Twitter Inspired Commentary from ADA2012

I don't twitter.  I just never have.  But Ellen Ullman (a huge source of information on type-1 diabetes) pointed out that many twitterers (twitteri?  what is the plural of people-who-twitter?) at the American Diabetes Association meeting had the tag #ADA2012 or #ADA12.  So by searching for those tags,  you could see what people were saying about the meeting.    That sounded interesting to me, so I looked through about 1000 tweets and found the following ones that I thought were worth commenting on.  Many of them have nothing to do with my normal topic of  clinical trials aimed at a cure, but all were interesting.  Below each tweet, I have included some commentary.

Obviously, the tweets (in green) are not my work, but the commentary (in black) is.  Also, I often saw the same tweet many times, and sometimes by different people.  So I'm sorry if I'm listing a retweet rather than an original tweet, and some tweeter is not getting the credit they deserve.   Finally, I don't know if I was viewing all tweets that had the right hash tag, or just some of them, so I'm also sorry if I completely missed some tweets I should have seen.


Here are some tweets and my comments on them:

kellyrawlings Kelly / Diabetes
Fonseca: 98% of young researchers supported by ADA have remained in diabetes rsrch. (Enhance/support careers for future breakthrus)

This is an important point.  A lot of people think of research in a linear way: more money leads to more research.  But I think research is more of a "chicken and egg" circle.  More money leads to more research, and more research leads to more researchers, and more researchers leads to more money, and the circle rolls along.

Sure, money encourages research and that means there are more people researching type-1.  But then those people write more grant requests, and if more are written, more will be approved and funded.  If more researchers are focusing on type-1, then more editors and peer reviewers will be familiar with type-1, so more papers will be published, and so on.  If more researchers are focusing on type-1, then they will need to hire more post-docs, grad students, and even undergrads, and that means more people researching type-1 in the next generation, and so on.


diatribenews diaTribe
At ADA 2012 ORIGIN results out ~ no difference in CV outcomes or cancer w/ @Sanofi_Diabetes's Lantus. Omega-3 fatty acids also neutral.

About three years ago, some research was published which suggested that use of Lantus insulin was associated with cancer in type-2 patients.  That created quite a stir.  I reviewed the research available then (from a type-1 point of view), and thought the Lantus-cancer connection was probably wrong.  If you are a member of the Brave Buddies group, you can read by previous discussion here:

http://health.groups.yahoo.com/group/bravebuddies/message/3904 

Anyway, the ORIGIN study was a huge study specifically focused on checking out if there was a Lantus / cancer link.   It found there was no link, and also no link to cardiovascular problems, either.  Several people tweeted this news.   They also looked at Omega-3 fatty acids, and found no good effect from those.

Lantus appears to be safe.  From a research point of view, I suspect the matter is closed and no one will bother starting any more research on this point.  The ORIGIN study was very large, and focused specifically at this particular question.


amdiabetesassn Amer. Diabetes Assn.
Vitamin D deficiency risk factor for diabetes, but researchers found high doses had no impact on development of diabetes.

I'll try to find the actual paper on this, but it fits with the previous research that I know about, and which I've blogged about here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Vitamin%20D
http://cureresearch4type1diabetes.blogspot.com/2010/08/cinnamon-and-vitamin-d.html


Considering  the following tweets together, as one issue:

diabetesmine DiabetesMine
There was a 23% increase in type 1 diabetes between 2001 and 2009. http://t.co/bg26kTED - AB
sixuntilme Kerri / Diabetes
V. uncomfortable discussion about the rise in T1 dx. PWD finally living to reproductive age cited as a potential "cause." !?!?!!!!
diabetesmine DiabetesMine
Rosenstock responds, D-camp to blame for type 1 epidemic because campers marry each other. Ah, so THAT explains it!

That 23% number doesn't surprise me, and I don't understand why some people do find it suprising/alarming/unexpected.  It is well known that type-1 has a large genetic component, and that up until 1920 almost all of the people who were diagnosed with type-1 died before having children.  So of course the genetic component of type-1 is growing in the population.   That's a good thing, because the alternative is dying young, which is much worse.  As people who have type-1 diabetes continue to live longer, more healthy, and more normal lives, the genes for type-1 will continue to become more common in the population.

The real question is this: is that 23% growth expected based on the genetics, or is there some environmental factor which is also causing it to go up.  That's important, because it might point to something that can be avoided, which might be a cheap and easy way to prevent type-1 diabetes.  Also, it might point to new treatments to prevent or cure type-1 diabetes.

So which is it?  We don't know.   We can't know, because we don't know the exact genetics of type-1 diabetes.  We know several genes that make it more likely, and a few that make it less likely, but we have no idea the exact genetics or the exact rate of type-1 given the genes in the population.  So anyone who says "the rate is so high that there must be an environmental factor" is just peddling fear.

