmunton protocol has a much higher success rate (in terms of % of people who don't need to use insulin for some period of time) and a much longer remission rate (length of time they don't need to use insulin). However, it requires the person to take immune suppession drugs for the rest of their life. Those drugs have serious side effects, and taking them for years or decades raises the chance of problems in the future (like cancer), and Diabecell doesn't have those side effects.

But I do think that the first commercial impact that Diabecell is going to have is on the Edmunton protocol clinics. Right now, only a few diabetics get an Edmunton protocol beta cell transplant. The ones who do are often "brittle" diabetics who experience seizures and are either worried about driving, or worried about "dead-in-bed" or both. Those diabetics will now have an alternative to the Edmunton protocol, and we will see over the next few years how many of them take advantage of it.

From Here to a Cure
One obvious question is, if the current Diabecell is not a cure, can they make it into one? And if so, how long will that take? I think there are two steps needed for Diabecell to become a cure (by my definition):
First, it needs to work better. Right now, about 90% of the people who get the treatment, continue to need to use insulin. That's not a cure for me.
Second, they need their treatment to last longer. Since it requires an operation, I think it needs to last at least a couple of years. Five or ten years (or longer) would be reasonable for a cure for me.

The big unknown for me is how hard will it be to improve Diabecell in these two ways. If it is just an engineering issue, then that is great news: if they can just tinker with it and gradually improve both the success rate and the duration, that would be great. They could tinker with it for 5 to 10 years and end up with a cure. On the other hand, there might be a research issue in there that they need to solve. That would require scientific research and a breakthrough of some kind to make it more successful and last longer. Research breakthroughs are much harder to predict. You might get it in a year, or maybe never.

Getting Approval Elsewhere
Another important question is, how quickly will LCT get approval in other places like the US and the EU? I'm not an expert in government approval, and I know some of my readers know this area much better than I do. However, I don't think getting approval in Russia is going to speed up the process for getting approval in the US. I think they are still two or three large clinical trials away from US approval. Remember, in the end, only 8 people have completed clinical trials with Diabecell, and that only lasted a year. Eight or twelve more are in the middle of a second trial. But even if you stretch this to the max, it is still just 20 people for a year or two each. I'm not sure if that is enough data to even start a phase-III trial (as defined by the US FDA).

This is an important point: LCT got their approval in Russia, because the standards in Russia are much lower than the US and EU. (I'm sure the LCT guys will have a much nicer way to phrase this. And I'm sure they will be unhappy that I'm so blunt.) But, my understanding is that the research they have done to date is no where near enough to get approval in the US or EU, and they are not trying to, right now. (As I pointed out above, I'm not even sure it is enough to start a phase-III trial.) Obviously, if you believe that the US FDA and the EU EMEA over regulate and are a bunch of "nervous Nellies" that tie up promising treatments in red tape, well here is your chance to get a treatment that hasn't yet gone though all that approval process. To be a little crass: nothing bad happened in the first 20 people; your kid (or yourself) can be number 21.

The LCT press release talks about starting a pivotal study in New Zealand in 2011. (Pivotal usually means the first phase-III study, designed to provide proof of efficiency and safety. Remember that even after this study, to get US approval they will need to do a second ("confirmatory") phase-III study and get marketing approval.) So it still feels to me like they are 3-6 years away from approval in either the US or EU. Although the Russian approval was quicker than I thought it would be, so maybe these guys are just faster than I expected.

Cost and Availability
Dr. Elliot at LCT estimated a cost of AU$ 150,000 per operation to start, which is pretty close to US$ 150,000. There was no mention of exactly how soon the procedure would be started. There are issues of training, and of transporting the cells from New Zealand to Russia. At the start, there will be volume limitations, based on the size of LCT's herd of pigs. With that all said, I assume as more people get the procedure done, there will be economies of scale, and it will get cheaper. An important part of the economic calculations is how long the implanted cells will work. After all, $150k once is quite different than $150k every ten years, or every year! And we don't know how long it will last.

