Talking With Dr. Faustman

A few weeks ago I was able to meet Dr. Denise Faustman in person. We had previously exchanged emails, but this was our first face to face meeting. She was in town (together with Russel, her business development guy) to give a presentation on her research to interested parents. A local family was hosting her presentation, including providing wonderful food and wine for a large number of families to come and hear her. A member of brave buddies worked with the host who was kind enough to invite me. The Initial plan was for me to just attend. However, they realized that I would have different questions than the other people at the talk, and her answers to my questions would not be of interest to the others. Therefore, they suggested that I come early, and we have a conversation ahead of the regular talk. This sounded like a great idea to me. I asked Dave Forer, another Brave Buddy, to attend as well. Dave is a statistician who has worked on clinical trials for 20 years (although not for type-1 diabetes), so he brought a lot to the table [d1]. (Throughout this posting, marks like [d1] refer to extra discussion at the end of the post.)

This posting is made up of two parts:
    1. A status update on Dr. Faustman's BCG research.
    2. Some thoughts on speaking directly with Dr. Faustman.

Dr. Faustman is a famous and controversial figure in type-1 research.  You can read more about her research in my previous blog postings:
http://cureresearch4type1diabetes.blogspot.com/2008/10/faustmans-research-part-1-history.html 

http://cureresearch4type1diabetes.blogspot.com/2011/08/dr-faustmans-phase-i-results.html 

but the bottom line is that in November of 2007 she started a 7 month phase-I clinical trial with BCG which she hoped would cure type-1 diabetes, or at least be part of the cure.  Data from that study has not been published.  

Status Update and New Information

• The paper with the results from phase-I has been submitted for publication, but has not been accepted for publication, as yet.  So no peer-reviewed results (or detailed results of any kind) on the results of her phase-I clinical trial of BCG have been published.  Nothing has changed there.
• Dr. Faustman is no longer making public the poster that she had presented at the ADA conference last June 2011.  This poster was the most detailed information available on the phase-I clinical trial (including important C-peptide data [d2]) so making it unavailable is a serious step backwards. 
• Because it was still being designed, Dr. Faustman would not share with me any details of the planned phase-II clinical trial.  (One of her slides said it would include 60 people, but she made it very clear that was a goal, but could change for any number of reasons.) 

So my overall summary of movement in the last 8 months is: no visible forward progress, and an important step backward.

Talking to Dr. Faustman

My strongest impression of Dr. Faustman is that she comes across in person just like her advocates come across on the net.  She is incredibly optimistic about her research, and extremely driven to move it forward.  She is very passionate about it, and that passion comes through everywhere and all the time. She has explanations and reasons for all the delays in her research, all the results that don't quite add up, all the previous failures with BCG, and so on.

However, there is a big difference between talking with Dr. Faustman's advocates on the web, and talking with her in person.  When an advocate says something that doesn't mesh with what I know about research, I just assume that person is confused.   However, when Dr. Faustman herself says things like that, the effect for me is much more jarring.

The most important example of this is her answer to the question: why were only three people dosed with BCG in the phase-I trial?  Read [d3] for discussion of why this is a critical question.  Her answer was that the FDA would not allow more people to be dosed.  Because of it's importance we spent quite a while discussing this, and she was very consistent that the 3 person trial size was because of the FDA.

However, I've followed dozens of trials aimed at curing type-1 diabetes during this time, and every one of those other trials had more than three people.  Some of them involved new drugs, and others involved drugs with known side effects much worse than BCG's side effects.   Additionally, I researched all the trials using BCG.  There are dozens of those as well, and (again) every one of them uses more than 3 people.  Some of those trials involved far larger doses than Dr. Faustman is giving. [d4]

So I am supposed to believe that the FDA went to Dr. Faustman and said something like this:  Lots of other people are studying drugs to cure type-1 diabetes.  Some of these drugs have never been used for anything before, and we allow all of these groups to test more than 3 people in their trials.   Also, lots of other groups are studying BCG specifically for other diseases, sometimes in much higher doses than you are using, and we also allow all those groups to test more than 3 people.  However, Dr. Faustman, for you and you alone, we are limiting your phase-I trial to 3 people.

Except I don't believe that.  Having Dr. Faustman tell me that the FDA limited her phase-I trial to 3 people created a real credibility gap for me.

There were a total of three issues where things that Dr. Faustman said were not consistent with what I know about research from other sources.  Another example was the question: why won't you make the poster public, which you previously showed at the ADA poster session 8 months ago?  At first the answer was: ADA won't let me.  Neither Dave nor I had ever heard of such a restriction before.  The poster was made public at the conference, what possible reason would they have to restrict it later?   It's completely unbelievable to me.  Dave also expressed his doubts about this explanation [d6], and when he did, the rationale shifted.   There were ADA restrictions, but also the authors of the poster had a meeting and decided jointly not to present the poster data publicly any more.  So then the question was why?  Several reasons were given, all quickly: maybe the data had been misinterpreted by others, maybe they were afraid it would be misinterpreted, maybe they were afraid people would start using BCG off label, maybe the research was limited.  But again, in all the dozens of research projects that I've followed, the researchers are always making more data available, not less data [d7].

Because her paper with phase-I results had been submitted for publication, but had not been accepted, we could not talk about any of the data in it.

I also tried to find out why her phase-I trial took so long.  When the phase-I study started in Nov-2007, it was supposed to end in July-2008.  It actually ended in late 2010 or early 2011.  So a 9 month trial actually took about 36 (or a few more) months.  I asked specifically about why they stopped recruiting patients for an 8 month period.  Read [d8] for more discussion on why this was important.  However, that discussion led nowhere, because Dr. Faustman said she did not know about the recruiting gap, and did not want to comment on any of the information in the FDA's clinical trials record.

The result of all this is a lot of frustration for me.  I ask about data which should be available.  I get reasons why the data is not available.  I ask about different data, I get different reasons why it is not available.  At the end of the evening I have a large number of reasons [d9] why there is no data, but still there is no data; just requests for funding and support.

After our discussion, I listened to her presentation to the other parents.  It was pretty standard stuff about the history of her research including results from her NOD mouse work, and one slide from her human blood work.  But for me, one of the striking parts of the evening, was left out of the presentation:  There was no information on what had happened to people who had gotten BCG in her phase-I trial!  She's trying to raise money for a phase-II trial, without showing the results from her phase-I trial.  And we know the phase-I study has been completed and analysed many months ago, because abstracts were presented at the ADA meeting 8 months ago.

Summary

My wife read a draft of this post, and turned to me, and said:  "It sounds like she didn't have any new data and you were frustrated."   It's a great summary.

I was hoping that speaking directly to Dr. Faustman would give me some understanding on why her phase-I study took so long, was so small, why the results still have not been published, and why she was collecting money for a phase-II study before publication of her phase-I results.  All of these actions can be viewed as signs of possible research failure in her phase-I trial.  However, none of my questions were answered in a way which allayed my worries.

Thanks!

I want to particularly thank the members of Brave Buddies who went out of their way and put a lot of work into making this meeting possible.  I'd also like to thank Dave, who drove a long way, and contributed a lot of knowledge and expertise to the discussion.

Extra Discussion and References


Note that in a couple of cases below, I've quoted Dave from email that he sent me.  He gave permission for each quote and reviewed this posting.  (All mistakes are my own.)

[d1] The company that Dave works for is a small one, and does not do research, sell, or develop any products for the type-1 diabetes market.

[d2] C-peptides were a secondary outcome of the study.  However, they are what the FDA uses to evaluate potential cures for type-1 diabetes, which is why I describe them as an important outcome of the study.  The most important outcome, however, is the primary outcome: the measurement of autoantibodies.  That data is still a complete mystery.

[d3] 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 strong 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. This study is the smallest phase-I clinical trial that I have ever seen in all my coverage of type-1 diabetes research.

[d4] For comparison, phase-I trials of already approved drugs (similar to BCG) include: Anakinra which dosed 15, Etanercept dosed 18, AAT dosed 15, etc. So a 3 person study really stands out as being much smaller than the others. 


[d6] In later email, Dave repeated that point: "any poster presented at a scientific meeting is henceforth 'public' and should be disseminated on request. This is a basic convention of science in America and in clinical trials."

[d7] Not showing us the data from the poster did not sit well with Dave, either.  Days later he sent me these two quotes: 

If she had commercial interest in the drug, there would be more of an argument for confidentiality of the results. But she is very vocal at saying that she wants this drug to be available to all. Therefore she should feel free to show any and all data.

Also, she says that the treatment approach she is pursuing here is one for which the rest of the experts in the field are bearish [negative] on. In all history of science, if a scientist is in disagreement with the rest of their peers, it has always been the case that they show their data to any and all who would spend their time looking at it. They need to convince the rest that they are correct and should jump on any chance they get to show they’re data. That’s science! [emphasis in original]

[d8] Obviously, long delays in a research project are a bad sign.  Research is fundamentally uncertain, and while  it is common for trials to last a little longer than expected, it is very rare for a type-1 diabetes trial to last more than twice as long as expected, and this trial lasted more than four times as long as expected.  The only objective information available to the public on this trial is the clinical trial record, and the record shows that there was an 8 month time period when they officially stopped recruiting patients for the trial, and then started again afterwards.   This is very unusual for the type-1 trials that I follow.  Only one other study had something similar to this, and it was such a big deal, that they issued a press release to announce it.  So asking Dr. Faustman directly about this 8 month hiatus seemed like a good idea.


[d9] I'm deliberately not using the term "excuses" here, because of the negative connotations.  But when you are sitting across the table, and asking for data that was publicly shown 8 months ago, and you get this song-and-dance about why it's not available now.  Boy, does it sound like an excuse.

The Clinical Trials record, complete with a history of every change made to it, can be seen here:
http://www.clinicaltrials.gov/ct2/show/NCT00607230

Scott King's blog on this research which describes what he saw on the poster: 
http://www.hanumanmedicalfoundation.org/blog/2011/07/04/highlights-of-ada-scientific-sessions-i-bgc-trial/

Dr. Faustman's ADA abstract from 2011 is no longer available at the conference web site, but you can see the body here:  http://forums.childrenwithdiabetes.com/showpost.php?p=740311&postcount=2

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/

More Information on Zhao's Stem Cell Educator

Zhao's Stem Cell Educator phase-I trial, which I blogged about here:
http://cureresearch4type1diabetes.blogspot.com/2012/01/zhao-et-al-tianhe-publish-successful.html
has generated a lot of interest, so I've done some extra research on it, and this blog contains what I've learned.

Good News First

The best news that I gathered about this work, is that the published paper is not the final report on a 15 person clinical trial.  Is is the initial report on the first 15 people treated in a clinical trial which is on-going and continuing to enroll more people.  This is great news, for two reasons.  First, because it means that they are continuing to follow those 15 people.  With a little luck we can look forward to follow up reports describing what happens to these people in another year, two more years, and so on. Also (again, with some luck) we can expect reports on 50 people, 80 people, maybe even more people.  All this data is already being gathered as part of the current clinical trial.

The next good news is that the researchers very much want to start a clinical trial in the US.  That will take some time, due to regulatory approvals.   If they do start a trial in the US, it is likely to be similar to the one in China [d1].

Several people have asked me how this treatment works, and this is how it was explained to me:
First, there are proteins which train the body's immune system not to attack itself [d2].  These proteins are found on stem cells, so exposing immune system cells to the stem cells has the effect of training the immune cells not to self attack.  Second, these researchers believe that there are cells in the pancreas which are ready to become beta cells[d3], and also that there are stem cells circulating in the blood stream [d4] which can turn into beta cells.  They don't know which of these two routes are creating the new beta cells, but they believe some combination of them is creating enough beta cells to cause the large decrease in injected insulin and increase in C-peptide.

One question that I had was basically this: "Do you really think that the body can regrow so many beta cells that it can generate 25 to 38% of it's own insulin in just a few weeks?  No one else has seen anything like that when using other techniques to stop the autoimmune attack."  The answer was that was exactly what they thought was happening.  First, it was the theory that explained the results the best, and second, it was what they saw in their animal studies, so they were not surprised to see it in people.  We can only hope this is correct.  Future trials will tell.

I did ask if there was anything special about stem cells from the umbilical cord, which made that particular type of stem cell important to the research.  The response was no.  They expected that many types of stem cells would work, but they choose to use umbilical cord cells because they were convenient to use and  easy to get, as compared to other types of stem cells.

The researchers have professional connections to researchers in Amman, Jordan and Hue, Viet Nam, and that is why they might start clinical trials in those places.  Because there will be fewer regulatory hurdles, those studies could start more quickly than the one in the USA.  My feeling was that if they did studies in those place, the studies would be similar to the Chinese one, but they would try to improve ("optimize") the procedure.

Finally, I want to say that I have heard from several different sources (all private communications) that the researchers are in touch JDRF to discuss the funding of future studies.   They may well be in contact with other organizations, I hope that they are, but I've gotten specific information about JDRF.

Not-So-Good News Second

It does not look like this is the kind of treatment that the FDA is likely to allow under the "surgical exception" that I discussed in the previous discussion of this research.  So therefore, it is likely that a full FDA approval cycle will be needed, so about 4 clinical trials (and I'm not sure if this first one would count [d1]).

I do not think that any of the patients were ever free of injected insulin.  So I don't think they cured anyone, even temporarily.  On the other hand, I got the feeling everyone was helped to some degree.  In some research, there are some people where it just doesn't work.  Those people are sometimes called 'non-responders" and I think there were few to none "non-responders" in this trial.