The next time somebody tells you that the growth of type-1 diabetes is so high that it MUST be (at least partly) caused by an increase of an environmental factor, ask them a simple question: How much should type-1 diabetes grow, based on the the increased type-1 genes in the population?   If they can't answer the question about genetic contribution, then they can't be sure about the environmental contribution.



diabetesmine DiabetesMine
Study shows that pumpers who took more than 12 boluses a day had avg A1c of 7.3%. 7-12 boluses was 7.7%. - AB

Put another way: people who do more testing and more boluses with their pump, have A1cs that are .4 better than those who do less testing and less bolusing.  Doesn't sound surprising to me at all.  I do have two thoughts:

• Many people think that a drug is successful if it lowers A1cs by .5 (this is usually in type-2 diabetics).   However, this data suggests that anyone who is currently using they pump 6 times a day or less, can get that same improvement just by using their pump more.  Some people will think it is easier/better to just take the drug, others will want to use the pump more, while still others will want to do both.
• This also suggests to me that clinical trials that don't have a placebo group, need to show more than .5 A1c improvement to be taken seriously.  Because someone newly enrollowed in a trial may take better care of themselves than previously.  Now that someone is following them, they might be more careful to do more tests and boluses, so their A1c will naturally go down no matter what is being studied.  If there is no placebo group to compare to, we might see headlines like "Stinging nettles lower A1c by .4!" when it is really just the diabetic paying more attention that is having this effect.

kellyrawlings Kelly / Diabetes
Berg: Adherence seems best when parents remain involved in adolescent d care even while "training" child to assume responsibility

Makes sense to me.  (Although I don't like the the term "adherence".  Couldn't they say something like "care seems best" or "care is most effective".)


adamagerika Erika Gebel
Artificial pancreas keeps kids under 7 w/ T1D in target BG overnight 5.3 hours vs. 3.2 w/ usual care, less hypo too(A. Dauber)
birdwingpress Haidee Soule Merritt
I might buy a podcast of Ed Damiano's presentation on closed-loops; I find his voice very reassuring

This is good news for artificial pancreas watchers, especially since that is a large difference.  I'll try to find both of these papers paper for an update on AP work in general.


adamagerika Erika Gebel
Treatment for new onset T1D (abatacept)slows decline of beta cells, lowers A1Cs. Benefits persist 1 yr after treatment. (T. Orban)

This is right up my ally, and I'll find the paper and blog on it.  My last update on this is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Abatacept


kellyrawlings Kelly / Diabetes
Patients typicly blame selves 4 not reachng trtmnt goals and may use self-deprecatng language. Such guilt harms self problem solving

A good thing to remember.  (I feel like I'm retweeting this, but in a blog.  Is there a world for that?  Am I blogtweeting it?)


diabetesmine DiabetesMine
1 in 10 kids have DKA each year, 1 in 15 has a seizure. -

My first thought was: Wow!  that seems high, but perhaps not.  A lot of people did not like the JDRF ad about "dead in bed", and many did not like my analysis of the data they used, which is here:
http://cureresearch4type1diabetes.blogspot.com/2011/12/dead-in-bed-what-is-chance.html
but if the 1 year seizure rate is 1 in 15, then I think that supports a higher-than-we-want-to-admit "dead in bed" rate.


diabetesmine DiabetesMine
Day 2 at ADA 2012- new smaller OmniPod looks awesome! Already submitted to FDA. Can't wait -AT

I'm including this because I know there are a lot of OmniPod users out there who are waiting for this.


diabetesmine DiabetesMine
Not surprising to c up to 50% decline of CGM use in 1st months bcuz of frustrations like lags, inaccuracy, cost, too much info. MH

Sounds to be like the "early acceptors" (the people who are willing/eager to use new technology) are willing to use CGMs as they exist now, but there is a large mass of people who want something smoother and more thought out.    My guess is that we will need another generation of CGM improvements before we can entice more people into using them.   Remember, that 50% return rate, is for people who like the concept; people who think they needed or wanted a CGM, but then stopped using it when they actually had experience of how it works.  That's a high return rate, for any gizmo.


carissa94 Carissa Jones
Novanex, a new company exhibiting at ADA 2012, has developed a non-invasive glucose monitoring technique that works by measuring body temp!

Here's the company's web page: http://novanexinc.com/index2.html  and you might want to look here as well: http://novanexinc.com/products.html.

I would be interesting for someone to track how long it takes to get this approved, and what sort of testing is required.  (I don't have the time myself: it's not a cure, but I am curious about it, and I bet others are as well.)  I will say that over the years I have heard about many non-invasive BG tests, and somehow none of them have actually made it to market.


kellyrawlings Kelly / Diabetes
Change the research vocab: partners not subjects: http://t.co/xqOnFD1Z 

I agree with this completely!  My blog stopped using the term "subjects" years ago.  (At least I hope I did!)  Although I don't use "partners";  I think that goes too far.  In my mind, clinical trials are done on people;  maybe patients, but certainly not subjects.  The whole relationship between researchers and patients is changing, but that is way too big a subject to cover here.


a_sweet_life ASweetLife
ADA 2012 update - Dr. Kevan Herold (now at Yale) giving an update on teplizumab, an anti-CD3 monoclonal antibody..
catherine_price Catherine Price
Question: What dose of anti-CD3 did you use? Answer: The right dose.
related tweet:
disclosure: I'm totally biased in favor of anti-CD3 b/c I got it, and it worked.

And here I thought Teplizumab was dead as a cure for type-1, I'll have to see find out more details about what Dr. Herold said.

marimacia Mari Maciá
Esperanza“@diabeticnews: Type 1 Diabetes Stem Cell Treatment Shows Promisehttp://t.co/HxFyPooA” 

This is a confirmation of the "Burt" trial which I have blogged on before.  People went insulin free for years, but there is a real danger of death (although no one has died in the trials to date).  So far, three different groups have run similar protocols and gotten similar results, one in Brazil, one in Poland, and now these guys in China.

You can see my previous blogging on this research here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Burt

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 (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/

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

Kamada Announces Something On Their Phase-I Trial of AAT

I know the headline is vague, but the news is vague.  This is what they said:

The trial found stabilization and even improvement in diabetes measures of the patients, and a high safety profile in the 20 children and adolescents tested.

Diabetes measures in most of the patients showed stabilization and even slight improvement.

Notice that no actual numbers are provided, and not even what they were measuring!  In my experience, this is a new high-mark in terms of vagueness.   However the safety information is nice.  AAT is already approved for another use, so it has some assumption of safety.  But, that other use is a rare one, so more safety information is important.  Here is a piece of solid news, which was also included, and which I'm happy to hear:

The company expects to publish the final report on the clinical trial in late 2012.

News article: http://www.globes.co.il/serveen/globes/docview.asp?did=1000741416 

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. In addition to this trial, there are 2 or 3 other clinical trials underway testing AAT on type-1 diabetes. And this is part of a more general anti-inflammation technique to try to cure type-1 diabetes. Most researchers believe that inflammation is a result of the body's immune attack on it's own cells. That is, the underlying immune problem causes inflammation and also causes beta cells to die (which causes the symptoms of type-1 diabetes). However, some researchers believe that the underlying immune problem causes inflammation, and that this inflammation kills the beta cells, which then causes the symptoms of type-1. The difference is that, in the second model, if you stop the inflammation you can stop the symptoms of type-1 diabetes (the high BG numbers and the low C-peptide numbers). That is a big difference. But this second model is still a minority opinion.

Previous blogging on AAT: http://cureresearch4type1diabetes.blogspot.com/search/label/AAT

Diamedica Plans to Start a Human Trial of DM-199 


Diamedica has talked about starting a human trial of their DM-199 drug in the past, but I've not blogged about it, because I didn't see any activity.  However, in their most recent press release (URL below) they do say that they have submitted the IND (Investigative New Drug) paperwork.  This is the first step to starting a clinical trial.  So even though I have not seen anything on the FDA's Clinical Trials web site, I'll provide some background here.

This quote is from their web site:

DM-199 Type 1 diabetes - is a novel recombinant protein which has been found to target the three main aspects of Type 1 diabetes by increasing regulatory T cells, reducing insulitis and improving glucose control in [tissue] studies, specifically:

• Halts autoimmune attack - significant dose dependent delay in onset of diabetes in NOD mice leading to a 12x increase in C-peptide (a primary clinical endpoint) to 5-6 nM. [Delays and reduces the onset of type-1 diabetes when given during and before the honeymoon phase.]
• Proliferates beta cells - 1,277% increase in insulin producing beta cells, restoration of blood insulin to near normal levels. [Treated mice generate a lot more insulin of their own, almost as much as non-diabetic mice.]
• Improves glucose control - 291% increase in peak glucose infusion rate ... and a 1.6% improvement in HbA1C (measure of blood glucose levels) in a ZDF rat model. [ZDR rats are an animal model of type-2 diabetes. Photo below.  Obviously, A 1.6 improvement in HbA1C would be a great treatment, even if not a cure, if we can do the same in type-1.]
• Human clinical trial - proof of concept - in a Phase 2a clinical trial with first generation DM-99, glucose levels were lowered by up to 48% after a meal [I have not been able to find a description for this study, or the results, anywhere. I'm not sure if this was done on type-1 or type-2 diabetics.]

Press release: http://www.diamedica.com/news/diamedica-provides-update-dm-199-dm-204-and-appoints-mr-ed-rady-senior-consultant-licensing-par

More info on ZDR rats: http://www.criver.com/en-us/prodserv/bytype/resmodover/resmod/pages/zdfrat.aspx

Background

DM-199 is recombinant protein, a new and improved version of DM-99. DiaMedica has previously done research in animals on DM-99, and they believe that all those good results will also apply to DM-199. It looks to me that all future research will be in DM-199, but they will continue to cite older research on DM-99, to support DM-199 safety and effectiveness.

Here is a newspaper report and a press release based on good results (in animals) with DM-99:
http://diamedica.com/news/diamedica-announces-positive-final-results-type-1-diabetes-study
http://www.marketwatch.com/story/diamedica-announces-positive-final-results-in-type-1-diabetes-study-2010-10-14-114750?reflink=MW_news_stmp

And here is some literature by the company itself:
http://www.diamedica.com/sites/default/files/DiaMedica-may-hold-Holy-Grail-for-diabetes-biotuesday-Feb-6-2011.pdf

This drug is currently in phase-II trials for type-2 diabetes, but has not yet been tested in people for type-1 diabetes. The animals studies are clearly aimed at type-1 diabetes, and they claim both beta cell regeneration and lowering the autoimmune attack.


Victoza (Liraglutide) Starts Another Phase-II (but as a treatment)


Liraglutide is a GLP-1 analog which is sold under the name Victoza and is approved for use in type-2 diabetics in the USA, the EU, and elsewhere. (The most common GLP-1 analog is Byetta.) In addition, there is active research to see if this drug will help type-1 diabetics. My current option is that this research is aimed at providing a better treatment, rather than a cure for type-1. However, this posting gives a summary on the research, since there is quite a bit going on.

Here are the studies ongoing:

NCT01206101 phase-II 50 people March 2012 - Jan 2015 Novo Nordisk

NCT01536665 phase-II 42 people Feb 2012 - Sept. 2012 Novo Nordisk
NCT00993720 phase-II 30 people Oct 2009 - Oct 2010 Hvidovre University Hospital
NCT01299012 phase-I 10 people Oct 2010 - June 2011 University at Buffalo

But what do we know right now?

Here is the results section from the study:

In all fourteen patients, mean fasting and mean weekly glucose concentrations decreased significantly after one week from [an average of] 130 to 110 and from [an average of] 137.5 to 115 respectively. Glycemic excursions also improved significantly at one week. The mean S.D. of glucose concentrations decreased from 56±10 to 26±6 mg/dl (p<0.01) and the CV decreased from 39.6±10 to 22.6±7 (p<0.01). There was a concomitant fall in the basal insulin from 24.5±6 units to 16.5± 6 units (p<0.01) and of bolus insulin from 22.5±4 units to 15.5± 4 units (p<0.01).

From my point of view, the results are underwhelming.  People who already have great control (BGs of 130?  that would be great!) dropped about 20 points.  I'm not sure taking a second drug (a once a week injection) to go down 20 points is worth it.   Now, if the impact is actually 15%, that's a little different, but it's still not a big result (in my opinion).  Now the use of insulin dropped about 30%, and that is a pretty big result.

Abstract:  http://www.eje-online.org/content/early/2011/06/06/EJE-11-0330.abstract

Wikipedia: http://en.wikipedia.org/wiki/Liraglutide
News: http://medicine.buffalo.edu/news_and_events/news.host.html/content/shared/smbs/news/2012/02/dandona-ada-liraglutide-120.detail.html

Public Citizen has officially petitioned the US FDA to remove Victoza from the market.  I would love to write up a full blog on why they think it's dangerous, and why the FDA thinks it's safe, and the trade offs and assumptions involved.  It is a great "teachable moment."  But I doubt I'll have time.  For now, Victoza is on the market.

Discussion of Phases

You might notice that of the four studies going on right now, three are phase-II and one is a phase-I, but that the phase-I study actually started after one of the phase-II studies. Furthermore, Victoza was approved for use in the USA in January 2010, so at least two of the studies could have been phase-IV ("post approval studies").  So why weren't they?  I'm not sure the official answer, but my unofficial answer is simple: researchers have great leeway to call a study phase-I, II, III, or IV as they wish.  Different researchers choose different phase numbers to try to manage expectations.

Discussion of Money

One of the interesting things about this research, was the cost.  The press release from the University of Buffalo says that the ADA is putting in about $600,000 and the study will enroll about 45 people.   For comparison, Dr. Faustman's BCG trial, cost about $10,000,000 and dosed 3 people (according to the published information).   So that means that Dr. Faustman's trial cost over 200 times as much (if compared on a dosed patient by dosed patient basis).  Remember that in both cases, the drug being used was already approved for use for another disease, and in both cases, it has already been used in type-1 clinical trials.

Can Propecia / Finasteride Cause Type-1 Diabetes?

I was recently asked if Propecia / Finasteride could cause or trigger type-1 diabetes.
Propecia is a trade name for Finasteride, and is commonly used for male-pattern baldness.  It changes the way the body processes testosterone (a "male" hormone).

I had not heard of any connection between them, and searched my "usual sources" and did not find any evidence that the drug could cause, or could trigger, type-1 diabetes.  It is sometimes given at the same time that adults are often diagnosed with type-2 diabetes, but that has nothing to do with type-1 diabetes, and there is no evidence of causality or association.  Diabetes is not listed as a possible adverse effect in drug's "package insert".  And I could not find any case reports of a link, nor any research studies showing a link in people.  I didn't check in animals.

I was able to find an FDA briefing document on Finasteride given for a kind of cancer.  This dose was five times larger than the dose for hair loss, and in a very large study (20,000 people total), the levels for "Diabetes Mellitus" for both treated and placebo groups were the same (but no separation between type-1 and type-2, unfortunately).  So again: no connection.

Wikipedia: http://en.wikipedia.org/wiki/Propecia
Side Effects: http://www.drugs.com/sfx/propecia-side-effects.html

Health Blogger Could Be Jailed for Giving Health Advice While Unlicensed
Read all about it here:
http://www.theatlantic.com/technology/archive/2012/04/health-blogger-could-be-jailed-for-giving-health-advice-while-unlicensed/256288/
http://www.carolinajournal.com/exclusives/display_exclusive.html?id=8992

Note that this guy describes himself as a type-1 diabetic and so the reporter for "The Atlantic" does as well, but others refer to him as a type-2.  He was diagnosed in middle age, he was on Actos prior to dx (which suggests that his doctor thought he was type-2) and there is no mention of antibody tests.  On the other hand he had a BG of 700+ when diagnosed. Anyway, the gist of his blog is that carbs are bad and that nutritionists are wrong for suggesting that people eat more of them.  That's a whole can of worms in itself, but the reason I'm posting this is much more because of the "blogger might be charged with a misdemeanor crime" aspect of it, then exactly what the blogger is saying.


Notes on this Blog

I have two pieces of news about this blog:

First, I've got a large non-blog event happening in my life right now, so I'm expecting fewer blog postings in the next six months or so, compared to the number in the past. In the past, I often did 2-3 per month, but I'm expecting 1 or 2 per month, and maybe only 1 every two months for the next 6 months or so.

Second, I'm planning on turning off anonymous commenting on my blog in the next few weeks. If you just read email or by posts on internet forums, then this will not effect you, but if you read my blog directly (URL is at the bottom of this posting), then you will no longer be able to comment anonymously there.

I'm not making this change because I've gotten bad anonymous comments. If you look at my comments you can see anonymous ones that are good and that are bad. The same is true of the named, non-anonymous ones. I'm making this change because I have come to believe that anonymous comments are bad for the internet and bad for society (as the two merge). People who would never be vandals out in the open, might, if they think they are anonymous. So although my blog doesn't see a lot of that, I'm turning it off anyway. It is a statement that I think anonymity on the net is not a good thing. If you are not willing to put your name behind it, you shouldn't do it. Fake names are bad enough, but total anonymity is worse.

Read more at: http://doctor.ndtv.com/faq/ndtv/fid/10081/Can_the_drug_Propecia_lead_to_diabetes.html?cp

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/

Three Months of New Studies

I decided to take a look at all the studies which were reported for the first time in the FDA's Clinical Trials site between January 1st and April 1st of this year.  Registration at this site is required for all studies done on people in the US, or that will be submitted for eventual FDA drug approval, and here I"m looking at all the new ones (not updates to existing ones) for a 3 month time period.  Here is a quick summary:

51 type-1 diabetes studies started, of which:
  2 Were testing new (non-insulin) treatments for type-1
  5 Artificial Pancreas studies
  2 Studies aimed at curing/delaying type-1 during the honeymoon phase.
(none were aimed a curing established type-1 diabetes)

Obviously, I'm going to discuss these nine, and especially the last two more below, but first, I want to give a very quick summary of the other 42 studies.  The largest group (14) were testing different types of insulin (Aspart 30 or 70, Degludec, Levemir, and so on). About 5 studies were aimed at complications, about 5 had psychological targets, 2 involved new ways of giving insulin, and 2 were new BG measuring techniques, 3 involved food or diet, and so on.

If I had to select the silliest study that started in the first quarter of 2012, it would be this one: "The Effect of Guided Imagery in Children With Type 1 Diabetes Mellitus on Glucose Levels and on Glycemic Control" (NCT01567254). Unfortunately, the clinical trial record doesn't say who is funding it.

New Clinical Trial of Proinsulin Peptide on Honeymooners

Proinsulin is made by beta cells, and it is later broken down into insulin and C-peptide.  These researchers hope that giving proinsulin to type-1 diabetics in their honeymoon phase will teach the immune system not to attack itself.  This is similar to how repeated injections of peanut antigens are used over time to stop allergic reactions to peanuts.  (Note that while this trial is on honeymooners, the peanut trick works on people who have been allergic to peanuts for a long time, so it is not clear to me that this general approach is limited to honeymooners.)

There have been several clinical trials aimed at giving insulin or closely related molecules to people at risk of diabetes or in the honeymoon phase to try to train the immune system not to attack the body's own beta cells.  So far, these have not cured or prevented, but a few "rays of hope" have been seen.   So the work is continuing as researchers refine their techniques and try variants that were not tried before.  This type of treatment would likely need to be combined with a beta cell regeneration technique to result in a cure for established type-1s, and maybe for honeymooners as well.

This study will run for 3 years, and will enroll 24 people.   Two groups of eight will get proinsulin at different doses, and one group of 8 will be the placebo group.  This is double blind, placebo controlled.

This trial is being done at Cardiff, Newcastle, and London in the UK, and is part of the research done by the Diabetes Vaccine Development Centre.

Clinical Trial Record:  http://www.clinicaltrials.gov/ct2/show/NCT01536431
Patient information: http://medicine.cf.ac.uk/media/filer/2011/11/08/monopep_uhw_participant_information_sheet.pdf
Wikipedia: http://en.wikipedia.org/wiki/Proinsulin

New Clinical Trial of GABA on Honeymooners

GABA is sold as dietary supplement in the US, but this is the first trial I know of to test for type-1 diabetes in people.  It is being done by Dr. Lunsford at the University of Alabama at Birmingham.  They will measure C-peptides, A1Cs and change in insulin use over a 1 year period.  This study is double blind and placebo controled: A total of 30 people will be enrolled, 20 will get GABA and 10 will get the placebo.  To enroll,  patients must be within 12 weeks of diagnosis, although they haven't started to enroll quite yet.  The paper was filed in March, and said they planned to start in April.

Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01561508
Wikipedia: http://en.wikipedia.org/wiki/GABA

Some Discussion of GABA

One obvious question is, why does GABA work?  I'm not exactly sure.  GABA has been studied in relation to type-1 diabetes since at least 1990.  Some work suggests that it is a immunmodulator, so lowers the immune systems attack on the body's beta cells.  Other work suggests that it lowers inflammation, so if inflammation is a trigger of type-1 diabetes, then that is a mechanism for GABA be effective.  GABA and GAD are interrelated chemicals in the body, and GAD is the most common target of autoantibodies in type-1 diabetes, so there might be a mechanism there, as well.

This research provides a strong counter example to the idea that "generic drugs can't get funding for research" or "no one will work with cheap, available drugs, because there is no profit in it" or similar canards.  GABA is widely available "over the counter" (no prescription) right now.  It is not covered by a patient, and there are dozens of companies that sell it.  Yet these researchers are able to fund and run a clinical trial for it.   GABA was reported to have cured type-1 diabetes in mice in June 2011, so it looks like it will move from mice to people in a year, which is quick.  Most treatments take about 2 years to make that transition: http://t1dcuredinmice.blogspot.com/2011/06/gaba-by-prudhomme-at-st-michaels.html

Artificial Pancreas Studies Starting in Q1 of 2012

I'm still trying to find a good way organize these, since there are so many.  My current thinking is to divide them by "stage"  (based on the JDRF's six stages of AP development), and then further divide them into commercial development and academic research, and then (finally) list them by research group.  So that is how they are described below.
Background blog posting: http://cureresearch4type1diabetes.blogspot.com/2009/09/background-for-artifical-pancreas.html

Important note: I've tended to name the research groups after one researcher involved, but I'm not sure that is a good way to do it.  I'm sorry if these groups are named after the wrong person, and I know they are all partnerships, with many people working together, I just don't have a better way to name them right now.  The names below are not designed to slight the many other researchers involved in each project!

All of these studies are recruiting new participants.

Hovorka's Group in Cambridge, UK.  Stage 3 or 5. Academic Research
12 people total, runs from May 2012 to December 2012.  Open label (non-blind, no placebo).
This study is looking specifically at children 2-6 years old, and using deluded insulin to better support them, over a 2 day period.
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01557634

Group in Montreal, Canada.  Stage 4 / Stage 6.  Academic Research.
12 people total, starts in January 2012.  Open label, cross over design.
This study is using a dual-hormone AP and is comparing how well it works when the pump is told about means vs. when it needs to handle meals without being forewarned of them.
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01519102

Hovorka's Group in the UK.  Stage 3 or 5. Academic Research
20 people total, runs from August 2011 to August 2014.  Open Label.
This looks like a long term trial of an AP, lasting 18 months, rather than the 1-3 days as is common in other studies.
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01534013

Montpellier University Hospital, Montpellier, France
10 people total, runs from Feburary 2012 to March 2014. Open label.This study is testing insulin delivery which is Intraperitoneal (injected into the body) rather than just under the skin, which is normal, or into a vein, which has also been done.
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01555788

Dr Ward's group in Oregon, USA.  Stage 6 Academic Research
10 people total, runs from March 2012 to September 2012.  Open label.
Inpatient testing of dual hormone AP.  In previoius studies, these researchers used the same hardware but entered data by hand.  In this test, they are using a truly closed loop, without human intervention.
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01552603


New Treatments for Type-1

One of the studies was testing Sitagliptin as an additional (to insulin) therapy for type-1 diabetes.
This is a 30 person study which is recruiting now and is expected to finish in March 2015.  It is single blind, and is testing 3 different doses of the drug, and one placebo group.  This study is being done at the Albert Einstein College of Medicine in the Bronx, New York City, USA.
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01530178

The other was testing Liraglutide to see if it changes the glucagon response during low BG episodes.  (I'm not sure why this is important.)  This is a 42 person study which is recruiting now and is expected to finish in September 2012.  It is double blind, placebo controlled.  Three different groups which each get a different dose of Liraglutide for some time, and then placebo for some time.  This study is being done by Novo Nordisk in Graz, Austria.
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01536665
Portal to all Novo Nordisk clinical trials: http://novonordisk-trials.com/website/content/worldmap-new.aspx


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/

Encapulsated Beta Cells and Sernova

This blog contains two parts.  The first is a general update on encapsulated beta cells as a possible cure for type-1 diabetes, and the second is some background and an update specifically on Sernova corporation's work on encapsulated beta cells.

General Update on Encapsulated Beta Cells
The basic idea, is that you take working beta cells and wrap them in some kind of barrier (called "encapsulation"). It must allow nutrients and sugar to flow into the beta cells, and insulin to flow out of the beta cells, but must stop the body's immune cells from getting to the beta cells.  So it must not be a complete (impermeable) barrier, but a "smart" or partial barrier.  The beta cells generate insulin in response to blood sugar.  Because they are encapsulated, the body's own immune system can not attack them.  This means both that the body's broken autoimmune attack does not kill off these beta cells, but it also means that the body's natural attack on any transplanted organ doesn't happen either.  These are both good things.

For more background, the Dec-2011 Countdown (a JDRF Publication) has a good article on Encapsulation: http://countdown.jdrf.org/Features.aspx?id=8589934725
Obviously, it focuses on JDRF's work, but it also contains a lot of the history, complexities and past problems of using encapsulated beta cells to cure type-1.  The discussion of past problems is important.  Many people seem to assume that since encapsulation sounds like a good and simple idea, it is a good idea and simple to implement.  However, different researchers have been working on this idea for over 20 years, and a cure has not been forthcoming.  So obviously, it is not as simple as it sounds.

Below I discuss status for all the encapsulated beta cell projects that I know of.  The basic summary is that one commerical company and two academic teams are in clinical trials now:  LCT is in phase-II trials and the others are phase-I, by my standards.  Sernova hopes to start clinical trials this year, but not on encapsulation directly, and the rest are in animals trials.

Status of LCT http://www.lctglobal.com/
LCT has completed a phase-I clinical trials in Russia, and has one ongoing in New Zealand.  They have also started a third clinical trial in Argentina.  At one time, they were hoping to have commercial availability in Russia in 2011, but that did not happen.  Results in people have been mixed.  A small number of people have been cured for short periods of time, and most people see improvement in their  BG control.

Status of AZ-VUB  http://clinicaltrials.gov/ct2/show/NCT01379729
This is academic research with human beta cells.
A 10 person trial, started in 2011 ends in 2013, but then patients will be followed until 2018.

Status of Université Catholique de Louvain http://www.clinicaltrials.gov/ct2/show/NCT00790257
A 15 person trial, started in 2008 and running until 2013.

Status of Sernova http://www.sernova.com/s/Home.asp
I discuss this more below, but Sernova hopes to start phase-I clinical trials in the first half of 2012 [d1].
They have already completed large animal trials.
Recent Interview: http://aheadoftheherd.com/Newsletter/2012/Ahead-Of-The-Herd-With-Sernova.html

Status of Cerco   http://www.hanumanmedical.com/  http://www.hanumanmedicalfoundation.org/type-1-diabetes-research.html
These guys are doing large animal studies now, and hope to start human trials in 2013 [d1].

Status of ViaCyte  www.­viacyte.­com
These guys are using putting embryonic stem cells into their encapsulation, which is different than the other research teams listed here, who are mostly using pig cells.  These guys have cured mice and are doing animal safety studies now, and hope to start clinical trials in 2013 [d1].
Interview: http://www.diabetesmine.com/2012/01/whats-up-with-diabetes-stem-cell-research-firm-viacyte.html

Status of Nuvilex    Cured In Mice! Nuvilex
These guys are "cured in mice".  We'll need to see what happens in people.

Background on Sernova

Sernova has a long and interesting history, which I summarize here:

It has been known for a long time, that the body's immune system does not have complete coverage within the body.  For example, the immune system is not good at attacking viral infections in the eye (for example)[d2].  One of the things that the body's immune system does not attack is your own sperm cells (or egg cells).  If you think about it, these two cells have a different genetic makeup then your body, and they might be identified as foreign invaders and attacked by the immune system.  However, this does not happen.   For sperm cells, the body has special cells, called Sertoli cells, that  are located next to the sperm cells and prevent the immune system from attacking them. [d3]

So, long ago (about 15 years) and far away (Mexico) a transplant surgeon named Rafael A Valdes-Gonzalez decided to implant into people a mixture of Sertoli cells and beta cells from pigs.  The Sertoli cells would protect the transplanted beta cells from the body's immune system. (See [d4] for discussion on pig cells, and [d5] for discussion on ethical apprvoals.)  Dr. Valdes-Gonzalez thought he was on the track to a cure, and published some promissing results [r1], but others were not so sure [r2].  Also, the standards for exotransplantation were still being created, and no where near as well formed as now.  So there was some controversy [r3].