What's The Big Deal?
One way to look at this news is this: nothing has changed in the research. The results LCT has today are the same as the results they had yesterday. The only difference is Russian government approval. So why is this important news? I think that part of the answer involves the pace of progress in research vs. the commercial world. Things happen more quickly in the commercial world. Economic pressure and competition between companies do that. This news marks part of the transition for LCT from the world of research to the world of commerce. Not a complete, black and white conversion from one to the other, but a shifting of importance. Another part of the answer involves availability. Up until now, you could only get the treatment as part of a research study. In the future, anyone with money and desire will be able to get it. So availability will be controlled by the patients who choose to get the treatment, rather than researchers who choose to provide it. (That's over simplified a little, but you get the idea.)

Newspaper article: http://news.smh.com.au/breaking-news-national/animaltohuman-transplant-first-20101210-18sfk.html
Press release: http://www.lctglobal.com/html/blob.php/LCT%27s%20Diabecell%20Registered%20for%20Sale%20and%20Use%20in%20Russica_101210.pdf?attach=0&documentCode=2409&elementId=20084
Forum: http://islet.org/forum/messages/54131.htm
Previous blogging on LCT: http://cureresearch4type1diabetes.blogspot.com/search/label/LCT
Previous status on LCT: http://joshualevy.pbworks.com/w/page/13864073/DiabetesCureReadyForHumanTrials#DiabecellbyLivingCellTechnologies

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials
Email: To get these blog entries emailed to you join the Google Group: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

How to find a clinical Trial

2010-12-06T17:20:00.000-08:00

The decision to join a clinical trial is a personal one, which I believe is best made between the person with type-1 diabetes (or parents), and their doctor. However, I know that some type-1s don't have regular endocrinologists, and also some doctors don't tell their patients about available trials (for a number of reasons). Therefore, I've put together this blog on how to find clinical trials, so that people with type-1 diabetes, who want to, can discuss these trials with their medical team.

Non-Honeymooners: Don't think that just because you have established type-1 diabetes, there are no clinical trials worth participating in! This is not true, on two separate fronts. First, there are some trials aimed a curing established type-1 diabetes. (LCT, Exsulin, Liraglutide, Xoma 52, are examples.) Second, there are always lots of trials about better treatments for type-1 diabetics (which I do not cover in this blog) but which can improve the "standard of living" of established type-1 diabetics.

Honeymooners: Many of the studies currently underway that may lead to a cure somewhere down the line, are only recruiting "honeymoon" diabetics. Usually, people who have had type-1 diabetes for a few weeks or less. (Although this varies study to study.) So, for trials aimed at curing type-1 diabetes, honeymooners are most in demand. But the honeymoon time period is also the hardest for type-1 diabetics and their families. They are getting used to so many new things: blood checks, counting carbs, dosing, needles or pumps or both, etc. So in that way, it is a bad time to be participating in a clinical trial. This is a fundamental dichotomy that each family must work out for itself: do you want to participate in a clinical trial soon after diagnosis, or not?

Finally, please don't wait for me to publish a posting calling for volunteers for a specific clinical trial: I don't do that. I publish when a study starts, but often it is only recruiting at one or two places then. More recruiting centers often come "on line" in the weeks or months after I post. So use the web sites described below to see when a trial is recruiting near you. While I don't push specific clinical trials, I do hope that all type-1 diabetics (both newly diagnosed and long established) consider the available clinical trials. While the decision to enroll is for each person/family to make themselves, I think it would be a shame not to even consider the possibility.

How To Find Clinical Trials for Type-1 Diabetics

If you are looking for clinical trials, then JDRF already has exactly what you are looking for:
https://trials.jdrf.org/selfreg/
I'm not sure how good the coverage is internationally, but in the US, it seems quite good.

If you can not go to the link above, then go to JDRF's main page: http://www.jdrf.org/
and click "Get Involved"
and then "Participate in a Clinical Trial"
and then "Register Now"

It you need to fill out some data, like how old you are, and when you were diagnosed, and some other stuff, and then it matches you up with clinical trials in your area. Pretty sweet!

Although run by the JDRF, it returns clinical trials no matter who is funding them. You get a list of results, and the trials that are funded by JDRF have a little "JDRF" icon on them. Once you are registered, it will send you email every now and then telling you about new clinical trials in your area, for your age, and that match your profile. You configure how often you get these emails. The emails contain links to simple data pages, that tell you the basics of the clinical trial, where it is being done, the inclusion/exclusion criteria. All very nicely done.

