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

This blog posting contains two different new items, with a short note on each:

The One That Got Away

The first article covers some work in Multiple Sclerosis (another autoimmune disease):
https://www.painnewsnetwork.org/stories/2019/1/16/experimental-stem-cell-therapy-reverses-ms-in-some-patients
The article reports on a promising phase-II study on an incurable disease.

The reason I'm discussing it here, is because this researcher was involved in very similar clinical trials on people with type-1 diabetes, many years ago.  Those trials were the most successful ever done.  People did not use injected insulin for years.  You can read my previous blogging here:
https://cureresearch4type1diabetes.blogspot.com/2010/11/snarski-confirms-burts-phase-i-results.html
or more generally here:
https://cureresearch4type1diabetes.blogspot.com/search/label/Burt

But years ago, this researcher switched from Type-1 Diabetes to Multiple Sclerosis.  Why?  Because of safety trade offs.  One researcher told me that the T1D version of this treatment would likely have an expected death rate of 1%.  In actual studies (on people!) the death rate was about 1 in 65.  For a disease like Type-1, that is not acceptable.  But for a disease like Multiple Sclerosis (which can lead to death after 10-30 years, and which often has a much bigger quality-of-life impact), maybe it is acceptable.

So, while I'm sad that the type-1 world will not benefit from this research (at least not in the short term), I am happy that our disease is not so dire that a treatment like this is viable.

Phase-II T-Rex Trial Reports Unsuccessful Primary Results

On a completely different note, the T-Rex Trial reported its primary end point.  For background,
you can read my previous blogging about this research here:
https://cureresearch4type1diabetes.blogspot.com/search/label/Polyclonal%20Tregs

A quick summary of this treatment is as follows: remove one specific type of T regulator cell (called "CD4(+)CD25(+)CD127(lo)") from a person with type-1 diabetes.  Grow them out so you have about 500 times more, and then put them back in the same person.  Since regulatory T cells naturally regulate the body's immune system, and the patient now has more of them, the hope is that they will prevent the autoimmune attack which causes type-1 diabetes.

In February, the T-Rex trial reported its primary end point results at 1 year, and they were unsuccessful.  The exact quote was:

no improvement in the primary endpoint of preservation of C-peptide levels vs. placebo at 1 year was observed at the group level (using the standard mixed meal tolerance test)

Of course, the company is hopeful that they can find some good news by reanalyzing the data, looking at subgroups, etc.  but I'm very dubious about this.  In the type-1 diabetes research that I follow, I have yet to see this kind of reanalysis yield a success after the primary analysis was unsuccessful.  The trial is scheduled to collect data for two years, so there should be another update in about a year.

This information all comes from a corporate press release.  There was no mention of a research paper.

Press Release: https://www.caladrius.com/press-release/caladrius-biosciences-reports-top-line-data-for-the-phase-2a-sanford-project-t-rex-trial-of-clbs03-for-recent-onset-type-1-diabetes/
News coverage: http://www.evaluate.com/vantage/articles/interviews/caladrius-refuses-give-tregs-diabetes

Joshua Levy
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com 
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF, JDCA, or Bigfoot Biomedical news, views, policies or opinions. In my day job, I work in software for Bigfoot Biomedical. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Phase-II Results from Rebooting The Immune System To Cure Type-1

First, a discussion about naming.  In the past, I've referred to this treatment as the "Burt" treatment, because that was the senior (last listed) author of the first paper I saw on it, and because I didn't have a better name for it.  I haven't seen Dr. Burt's name on clinical trial for this treatment in many years, so it's no longer an appropriate name.  But I don't have a better name.  In any case, you can read my previous blogging about this treatment under the label "Burt" on my blog:
http://cureresearch4type1diabetes.blogspot.com/search/label/Burt

Second, a little background. The original clinical trial of this treatment, in Brazil, was one of the very few clinical trials which 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 as long as the study ran. Some of these people were followed for years. This was not just a "couple of weeks" or even a "couple of months" event.

Third, some important safety issues. 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, which can cause death. 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 level of risk is higher than other possible cures for type-1 diabetes.