So, when it was time to start a larger, more carefully controlled clinical trial, to resolve the doubts about the effectiveness of the treatment, the local trial review board did not give it's approval.  They pointed out that the current standard was that animal studies (preferably large animal studies) should be done prior to human studies (to assure a basic level of safety and a reasonable chance of success).  These studies had never been done.  Dr. Valdes-Gonzalez  was a transplant surgeon who was not focused on running animal trials.  As far as I know, the Mexican project has not made a lot of forward progress since then.  However, at one time around 2004, they were "open for business" at about US $35k for the operation[r4].  I don't know what the current status is.

Obviously, a lot of people were unhappy about the lack of forward progress.  One of these people was Dr. White, a Canadian researcher.   He decided to develop the Sertoli+Beta cell treatment, starting from animal trials, and worked with Sernova corporation to do so.

Sernova is working on two related projects.  The first is a pouch system which holds transplanted cells together in one place (but does not encapsulate them, there is no barrier involved).  The second is the Sertolin(tm) system, which is designed to use Sertoli cells to prevent an immune attack on the transplated cells.

Here is a quote from their web page:

Sernova, is developing two novel closely integrated proprietary platform technologies. The first is the Cell Pouch System™, a scalable device providing a natural "organ-like" environment for therapeutic cells such as insulin producing islets for diabetics and the second is Sertolin™, a cell-based technology providing an immune-privileged environment for donor cells, reducing or eliminating the need for anti-rejection drugs.

Also, their home page includes two video presentations and a power point presentation which describe what they are trying to do.

Sernova has announced that they hope to start phase-I trials for their Cell Pouch System in the first half of 2012[d1], so that is great news.  But it is limited news.  By itself, this provides no immune barrier, so it's not even part of an eventual no-rejection drug cure.  Is just a step in that direction.  Sernova has said that they are hopeful that if the pouch is successful, it means that in the future only local immune suppressive drugs would be needed.  Because the beta cells would be limited to one specific place, immune suppressive drugs would only be needed right there, also.  Since local immune suppression is safer and has less side effects than whole body immune suppression, but there's no way to know if the difference will matter.

Extra Discussion

[d1] When I use the phrase "hope to start clinical trials in ..." that means that the company or organization has said that publicly.  It does not mean it will happen; nor does it mean that I think it will happen.  Researchers in general have a strong tenancy to think they will start human trials much sooner than they actually do.

[d2] and some researchers at DRI are experimenting with transplanting cells into the eye, specifically to take advantage of this, but no human trials as yet.

[d3] After reading this, you might ask yourself, why bother with transplanting the beta cells at all?  Why not just put Sertoli cells right next to existing beta cells, and then they would protect the beta cells from the autoimmune attack.  People are working on that:
http://t1dcuredinmice.blogspot.com/2009/10/sertoli-cells-by-fallarino-at.html
but it has not progressed to human trials, yet.

[d4] The insulin generated by pig cells does work in humans.  For decades, humans injected pig and cow insulins as standard treatment.  It is only in the last 40 years or so that we have used human insulin from genetically engineered bacteria.  Prior to that, it was all animal origin insulin.

[d5] I've read several different accounts of the ethical approvals that this research had, and what it needed.  My belief is that it did have the proper approvals from the proper authorities at the time that it started, although some have claimed that the ethical approvals were lax.

References

Here are a link to PubMed references for all of Dr. Valdes-Gonzalez's work:
http://www.ncbi.nlm.nih.gov/pubmed?term=%22Valdes-Gonzalez%20R%22%5BAuthor%5D

[r1] The good results:
Three year follow up: http://axacell.com/uploaded/Publication%20Three%20-yers%20May%202007.pdf
Four year follow up:  http://www.eje.org/content/153/3/419.full.pdf+html
Long term follow up: http://www.ncbi.nlm.nih.gov/pubmed/20964645

[r2] I doubt this is a complete list of the doubters:
http://www.eje.org/content/154/6/917.full

[r3] This is not a complete list on the controversy, but enough to get you started:
http://www.ualberta.ca/~dcl3/Ref_2007-Aug-17/islet%20transplantation/islet_xenotransplantation_are+we+ready+for+clinical+trials.pdf
http://www.nature.com/nature/journal/v419/n6902/full/419005b.html
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)09285-1/fulltext
http://www.lancet.com/journals/lancet/article/PIIS0140-6736(02)09287-5/fulltext

[r4] http://eprints.qut.edu.au/3449/1/3449.pdf

Finally.....

I found this on the JDRF's "For Scientists" web site about encapsulation in general:
http://www.jdrf.org/files/General_Files/For_Scientists/MS2011/FY12_Encapsulation_Consortium_RFA_11.16.11.pdf


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.
My Blog: http://cureresearch4type1diabetes.blogspot.com
Mouse blog: http://t1dcuredinmice.blogspot.com/

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/