If you want to do more searching on your own, then you can check out the following web sites:

http://www.immunetolerance.org/
The Immune Tolerance Network (ITN) is a very interesting organization, which I view as part of the "infrastructure" of diabetes research. They help researchers organize and run clinical trials aimed at stopping autoimmune attack, and similar subjects within the immune system. They cover research into type-1 diabetes, and also related autoimmune diseases. At any one time, they usually have a dozen or so studies going on, and a couple are recruiting all the time.

Because ITN runs a network of doctors who cooperate in clinical trials, their trials often recruit at many different sites all over the US (and sometimes the world), so you have more chances to enroll.   Their studies are more likely to be available near you.

About ITN: http://www.immunetolerance.org/public/about-us
Type-1 Studies Recruiting Now: http://www.immunetolerance.org/public/clinical-trials/Autoimmune+Diseases/Type+1+Diabetes+

http://www.clinicaltrials.gov
This is the official FDA registration site for clinical trials. It covers just about everything in the US, and many trials not done in the US are registered here as well. It contains a lot of information, but is a little clunky to use. I think it is more designed for research professionals, than random people looking for a trial. You can search for phrases like "type-1" and "diabetes" and limit your search to studies that are recruiting right now, and even by location where they are recruiting.   Personally, I've found the JDRF site has the same information and is much easier for a patient or parent to use. But the FDA site has more info, so if you find a trial using the JDRF site, you can look up the same trial on this site, and learn more about it.

http://www.ukdrn.org/
This is the UK's official registration site for clinical trials.

http://www.who.int/trialsearch/
This is the UN's official registration site for clinical trials.

http://www.trialspotting.com.au/trialspotting/Default.aspx
You can try this in Australia.

Finally, if you are near a major university or diabetes research center, you might want to "reach out" to them.   I know that UC San Francisco, Stanford, The Barbara Davis center at University of Denver, DRI (in Miami), University of Florida at Gainsville, the Joslin center and Harvard (both in Boston) are all doing multiple studies.

Some of the information in this blog entry comes from a "sticky" Diabetes Daily thread: http://www.diabetesdaily.com/forum/research-clinical-trials/1006-how-find-clinical-trial

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. I have no relationship with any person or company running any clinical trial or recruiting for any clinical trial.
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials
Email: To get these blog entries emailed to you join this Google Group: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Possible Cures for Type-1 in the News (late Nov)

2010-12-01T17:03:00.000-08:00

Here are various news items on possible cures for type-1 diabetes which are in human trials, and related items:

Diamyd Completes Enrollment of their Second Phase-III Trial

Since this study follows people for about 15 months, it is very reasonable to expect that it will complete in mid 2012. Since this is the second phase-III trial, if successful, market approval might come in 2013 or 2014. Diamyd is a vaccine like treatment designed to teach the body's own immune system to stop attacking it's own beta cells. The company's description is this: "Diamyd® is thought to induce tolerance to GAD, thereby intervening in the autoimmune attack and preserving the capacity to produce insulin in patients with autoimmune diabetes". Remember, the phase-III trials are only in honeymoon diabetics.

Press release: http://www.marketwatch.com/story/diamyd-medical-diamyd-completes-screening-for-us-phase-iii-study-2010-11-10?reflink=MW_news_stmp

Leptin Starts a Phase-I Clinical Trial, but as Treatment, not Cure

I have blogged in the past about Leptin:
http://cureresearch4type1diabetes.blogspot.com/2010/04/possible-cures-for-type-1-in-news-april.html
http://cureresearch4type1diabetes.blogspot.com/2008/09/discussion-of-recent-press-reports-of.html

And here is the press release for the new news:
http://www.prnewswire.com/news-releases/juvenile-diabetes-research-foundation-and-amylin-pharmaceuticals-partner-to-investigate-metreleptin-as-potential-therapy-to-improve-blood-glucose-control-in-type-1-diabetes-108399354.html

Back in 2008 Leptin was presented (in the news, at least) as a possible cure, but by April 2010 it was presented as a possible new treatment. This most recent news makes it clear that it is a possible treatment for type-1 diabetes, not a cure. I don't expect to cover this research moving forward. Remember that even as a treatment, it takes 10 years to move through the regulatory process and get approved.