The Studies

This paper is not reporting on the results of one study.  Rather, it was reporting on a pool of patients enrolled at three different sites, one in Poland and two in China.  There were a total of 65 people included (24 in Poland, and 13 and 28 in China).  All studies enrolled people as young as 12, while the Polish study limited recruitment to the first 6 weeks after diagnosis, the Chinese studies accepted people for a year after diagnosis, but these are all honeymoon diabetics.  There were a few other differences in experimental procedures, as well.

The Results

The following points are all quotes from the abstract:

• A total of 59% of individuals with T1D achieved insulin independence within the first 6 months
• 32% remained insulin independent at the last time point of their follow-up
• All treated subjects showed a decrease in HbA1c levels and an increase in C-peptide levels compared with pretreatment.

The authors' summary of their own results (also quoted from the abstract) is:

1. That remission of T1D is possible by combining [bone marrow stem cells] transplantation and immunosuppression; 
2. That [their procedure] represents an effective treatment for selected individuals with T1D; and,
3. That safer ... therapeutic options [based on bone marrow stem cells] are required.

And I think that's an excellent summary.

Here are some other points that I'd like to make:

• Of the 65 people reported on, one died of sepsis; obviously, this is the worst adverse effect possible.
• 34 people experienced adverse effects (65 events in total).  There was no published data on severity of these events.   As an example, the most common adverse event was fever, but there are no notes on how serious or threatening the fever was.  Alopecia was the second most common adverse effect.
• The earlier in the honeymoon period that a person was treated, the more successful the treatment.

Discussion

There are lots of interesting discussion points in here, and I don't have time or space to go into all of them, but here are a couple:

The researchers believe that a specific type of immune cell, called a CD34+, is critical to success of this technique. Remember that the immune system has many different types of cells, which are often named based on proteins on their outside coating which have these "CD" numbers.  CD34+ is not a cell I have seen specifically "called out" in previous research done in people.  However CD34+ cells are found in umbilical cord blood, which has been used in human research, as well as in bone marrow (as in this trial).

The researchers did measure the long term health of the immune system after treatment, and their summary was "Immune system recovery was rapid and complete".  So they found no evidence of long term weakness in the immune system after this treatment.

What is the future direction of this work?  The researchers discuss two paths for future development of a safer cure based on this work.  The first path is to improve the treatment, by using less immunosuppression at the start, and stronger drugs to prevent infections during treatment.  There are many different immunosuppressive drugs in use, and it may be that a safer drug (or drug combination) can be used in the future.  Similarly, there are many drugs designed to prevent infection by bacteria, viruses, etc.  and it may be that there is a better combination of these drugs available. The second path, is to make the treatment more effective, possibly by increasing the number of CD34+ cells infused back into the patient.

Is this treatment a cure?  That depends on your view of safety.  With a death rate of 1 in 65, I think few people would consider this a cure.  However, if you assume that someone with type-1 diabetes lives (on average) 5 years less than someone without, then in an actuarial (purely mathematical) sense, this treatment does extend average life. This is comparing shaving a few years off of many people's lives vs. cutting a few lives very short.  While this might be a mathematically viable comparison, I don't think it's how most people really think, and certainly not in making decisions about their children.  But of course, research is fueled by hope for the future: what it will grow into, not limited to what it is right now.

Previous Blogging: http://cureresearch4type1diabetes.blogspot.com/search/label/Burt

Abstract: http://diabetes.diabetesjournals.org/content/63/9/3041?etoc

I want to thank the authors of the paper, who provided me with a copy so that I could blog on it.
Normally, this paper is behind a pay wall.

Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com 
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

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

News About Diabetes News

The biggest diabetes research meeting in the world is the American Diabetes Assoication (ADA) Science Sessions, which are in June (this year: June 8-12).  It is followed by the big European Association for the Study of Diabetes (EASD) Annual Meeting (this year: Oct 1-5).  So expect a lot of news over the next few months.  We are already seeing press releases from companies publicizing what they will report at these large meetings.

Phase-II Results from Autologous Hematopoietic Stem Cell Transplants by Li at Nanjing University

This is the third group to do a Burt-like cure for type-1 diabetes, and get similar results.
You can read my previous blogging here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Burt

But the basic summary is this: for recently diagnosed type-1 diabetics, this is the closest to a cure there is.  People have gone years after this treatment without needing to inject insulin.  This result has been reproduced in both Poland and China, after originally being done in Brazil.  The down side?  Safety.  This treatment requires a full immune reboot.  Very approximately: They kill off your old immune system, and you regrow a new one, so for a few days (or a few weeks) you are very susceptible to infections and you stay in a special isolation ward in a hospital.  As far as I know, no one has died, but the risk is there.  Plus, there are long term risks.

From the abstract:

After [treatment], 11 of 13 patients required significantly reduced doses of insulin for adequate glycemic control, accompanied by reduced levels of glycosylated hemoglobin but increased C-peptide concentrations. Three patients achieved exogenous insulin independence for 7-54 months. [Meaning one person was functionally cured for 4 1/2 years.]

Abstract: http://www.ncbi.nlm.nih.gov/pubmed/22419704
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01341899

Alefacept Finishes Enrolling a phase-II Clinical Trial

This study is also called "T1DAL", which I'm sure is pronounced "tidal".  This trial is being run by the Immune Tolerance Network, and they finished enrolling people in the trial on 30-April-2012.


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.


Why is finishing enrollment important? For two reasons.  First, because it is now possible to predict when they will finish collecting data.  (This study collects data for 2 years, so they should have it done by May-2014.)  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 recruite people, and how long it will take.   But at this point, all that uncertainty is behind the researchers.  From now on, it is just gather data, then analize data, and then publish data.  Researchers have a lot more control over those later stages, then over recruiting people in the first place.


Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT00965458


Company X Gets Orphan Drug Status for Drug Y

I often see headlines like the one above.  The most recent was "Andromeda Announces FDA Orphan Drug Designation for DiaPep277". I don't report that as news in this blog, because I don't consider it scientific progress.  Orphan Drug is a designation used by the USA and the EU.  Companies with such drugs have the legal right to sell them for a longer period of time without competition.  The idea is that the drugs target rare conditions, and companies could not profitably develop them, if they only got the benefit of "normal" legal protection, because the market would be too small.  So, if the condition is rare enough, then the government says it is an orphan drug, and then the company gets a longer period of time before others can manufacture the drug.  Now, type-1 diabetes is a very common disease (over 1 million people in the US alone, by most estimates).  So a type-1 diabetes drug would not qualify as orphan.  But drugs that only work in the honeymoon phase can get orphan drug status, because only a couple of tens of thousands people are in the honeymoon phase in the US at any time.  I'm not sure that was a result the people who originally wrote the law would have approved, but that is how the law has been implemented.

But in any case: this is good news for the company, because it mean bigger revenues (or longer revenues) if the drug is successful.  But it does not say anything about the chances of success for the drug.  It says more about the disease being treated, than the drug with the status.

Wikipedia: http://en.wikipedia.org/wiki/Orphan_drug

Omni Announces Some Phase-I Results for AAT

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. This treatment is based on the idea that treating inflammation can cure/prevent/treat type-1 diabetes.

There are several trials currently underway with AAT.    Omni recently announced some information about the first 12 people treated as part of their trial.  This trial is continuing to enroll more people.  This is a intermediate report of progress.  I'm hoping there will be more information published at ADA or EASD, but this is from their press release.  Note that they are reporting on 12 patients (all treated, no untreated comparison group), and that 7 of the patients were in their honeymoon phase, and 5 were not.

The treatment has been very safe and well tolerated by all the study subjects. 

Six months following the initial screening four of the seven [honeymoon] patients showed increased C-peptide levels, whereas most Type 1 diabetics progressively lose their ability to produce endogenous insulin, and, therefore, demonstrate progressively decreasing levels of C-peptide. 

Three of the seven [honeymoon] patients displayed decreased dependence on insulin during the 3-6 month period following the start of their eight week AAT therapy.

My interpretations (opinions) of the results:

• They don't provide any numbers:  no c-peptide numbers and no insulin number.  I've come to believe this is a bad sign.  I hope they publish this data soon.
• For established type-1 diabetics, it looks like AAT had no positive effect at all, in this small sample. 
• For honeymoon type-1 diabetics, Omni is trying to be optimistic, and it does look like the treated group did better in some ways than average untreated people.  However, the reporting is vague, no numbers are provided, few patients were treated, and things are naturally unsettled in the honeymoon phase, that it is very hard to see the data described so far as a successful result.  So I would not get excited about AAT yet. 

Press Release: http://www.omnibiopharma.com/_literature_136822/Omni_Bio_Diabetes_Trial_Data_-_May_30,_2012

A Personal Note

Several months ago my wife and I started looking for a new house.  That takes a lot of time, and actually buying one, even more so.  I'm happy to say that we were successful, and are in the middle of moving from one Silicon Valley town to another.  That is why I have not had the time to publish any blogs for a while.  It now looks like I will move into the new house in mid-June  (wooo-hooo!).  I hope to return to my normal blogging sometime in late July or August.

I know there are more things going on in the world of research aimed at curing type-1 diabetes than I have included in this blog, and I'm sorry it will take a while to get through the backlog.  I'm sure there will be a land side of new information from the upcoming scientific conferences, as well.

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/

Background on Four Types of Stem Cell Research

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 (late April)

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:

1. Haller's CSGF+ATG studies are trying a similar treatment, but without the most dangerous drug.
2. Snarski is replicating the Brazilian trial, and getting similar results (and no serious side effects so far).
3. 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.
4. 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

Snarski Confirms Burt's Phase-I Results

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

Update on Gitelman's ATG Phase-II Clinical Trial

Dr. Gitelman at UCSF has started a Phase-II human trial aimed at using ATG to cure (or lessen) type-1 diabetes. The goal of this study is to preserve remaining beta cells for people within 100 days from diagnosis. This study started in August 2007, and is expected to run until June 2011. So far it has enrolled 11 out of an expected 66 patients. It's a four day treatment (in hospital), and 12 follow up visits over a 2 year period. They are recruiting at a total of 9 sites (growing to 13), which are listed in the clinical trial page linked below.

Here is a quick summary of how they hope ATG (Thymoglobulin) will work:

Type 1 diabetes is caused by destruction of insulin-producing beta cells by T cells, part of the immune system. Thymoglobulin is a mixture of different antibodies that target T cells. This mixture includes the anti-CD3 antibody (and anti-CD3 treatments are in Phase-III trials already, having completed successful Phase-I and II trials). The researchers hope that this multi-faceted approach will be even more successful and have a longer lasting effect than with anti-CD3 alone, and may treat diabetes by several mechanisms. First, it lowers the number of T cells, so there are fewer to attack the beta cells. It also seems to alter the T cells remaining behind, rendering them less likely to be destructive. Following this depletion, the T cells that grow back in the following weeks may be reset and have a healthier balance (meaning that a special type of T cells, called regulatory T cells, will help keep the destructive T cells in check).

Using ATG to cure type-1 diabetes is an idea that flows from two sources. The first source is a line of clinical trials aimed directly at curing type-1 with ATG. Eisenbarth's work of long ago, a Phase-I trial done in Europe, etc. But it also has another source, which is Burt's Brazilian research as described below.

Discussion: How to Follow Up Burt?

One of the questions that I'm occasionally asked is this: when will there be a follow up to Burt's Brazilian research? When will there be a Burt, phase-II? This is a natural question, because Burt has -- by far -- the best results of any one. Many patients on that trial went years without using external insulin. No other study comes close. So an obvious question is: how do you move forward with that research.

Burt's research is the opposite of most. Most researchers use the smallest possible doses during phase-I. Phase-I is targeted at safety, so they use small doses to assure safety even at the expense of effectiveness. So for most studies, for phase-II studies, they move forward by raising the dose to try to make a safe treatment a more effective one. But Burt's research is the opposite. The effectiveness is the strongest yet, but there are real questions about safety. So you would NOT follow it up by raising the doses!

One way to follow up Burt's relative success, is by turning down the dose. Trade off a little effectiveness for added safety. Oversimplified a little: Burt's research involves using three drugs (ATG, GCSF, and cyclophosphamide), and reinjecting the patient's own precursor bone marrow cells (previously removed). Dosing with just ATG can be viewed as a "kinder, gentler" Burt. Especially since the cyclophosphamide is the most risky drug of the bunch. (I'll be posting on two GCSF clinical trials in the coming weeks.)

Since I'm a software engineer, I'll use a software analogy: Burt is doing a "hard reboot", Gitelman is trying for a "soft reboot".

Notes

One of the complexities of following the research, is that ATG is referred to by many different names by different groups. For example: Thymoglobulin, rATG, hATG, ATGAM, antithymocyte globulin, etc.

The cells that Burt is removing and then reinjecting are sometimes called "precursor bone marrow cells" and other times "adult stem cells".

The lead investigator for this clinical trial is Dr. Gitelman at UCSF. For those of you at Bearskin Meadows: yes, this is the same "Dr. Steve" who is often up there. I'm indebted to Dr. Gitelman for his insights into Burt's research and how it relates to other research, including his own. All mistakes, opinions, and oversimplifications are my own.

Patient oriented information on this trial:
http://www.type1diabetestrial.org

Previous Blog postings on this
http://cureresearch4type1diabetes.blogspot.com/search/label/ATG (blog on ATG)
http://cureresearch4type1diabetes.blogspot.com/search/label/Burt (blog on Burt)
http://cureresearch4type1diabetes.blogspot.com/search/label/Gitelman (blog on Gitelman)

Web pages (but these need updating):
http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials#ThymoglobulinalsoknownasATGbyGitelman (Gitelman)
http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials#ATGandothersbyBurtatUniversityofSaoPaulo (Burt)

Clinical Trial records for this study:
http://www.clinicaltrials.gov/ct2/show/NCT00515099 (Phase-II ATG)
http://www.clinicaltrials.gov/ct2/show/NCT00190502 (Phase-I ATG)
http://www.clinicaltrials.gov/ct/show/NCT00315133 (Burt)

Joshua Levy

Best News of 2008 in Clinical Trials to Cure Type-1 Diabetes

Here is my list of Best News of 2008 in Clinical Trials to Cure Type-1 Diabetes. I've based this list on these simple rules:

1. The best news is a cure, or a measurable improvement in BG, A1C, or insulin used.
2. The bigger the drop (in BG, A1C, or insulin used) and the more people helped, the better.
3. Results for non-honeymoon diabetics are better than the same results for honeymooners.
4. Results from later phase trials are better than results from earlier phase trials.

So with that in mind, here are five "best news" and a few special mentions. Note that I have not parked one "best" another "second best" etc. They are all really good news in different ways:

The "Big 5"

LCT finishes a phase-I trial, and shows some results
This news had it all: shows improvements for type-1 diabetics, works for people who have had diabetes for a long time, and marks the end of a clinical trial, with data we can see. Insulin usage dropped 24%, and almost everyone's A1C number went down. One person was cured (used no insulin at all) for a period of months.
Hope for next year: The start of a bigger trial and to see longer term data from this trial. Publication in a peer reviewed journal would be nice, too!

More data here: http://cureresearch4type1diabetes.blogspot.com/search/label/LCT
and here: http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#LivingCellTechnologiesDiabecell

Burt Publishes 3+ year follow up data for their phase-I trials
This is the most amazing results seen yet: more than half of the patients where completely and permanently cured (low BG, A1C, and no more insulin needed). Some for over 3 years! Safety concerns linger, and it was honeymoon only.
Hope for next year: Start a phase-II trial for this, or better understand the safety issues.

More data is here: http://cureresearch4type1diabetes.blogspot.com/search/label/Burt
and here: http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#UniversityofSaoPauloBurt

Diamyd starts two large phase-III trials
These guys are the closest to mass marketing a type-1 cure for some people. Their treatment shows improvements (lower BG, A1C and insulin usage) for many people, and might cure some people. It has only been tested on honeymooners, but once it is approved for general use, anyone will be able to try it. Their phase-II trails suggested that Diamyd use doubled the amount of surviving insulin producing beta cells. This means they require less insulin, and are very likely to have far fewer complicatoins in later life.
Hope for next year: See some intermediate results from this phase-III trial, or test it on non-honeymooners, or both!

More data is here: http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#DiamydDiamydTorGAD65
and here: http://diamyd.blogspot.com/

ToleRx starts a phase-III trial
These guys are also making steady progress on a treatment that may cure some people and improve the health of many more. It has been shown to lower BG, A1C, and insulin requirements, but has only been tested on honeymooners. People treated in phase-II trails required significantly less insulin even after 18 months, compared with untreated people. (Although they did not have a big milestone this year, MicroGenics is testing a similar CD3 based cure, and is only a half step behind ToleRx.)
Hope for next year: Maybe finish this phase-III trial, or test it on non-honeymooners, or both!

More data is here: http://cureresearch4type1diabetes.blogspot.com/search/label/tolerx
and here: http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#TolerrxTRX4orChAglyCD3

Gitelman and Osiris both started phase-II trails.
These are different immunology based cures, which are both at very similar point in their development. They are both being tested on honeymoon diabetics. Gitelman's research is based on previous phase-I research aimed a curing type-1 diabetes. The Osiris treatment has been tested in the past on several other immunological diseases, but this is the first time it has been tested as a cure for type-1 diabetes.
Hope for next year: probably nothing, but in 2010 good results from both!

More data is here: http://cureresearch4type1diabetes.blogspot.com/search/label/Gitelman http://cureresearch4type1diabetes.blogspot.com/search/label/Osiris
and here: http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#NIAID/ITNGitelmanThymoglobulin/ATG http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#OsirisTherapeuticsPROCHYMAL

More Generally

While the above paragraphs describe some specific research milestones of 2008, there are also more general good news out there. For example, I've been covering human trials aimed at curing type-1 diabetes for several years now, and every year I do it, there are more and more trials to keep track of. This year, for example, is the first year that there has been more than 1 phase-III clinical trial active. There were three of them at the end of the year. Will they all pan out? Probably not, but more trials means a bigger chance of one success. And we only need one success.

I'm also very intrigued by the new findings this year, about the importance of inflammation as a possible causative factor in type-1 diabetes. Although none of this research has yet led to clinical trials, it is clearly something new and different. As it is only a year old as a research direction, there is still lots of time for it to grow into something useful. Watch these guys:
http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#HarvardKoulmandaandStromAAT

Burt's Brazilian Research

I've gotten a couple of questions about Burt's research, which is being done in Brazil. Below is my update on this research, together with some thoughts on it.

What is he trying to do, and what is the current status of the Research?

The basic plan is a two pronged attack [r1]: First, drugs are given to shut down (or almost shut down) the immune system. Second, the patient is given drugs to stimulate adult stem cells, which are then removed from his or her blood, treated, and reinjected into the patient. [d1]

In some ways, this research is similar to Trucco's [r7] and also Gitelman's [r6].
Gitelman is using ATG in his research, and that is one of the drugs used in Burt's research as well.

What is the good news?

The good news, is that it works. Burt's results -- in term of curing people for months and even years at a time -- are amazing. Much better than any other research that I know of. More than half of the people treated stopped requiring insulin for the entire time they were followed: a period of months, in some cases years! The rest of the people (except one) required much less insulin after the treatment than before it. That's huge, and no other treatment has come close.

To be specific, one year after treatment, of the 15 patients treated, only two were using injected insulin at the end of the first year after treatment, and 11 of the patients had never (or almost never) had to use injected insulin after the treatment [r8]. The [r1] reference also contains A1C data for these patients, which is also very good.

In a later follow up [r5] the results were also good. Out of 21 patients (and excluding one who had DKA), 13 patients were permanently free of insulin for as long as the study followed them. Some of these people were followed for more than 3 years!. 6 more patients were insulin free for some months after treatment. Just eye-balling that data, it looks to me like those 6 were insulin free for about 66% of the months after treatment. Only 2 patients from the 21 treated were never insulin free.

What is the bad news?

The bad news, is that it might be dangerous; even deadly. This treatment is quite complex. High doses of immunosuppressive drugs are given, and then different drugs are given to create stem cells, and then those are treated with other drugs. Finally, another bunch of drugs are given to lessen the severity of various side effects of the primary drugs. So there is a lot going on. In particular, the immunosuppressive drugs have serious short term and long term side effects. Some of the patients in the clinical trials were hit by some bad short term side effects of these drugs (although nothing permanent). There are also long term dangers of these drugs. In some cases, drugs in this class raise your chance of getting rare cancers even years after they were used.

Now, all of the drugs given as part of this study are approved for human use (for other treatments), but they are also well known to have dangerous side effects. In many cases, these drugs are approved to treat deadly cancers where the general tolerance for side effects, and even the chance of death is much higher than for a child with type-1 diabetes. My biggest single problem in getting excited about this research, that I don't know exactly how dangerous these drugs are, in the doses given here.

An interesting digression on "honeymoon" only clinical trials.

This study is a classic "honeymoon only" clinical trial. Only people who had been diagnosed for less than six weeks were admitted into the study. On the other hand, if a person's body can regenerate new insulin producing beta cells (as many researchers now believe), then this cure could work on established diabetics, too. Burt and his team believe that giving the immunospressive drugs early (when the body still has some working beta-cells) is important. However, if the body naturally regenerates these cells, it may turn out not to matter so much.

Some discussion of stem cell research issues.

This work uses stem cells, and it is being done in Brazil, even though it is based on research done in the US. This has led some people to jump to the conclusion that it uses embryonic stem cells, and was forced out of the US by right wing Christian objections to embryonic stem cells. However, I do not think this is what happened to this particular research. Not only are these guys using adult stem cells, they're using the patient's own stem cells. So only the most wacko religious loony is going to object to that.

On the other hand, there are other ethical issues involved in this research, which you can read about [r2,r3]. Basically, they involve using children in the initial clinical trial. There is no doubt that this trial followed all the proper legal and ethical rules for Brazil; but doing phase-I research on children when the drugs given are known to have serious side effects does raise ethical issues.

If I had more time....

If I had more time, I would certainly spend some of it researching the safety profiles of the various drugs used in this research. After all, if the drugs are safe, then this research is showing the highest cure rate of anything out there. Conversely, if the drugs are dangerous, then they will need to do a lot of research to find safer alternatives or lower doses, before I will personally be interested in this treatment.

Another project, if I had more time, would be to create a simple table comparing the most recent results of different clinical trials. For each trial include data points like: % drop in insulin use (average and standard deviation), % drop in A1C, % chance that a patient will go a month without using insulin, % chance that a patient will go a year without using insulin, etc.

If I had a spare 10 million (US$) lying around....

If I had a spare 10 million to spend, I would try duplicating this research on non-honeymoon diabetics, and I'd do it in the US. After all, since these would be people who had type-1 for years, so it could be done on adults, and so it could be done in the US.

A few random thoughts.

One interesting complexity in this research, is that it failed on the first person it was tried on. That person had DKA. After that, people who had DKA were excluded from the study, and everyone had much better results. Almost all diabetics, at some point, get DKA for some period of time. So if this is to become a widespread treatment for type-1, then the role of DKA will need to be better understood.

This sort of treatment might already be a competitor of islet cell transplant therapies. After all, those people must be on immunosuppressives for their whole lives (although at low dose). It might turn out that Burt's short term, high does treatment is overall safer than the long term, low dose that they get now.

Extra Notes and References

[d1] this is the exact quote, which I have a hard time translating into English. If anyone knows more specifically what it means, here it is, from [r1]:

Hematopoietic stem cells were mobilized with cyclophosphamide (2.0 g/m²) and granulocyte colony-stimulating factor (10 µg/kg per day) and then collected from peripheral blood by leukapheresis and cryopreserved. The cells were injected intravenously after conditioning with cyclophosphamide (200 mg/kg) and rabbit antithymocyte globulin (4.5 mg/kg).

[r1] Abstract of the JAMA article published in 2007
http://jama.ama-assn.org/cgi/content/full/297/14/1568
http://jama.ama-assn.org/cgi/content/abstract/297/14/1568

[r2] http://jama.ama-assn.org/cgi/content/extract/298/3/285

[r3] http://jama.ama-assn.org/cgi/content/extract/298/3/285-a

[r4] Some results and discussion:
http://66.102.1.104/scholar?hl=en&lr=&q=cache:0B8eccFzyUUJ:www.scielo.br/scielo.php%3Fpid%3DS1516-84842008000600014%26script%3Dsci_abstract%26tlng%3Den+burt+diabetes+brazil

[r5] A different report:
http://www.scielo.br/pdf/rbhh/v30s2/14.pdf

[r6] Gitelmans work is described here, on my web page:
http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#NIAID/ITNGitelmanThymoglobulin/ATG

[r7] Trucco's work is described here, on my web page:
http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#Children%E2%80%99sHospitalofPittsburghTrucco

[r8] See the graphs here:
http://jama.ama-assn.org/cgi/content/full/297/14/1568/JPC70002F1