More Reading

The research below was all done in mice so I have not read it in detail, but it is listed, for people who want a lot more details.

http://www.omicsonline.org/2161-1025/2161-1025-1-104e.pdf (2011)
http://www.sciencedirect.com/science/article/pii/S1568997210001795 (Cord Blood Background 2010)
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0004226 (Mice Cure 2009)
http://www.springerlink.com/content/0640621007560k70/ (2009?)
http://www.sciencedirect.com/science/article/pii/S0006291X07012715 (Beta Cells from Blood 2007)
http://www.sciencedirect.com/science/article/pii/S0165247806002379  (2007)
http://www.sciencedirect.com/science/article/pii/S0014482706001558 (Why Stem Cells 2006)

Discussion and References

[d1] Unfortunately, the FDA doesn't give much weight to data from foreign trials, so things learned in other countries need to be relearned in the US, so the FDA will fully consider it.  I'm quite worried that even once the study starts in the US, they might be limited to a very small phase-I study, because the FDA will not consider the Chinese study as proof of safety, even it if involves more people than an American phase-I study.

One of the researchers involved told me a story -- equal parts funny and shocking -- about trying to get approval for a medical device that had been tested in Australia.   The FDA would not accept data from Australia.   They wanted studies re-done in the US, so they could review that data, as though Australia was some corruption ridden, third world country, without a quality regulatory system!

[d2] Although I'm not sure exactly which proteins they are referring to, the general idea that a protein could re-educate the immune system is not controversial.  Drugs like DiaPep277 and other antigen specific treatments are based on this idea.   Haller's work in Florida is based on similar ideas, although his effectiveness was no where near what Zhao and crew see.

[d3] Although this idea was controversial a few years ago, I think that consensus is shifting.  There is now some research that shows that stem cells already in the pancreas may be able to grow into beta cells.  Even stronger was a paper published last year (sorry don't have the reference handy) which showed very specifically that in mice, alpha cells in the pancreas could turn into beta cells that produced insulin in response to sugar. Plus there is the Joslin "Medalist" study (more than one) and  Dr. Faustman's paper just published last week which adds support to this same idea.

[d4] This was based on their own previous work in mice.  But I know that other researchers have been looking into this area.  Although the research in mice is not conclusive, there is some supporting evidence for this, in addition to the Zhao group.


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 (Feburary-2012)

Diamyd Publishes Their GAD Failure in Phase-III

Diamyd published a full, peer reviewed article on their phase-III clinical trial.  I don't think there is any new information there, but there are a lot of details to read.  However, I do think there are two lessons to be learned here.  One relates to spin.  Take a look at these headlines:

No Improvement in C-Peptide Levels With GAD-Alum‎
Autoantigen Tx Benefits Some Type 1 Diabetics
Type 1 Diabetes Treatment Disappoints in Trial‎
GAD-alum Antigen Therapy Fails to Halt Progression of Type 1 Diabetes‎ 

They are all actual headlines on different web sites for this same news.  That second one gives the news a different spin, than the rest. In this case, most of the headlines are accurate, but if you happen to see that one "outlier" headline, you will get a very different view of the results.

The second relates to timing.  The timeline for these results are as follows:

May 2011: Diamyd announces that the phase-III trial had failed it's primary end point (press release)
June 2011: Data on this failure presented at ADA 71 (non-peer reviewed scientific presentation)
Feb 2012: Publication in the New England Journal of Medicine (top-flight, peer reviewed publication)

The take home point for me, is that this study went from completion to publication in about 10 months.  Furthermore, this study was (a) very large, (b) negative, and (c) published in one of the most important peer viewed medical publications in North America.  All of these factors would usually make the publication slower.  So I think it is a particularly bad sign when trials are completed but have not published in a year or two or more!

Press Release: http://www.marketwatch.com/story/diamyd-medicals-phase-iii-study-published-in-the-new-england-journal-of-medicine-2012-02-02

Gardasil Vaccine does not Trigger Type-1 Diabetes

Obviously, this is not cure research, but I know some people continue to be nervous about vaccinations, and the Gardasil vaccine is given during the time when type-1 diabetes is often diagnosed, so this study should provide a lot of confidence that the two are not related.

Basically, a large health maintenance company (which runs both insurance and hospitals) compared their records for people who got Gardasil and people who were diagnosed with type-1 diabetes within 6 months. These records were then double checked "by hand" and compared to similar people who did not get the vaccine.  They looked for many different autoimmune diseases, including type-1 diabetes, and were able to cover a huge number of patient records (about 190,000).  This was a huge study, so it could generate good data even for relatively rare diseases like type-1.

I don't believe that any one study can prove something with absolute certainty, but I do think that this is very well done study, and should carry a lot of weight.

News Coverage: http://medicalxpress.com/news/2012-01-gardasil-trigger-autoimmune-conditions-vaccination.html

Personal note: I was reading something about Gardasil, and found a great quote by a cancer researcher.  I didn't save it, so this is a paraphrase from memory:  "For decades, people have been clamoring for a vaccine to prevent cancer.  We finally developed one, but some people don't like it, because it has something to do with sex!"

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 (January-2012).

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)

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)

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/