Single case of Putting Type-1 into Remission for One Year
This is a single patient report (not a research study). The patient had two diseases: ITS and type-1 diabetes. To treat ITS, she was given Rituximab about 15 months after being diagnosed with type-1. The result was that her type-1 diabetes went into remission for 11 months. (No need for external insulin during that time). This is reported here: http://care.diabetesjournals.org/content/33/9/e122.full

Obviously, this is interesting. Especially since there has already completed a phase-II study on type-1 diabetics, and got good results there, too. (Although I'm embarrassed to say that I've not blogged on the specific results of that study.)

Rituximab targets the CD20 part of the immune system's B cells (different from the pancreas's beta cells) to try to prevent the autoimmune attack. B cells are part of the body's immune system and communicate with the T cells, which actually attack the body's beta cells in the pancreas. By targeting the B cells, it is hoped this treatment will stop or lower the attack of the "bad" T cells.

Comment: Most treatments aimed at stopping the autoimmune attack are very focused on stopping the "bad" T cells which directly attack the beta cells in the pancreas. This treatment (if successful) opens up a whole 'nother way to stop the attack: by targeting the immune systems communication and support system, the B cells.

I have previously blogged on Rituximab here:
http://cureresearch4type1diabetes.blogspot.com/2009/07/update-on-pescovitzs-rituximab-phase-ii.html
And reported status here:
http://joshualevy.pbworks.com/w/page/13864073/DiabetesCureReadyForHumanTrials#RituximabbyPescovitzatIndiana

Cautionary Note: Possibly Faked Phased Clinical Trial Data
This news article made me very nervous; the impact could be to many other clinical trials.
Here is the article: http://www.russia-ic.com/education_science/science/science_overview/1202/

The basic summary is this: MannKind is developing an inhaled insulin doing several clinical trials in foreign countries, using contract clinical trial companies. (These are companies that specialize in just doing clinical trials for other companies. They don't develop drugs. They do testing of other company's new drugs.) A MannKind employee claims that some of the data reported by the contract clinical trial company in Russia is obviously false. All patients had the exact same blood pressure. Since FDA relies on these studies to do approvals, this is a big deal. This one case impacts MannKind, but the general problem could effect others treatments as well. Did that contract clinical trial company do other trials for other drugs? Is the problem limited to one company, or does Russia have systematic problems that put all Russian clinical trials at risk? You get the picture: it's bad.

Omission from Previous Blog Entry
In my last blog (comparing Burt's treatment with LCT's) I did not include the fact that LCT's clinical trials were all people with established type-1 diabetes, while Burt's were all honeymooners (people with recent onset type-1 diabetes). This is a serious omission. Working on established type-1 diabetes is a huge advantage over honeymoon type-1 diabetics, and that is a strong point in LCT's favor that was not included in the comparison. I'm sorry for this omission.

General Background Information

All "Animal Models" are not Equal
This is an interesting blog entry about "animal models" used to test type-1 cures:
http://www.solvingdiabetes.org/2010/10/24/animal-models-of-autoimmune-diabetes/

General Background for Understanding Type-1 Research
This article describes the immune system in general, what is meant by "honeymoon" and other useful words and ideas, but the Teplizumab clinical trial it talks about has since been stopped. Also the phase-I/phase-II/phase-III description is for new drugs or treatment. Already approved drugs or treatments can follow a slightly different path.
http://www.jdrftalk.org/2010/09/28/diabetes-and-autoimmunity/

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

Snarski Confirms Burt's Phase-I Results

2010-11-21T15:14:00.000-08:00

First, a little background. The "Burt" clinical trial in Brazil is one of the very few clinical trials which has actually cured people of type-1 diabetes. I know that is a provocative statement, so let me be clear: Some of the people treated in this trial did not need to use external insulin (yet still had reasonable A1C numbers while eating normal diets) for a long as the study ran. Some of these people were followed for years. This was not just a "couple of week" or even a "couple of months" event.

But, there are important safety issues to consider with this treatment. Basically, the treatment is to "reboot" the immune system, hobbling the immune system, and then treating it so that when it comes back, it does not attack the body's own beta cells. There are two serious safety issues here: first, during the time the immune system is down, the patient must stay in an isolation ward in a hospital, and is subject to opportunistic infections. Second, the act of shutting down the immune system is a big deal, and might cause problems "down the road". Cancerous tumors are a particular worry. Neither of these risks is completely unknown. Very similar immune system "reboots" are used today to treat cancer, and some other autoimmune diseases and their safety is understood. Never the less, the general level of safety is lower than other possible cures for type-1 diabetes.

So, with all that as prelude:

Snarski Confirms Burt's Phase-I Results
Second trial cures type-1 diabetes, in people, for months, but at what risk?

A Polish team has run a clinical trial very similar to Burt's, and gotten very similar results. Since Burt's results are the best in terms of curing type-1 diabetes, this is good news indeed!

The results from the published paper is pretty simple: 8 patients were treated, and 7 of them did not need external insulin again, for as long as they were followed. They were followed for an average of 7 months (longest was 16 months). The one who still required external insulin used about 10% of the dose before treatment. In personal communication this group said that as of November 2010 they had treated 15 patients and that 11 of them had remained off insulin (median remission duration of 16 months).

This team used a protocol very similar to Burt's, although not identical. However, the entire discussion of safety that applies to Burt applies here as well.

Some Discussion and Opinions

Because of the safety issues, I was interested in how many people volunteered for the treatment. For this group, 19 patients were offered enrollment, and 8 accepted it. So that means that basically 40% of the people who had the chance, considered this treatment "safe enough" to try it. This was an adults only trial, so the people making the decision are making it for themselves (not for their children). I would assume that as this treatment becomes more common, the perceived safety would go up.

The researchers for this trial consider the chance of death from this treatment to be less than 1 in 100 (but are are not specific about how much below it is).

Encapsulated Beta Cells vs. Immune System Reboot: Head to Head Comparison

In terms of results in people, there are two approaches to type-1 diabetes which are head and shoulders above the others: Encapsulated Beta Cells (with LCT in the lead), and Immune System Reboot (Burt and Snarski). No one else has cured type-1 diabetics for any length of time. So here is a (slightly irreverent) head to head comparison:

Cure Rates

Encapsulated Beta Cells: less than 20% of the people go into remission for over two weeks.
Immune System Reboot: more than 80% of the people go into remission for over two weeks.

For patients that did not go into remission, they generally used less insulin (for both treatments). However, I think the drop was great for the reboot patients, but I don't have detailed data to support that.

Cure Duration
Encapsulated Beta Cells: averages less than 3 months.
Immune System Reboot: averages over 10 months.
Note: these are both very rough estimates!

Cure Safety

Encapsulated Beta Cells: Very safe: no known short term or long term side effects. Out patient surgery.
Immune System Reboot: Less than 1% chance of death (but how much less?) Also, very small additional risk of cancers years or decades after the treatment. Surgery and hospitalized recovery time, lasting many days. No serious side effects seen so far.

Experience with the Cure

Encapsulated Beta Cells: Less than 16 people, Max duration less than 2 years.
Immune System Reboot: Over 30 people, max duration over 4 years (maybe 6 years in Brazil, I need to get updated information on that trial).
(This includes some personal communication from the Snarski group.)

Snarski Abstract: http://www.nature.com/bmt/journal/vaop/ncurrent/full/bmt2010147a.html
Burt Abstract: http://www.ncbi.nlm.nih.gov/pubmed/19366777
Another Abstract: http://www.ncbi.nlm.nih.gov/pubmed/19773265

Dr. E Snarski was kind enough to send me a pre-print of his group's paper, and provide valuable information for this blog posting. Of course, all mistakes here are my own. One comment that Dr. Snarski made very specifically was that "we should not yet talk about cure - rather the word remission should be used". I used the word "cure" in some parts of this posting, but that's me.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials