Friday, October 6, 2017

JDRF Funding for a Cure 2017

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

Let me give you the punch line up front: 63% of the treatments currently in human trials have been funded by JDRF. (And the number is 81% for the later phase trials.) This is a strong impact; one that any non-profit should be proud of. This summary does not include Artificial Pancreas research or stem cell growth trials, because there are so many of those that it would be hard to include them all.

Below is a list of all the potential cures, grouped by phase of trial that they are currently in, and separated into potential cures that JDRF has funded, and those that JDRF has never funded.

This list is a list of treatments, and many of these are being tested in more than one clinical trial.  For example, the "ATG and autotransplant" treatment is actually running three trials, but since they are all testing the same treatment, it is only one item in the list. The list below uses the following marks to show the nature of the treatments:
    (Established) One or more trials are open to people who have had type-1 diabetes for over a year.
    (Presymptomatics) One more more trials are open to people who have 2 or more autoantibodies, but have not yet started showing symptoms of type-1 diabetes.
    (Prevention) This treatment is aimed at preventing type-1 diabetes, not curing it.

Also remember that I give an organization credit for funding a treatment if they funded it at any point in development; I don't limit it to the current trial. For example, JDRF is not funding the current trials for AAT, but they did fund earlier research into it, which helped it grow into human trials. I also include indirect funding of various kinds. For example, the JDRF funds nPOD,  ITN, and several other organizations, so I include research done by these other groups as well.

Starting Last Year: Phase-II? Trials
Starting last year, I divided Phase-II trials into two groups.  Phase-II trials are "classic" phase-II trials; they are done after a successful Phase-I trial in type-1 diabetes.  What I call Phase-II? trials are done with treatments which are known safe, so they don't need Phase-I trials, but have never been tested on type-1 diabetes before.  These Phase-II? trials might be Phase-II from the point of view of safety, but they are Phase-I in terms of effectiveness, so I'm putting them in their own category.

Cures in Phase-III Human Trials
Summary: currently there is only one treatment in a phase-III clinical trial, and that is aimed at prevention.  It is funded by JDRF.  While I see the benefit of prevention, this is the sixth year in a row there have been no phase-III trials aimed at curing existing type-1 diabetes, and it's not a good thing. Even worse, I don't see a phase-III study starting even next year.  Some people might be discouraged by that, but for me, it's a reason to donate.  Money is the thing that is going to move the Phase-II studies listed below into Phase-III studies, and the Phase-I studies to Phase-II, create more Phase-I studies, and so on.
  • Oral Insulin (Preventative) 
Cures in Phase-II Human Trials
Summary: there are 22 trials in phase-II, and 17 of them have been funded by JDRF, while 5 have not. Here are the treatments that have been funded by JDRF:
  • AAT (Alpha-1 Antitrypsin) by Grifols Therapeutics and also Kamada 
  • ATG and GCSF by Haller at University of Florida (Established) 
  • Abatacept by Orban at Joslin Diabetes Center 
  • Abatacept by Skyler at University of Miami (Prevention) 
  • Aldesleukin (Proleukin) at Addenbrooke’s Hospital, Cambridge, UK 
  • Diabecell by Living Cell Technologies (Established) 
  • Diamyd, Ibuprofen ("Advil"), and Vitamin D by Ludvigsson at Linköping University
  • Diamyd, Etanercep, and Vitamin D  by Ludvigsson at Linköping University
  • Diamyd and Vitamin D by Larsson at Lund University (Prevention)
  • Gleevec by Gitelman at UCSF 
  • Gluten Free Diet: Three Studies  (Preventative)
  • Polyclonal Tregs by both Trzonkowski and Gitelman  
  • Stem Cell Educator by Zhao (Established) 
  • Teplizumab (AbATE study team) 
  • Teplizumab by Herold/Skyler/Rafkin (Prevention)
  • Tocilizumab by Greenbaum/Buckner at Benaroya Research Institute 
  • Umbilical Cord Blood Infusion by Haller at University of Florida 
  • Ustekinumab by University of British Columbia
  • Verapamil by Shalev/Ovalle at University of Alabama at Birmingham
Not funded by JDRF:
  • ATG and autotransplant by Burt, and also Snarski, and also Li 
  • BCG by Faustman at MGH (Established) 
  • Dual Stem Cell by Tan at Fuzhou General Hospital 
  • Stem Cells of Arabia (Established)
  • Vitamin D by Stephens at Nationwide Children's Hospital (Prevention)
Cures in Phase-II? Human Trials
Summary: there are 8 trials in phase-II, and 2 of them has been funded by JDRF, while 7 have not. Here are the treatments that have been funded by JDRF:
  • Rituximab by Pescovitz at Indiana University
  • Intranasal Insulin by Harrison at Melbourne Health (Prevention)
Not funded by JDRF:
  • Albiglutide by GlaxoSmithKline
  • Golimumab by Janssen
  • Ladarixin by  Emanuele Bosi of Dompé Farmaceutici
  • Liraglutid (Presymptomatics)
  • NNC0114-0006 and Liraglutide by Novo-Norsk
  • Rapamycin Vildagliptin Combo by IRCCS (Established)
Cures in Phase-I Human Trials
Summary: there are 24 trials in phase-I, and 15 of them are funded by JDRF, while 9 are not. Here is the list funded by JDRF:
  • Alefacept by TrialNet 
  • ßAir by Beta-O2's at Uppsala University Hospital in Sweden (Established) 
  • TOL-3021 by Bayhill Therapeutics (Established) 
  • CGSF by Haller at University of Florida 
  • Trucco at Children’s Hospital of Pitt / Dendritic Cells (DV-0100) by DiaVacs (Established) 
  • Exsulin and Ustekinumab by Rosenberg at Jewish General Hospital, Canada (Established) 
  • IBC-VS01 by Orban at Joslin Diabetes Center  
  • Metformin by Littleford at The University of Exeter (Prevention)
  • MultiPepT1De (Multi Peptide Vaccine) by Powrie at King’s College London
  • Nasal insulin by Harrison at Melbourne Health (Prevention)
  • Smart Insulin (MK-2640) by Merck (Established) 
  • Tauroursodeoxycholic Acid (TUDCA) by Goland at Columbia University
  • Polyclonal Tregs by both Trzonkowski and Gitelman 
  • Pro insulin peptide by Dayan at Cardiff University 
  • VC-01 by Viacyte (Established)
Not funded by JDRF:
  • CGSF and autotransplant by Esmatjes at Hospital Clinic of Barcelona (Established) 
  • Encapsulated Islets at University clinical Hospital Saint-Luc (Established) 
  • Gluten Free Diet by Carlsson at Lund University
  • Mesenchymal Stromal Cell by Carlsson at Uppsala University
  • Microvesicles (MVs) and Exosomes by Nassar at Sahel Teaching Hospital 
  • Monolayer Cellular Device (Established) 
  • Rilonacept by White at University of Texas 
  • Substance P by Vanilloid Genetics at Hospital for Sick Children Toronto (Established)
  • The Sydney Project, Encapsulated Stem Cells (Established) 
    Summary of all Trials
    55 in total
    35 funded by JDRF
    So 63% of the human trials currently underway are funded (either directly or indirectly) by JDRF. Everyone who donates to JDRF should be proud of this huge impact; and everyone who works for JDRF or volunteers for it, should be doubly proud.

    Just Looking at Trials on Established Type-1 Diabetics
    17 of these treatments (31%) are being tested on established type-1 diabetics.
    Of these, 8 are funded by JDRF
    So 47% of the trials recruiting established type-1 diabetics are funded by JDRF.

    Compared to Last Year
    In 2016 there were 42 treatments in clinical trials, in 2017 there are 55 (growth of 31%)
    In 2016 there were no treatments in Phase-III trials, in 2017 there is one.
    In 2016 there were 22 treatments in Phase-II and Phase-II? trials, in 2017 there are 30 (growth of 36%).
    In 2016 there were 20 treatments in Phase-I trials, in 2017 there are 24 (growth of 20%).

    A Little Discussion

    Although the growth of 31% looks really good, I'm a little worried that that high growth number is because of a mistake on my part.  In previous years, I would review the research and remove everything that had failed or was going nowhere for too long.  However, this year, I was hit by some extra work at my real job, and so did not have time to check the older research to see if it was still active.  My guess is that some of the research still listed here really should be removed, and I'll do that over the next few months.  Still, I do think there was growth this year, just not 31% growth.

    How I Count Trials for This Comparison
    • I give an organization credit for funding a cure if it funded that cure at any point in it's development cycle. 
    • I mark the start of a research trial when the researchers start recruiting patients (and if there is any uncertainty, when the first patient is dosed). Some researchers talk about starting a trial when they submit the paper work, which is usually months earlier. 
    • If there are different clinical trials aimed at proving effectiveness as a cure and as a preventative, or effectiveness in honeymooners and established diabetics, then those are counted separately. 
    • For trials which use combinations of two or more different treatments, I give funding credit, if the organization in the past funded any component of a combination treatment, or if they are funding the current combined treatment. Also, I list experiments separately if they use at least one different drug. 
    • The ITN (Immune Tolerance Network) has JDRF as a major funder, so I count ITN as indirect JDRF funding. 
    • I have made no attempt to find out how much funding different organizations gave to different research. This would be next to impossible for long research programs, anyway. 
    • Funding of research is not my primary interest, so I don't spend a lot of time tracking down details in this area. I might be wrong on details. 
    • I use the term "US Gov" for all the different branches and organizations within the United States of America's federal government (so includes NIDDK, NIAID, NICHD, etc.) 
    • I don't work for the US Gov, JDRF, or any of the other organizations discussed here. I have a more complete non-conflict of interest statement on my web site. 
    Some Specific Notes:
    • Oral Insulin: This trial was a phase-III trial, meaning that it was large and designed to provide enough information so that if, if successful, the treatment could be widely used. However, as it turned out, only part was successful, and that part was phase-II sized, so I don't think we will see widespread use based on this trial alone. You can think of this as a phase-III trial with phase-II results.
    • Serova's Cell Pouch and DRI's BioHub: These two clinical trials are both testing one piece of infrastructure which might be used later in a cure. They are testing a part of a potential cure. However, in both cases, the clinical trials being run now require immunosuppression for the rest of the patient's life, so I'm not counting them as testing a cure.
    • Substance P at Hospital for Sick Children Toronto: This trial is avoiding the honeymoon period by testing for insulin production.  Patients must inject more than 1/2 unit/kg to be accepted, therefore they will accept recently diagnosed people, if they are injecting enough insulin to be passed the honeymoon.  I'm counting this as "Established".
    This is an update and extension to blog postings that I've made for the previous seven years:
    Finally, please remember that my blog (and therefore this posting) covers research aimed at curing or preventing type-1 diabetes that is currently being tested in humans. There is a lot more research going on, not covered here.

    Please think of this posting as being my personal "thank you" note to all the JDRF staff, volunteers, and everyone who donates money to research a cure for type-1 diabetes:
    Thank You!
    Finally, if you see any mistakes or oversights in this posting, please tell me! There is a lot of information packed into this small posting, and I've made mistakes in the past.  As in previous years, I'll be at the Santa Clara (California) JDRF One Walk.  Come by and say "hi", or strike up a conversation about research.  I love to talk about research!

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

    Sunday, October 1, 2017

    Important Update For Stem Cells Arabia

    If you are interested in potential cures for type-1 diabetes, then I urge you to read this report from the JDCA about Stem Cells Arabia:
    (Note that as a Fellow of the JDCA, I did contribute to their report.)

    Stem Cells Arabia is in the middle of a clinical trial were they combine two stem cell procedures as a possible cure for type-1 diabetes.  However, the real excitement is fueled by the results of a very small pilot study they did previously.  The results from the pilot study were presented at a conference, but not published in a journal.  But those results are very strong: all four treated patients went months without needing to inject insulin and never needed anti-rejection drugs.  If you find that exciting (and I certainly do), then you'll want to read the JDCA report which contains more details, and you'll be looking forward to the results of their larger trial, which is expected to complete in early 2019.

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

    Monday, September 18, 2017

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

    Catching Up With NNC0114­-0006 (Anti IL-21)

    Back in 2015 Novo-Norsk started a clinical trial into a combo treatment of NNC0114-0006 and Liraglutide (which is more commonly known as Victoza).  I ignored this trial, because I thought that NNC0114-0006 was a new form of insulin, and they were testing a treatment for type-1 diabetes. However, I have since found out that NNC0114-0006 targets IL-21 and that Liraglutide may stimulate beta cell growth.  Therefore, this combination could have the effect of stopping the autoimmune attack while at the same time regrowing beta cells, and that would be a path to a cure.

    Liraglutide is approved for use in type-2 diabetes and works by increasing insulin production. Recently, experiments in mice have suggested that it works (at least partly) by helping the body grow more beta cells, and preventing the death of beta cells:

    NNC0114-0006 is an anti IL-21 treatment.  IL-21 is a chemical that the immune system uses for communication, and several experiments have suggested that too much IL-21 is important to creating type-1 diabetes:
    (and there are many more such studies.)

    So combining these two treatments provides a possible path to a cure.

    The Current Study

    The study that started in 2015 is a phase-II? trial (the question mark means that it is a phase-II trial, but there has never been a phase-I trial for this combination of treatments).  The basic study design is four groups: one group gets both treatments, one group gets two placebos, one group gets NNC0114-0006 and placebo, and one group gets Liraglutide and a placebo.  So they have all their bases covered. The study is large: 304 people recruited from 100+ sites all over the US and Europe.

    The clinical trial record says that this study is recruiting patients.  However, when I look at the list of locations, every one is marked "Active, not recruiting", "Completed", or "Suspended", so I'm very hopeful that they have recruited all the patients that they need.  That is important, because they expect to collect data for 80 weeks.  Their target completion date is April 2019.

    This is actually the fifth study of NNC0114­-0006.  You can see the list here:
    The four previous studies were smaller (between 10 and 65 people), and were done on other autoimmune diseases: Rheumatoid Arthritis, Crohn's Disease, and Systemic Lupus Erythematosus.

    Clinical Trial Registry:
    Other Study ID Numbers: NN9828-4150
    2014-001215-39 ( EudraCT Number )
    U1111-1154-7172 ( Other Identifier: WHO )
    REec-2015-1768 ( Registry Identifier: Spanish registry )

    Metreleptin Fails A Phase-I Trial

    Back in the 2008-2010 timeframe there was some hope that Leptin would cure type-1 diabetes, and a clinical trial was started in 2010.  Then in 2015 the trial was canceled by one of the sponsors.  Finally, now in 2017 the results have been published, and the conclusions are:
    Metreleptin is safe but may not be efficacious in improving glycemic control in patients with T1DM, although it reduces body weight and daily insulin dose modestly.
    You can read my previous blogging here:
    The abstract is here:
    Clinical Trial Record:

    Interesting Treatment for Multiple Sclerosis

    I usually do not blog on cures or treatments for other diseases.  However, MS, type-1 diabetes and several other diseases are all from the same family of "autoimmune diseases".  They are all caused by the body's immune system attacking a different organ or internal system.  So in theory, research into curing one of these diseases might help cure the others.

    So with that in mind, I thought this study was interesting:
    Multiple Sclerosis Therapy NKTR-358 Begins Phase 1 Clinical Trial:

    Basically, this company has a treatment which causes a person to generate more Treg cells.  Since Treg cells regulate the immune system, having more of them might prevent the immune system from attacking the wrong cells.  In type-1 diabetes, we have several research programs aimed at increasing Treg counts, but usually by growing more Tregs outside the body, and then infusing them into the body (T-Rex, Stem Cell Educator, and Stem Cells of Arabia are all working on similar ideas). NKTR-358 is a treatment which (they hope) will cause the body to generate more Treg cells, itself.

    Also, NKTR-358 works at least partially, by targeting the IL-2 receptor in the immune system, and this receptor is also an active target of research in type-1:
    (and the IL-2 targeted by NKTR-358 is different than the IL-21 targeted by NNC0114-0006 above.)

    Company Information:
    Some animal data:

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

    Monday, September 4, 2017

    ViaCyte Clinical Trial News: VC-01 is Fully Enrolled, VC-02 Starts

    This blog posting covers two important pieces of news from ViaCyte.

    ViaCyte's Phase-II Trial of VC-01 is Not Recruiting
    (But What does that mean?)

    I missed this news, when it was announced back in May 2017, but ViaCyte's Phase-II clinical trial of VC-01 is not recruiting more people.  I'm not sure if this is a "pause" between their phase-I group and their phase-II group, or if they have finished recruiting all people for both groups.  That's important because they are gathering effectiveness data for six months.  So whatever group they finished recruiting in May, they should have effectiveness data in November.  Effectiveness data for 15 people would be good, but from the full 65 people would be even better.  Since this trial is not blinded (and has no control group), they could publish their data as soon as they have it, if they want to.

    Also, they are gathering safety data for two years, so that same group will finish gathering safety data in May 2019.  The same "15 people is good 65 people is better" and "with no control group, they can publish if they wish" applies to this safety data as well.

    Clinical Trial Registery:

    Differences Between ViaCyte's VC-01 and VC-02 Treatments

    ViaCyte has started a clinical trial for their VC-02 stem cell implantation product, but as this treatment is not a cure (by my definition of "cure"), I will not be following it.  Don't mix up VC-02 with their earlier VC-01 product.  VC-01 is a potential cure, and I will follow it moving forward.

    I found this confusing: why would a company test a non-cure after they had a cure already in the pipeline, and ahead of the non-cure?  Why even bother with the non-cure?

    While VC-01 and VC-02 are encapsulated stem cells, the nature of the encapsulation is completely different.  VC-01 uses a "strong" encapsulation which prevents the body's immune system from attacking the new cells. This prevents both the normal rejection (ie. the foreign organ reaction), and type-1 rejection (ie. the malfunctioning autoantibody reaction) from attacking the new cells.  Therefore, VC-01 does not require anti-rejection drugs.  VC-02 uses a "weak" encapsulation which holds the stem cells together and in one place, and encourages new blood vessels to integrate into the encapsulation, but provides no immune protection.  People getting VC-02 will need to take anti-rejection drugs [d1].

    Both VC-01 and VC-02 have the same cells inside.  They both start with ViaCyte's PEC-01 cells. These are created by harvesting human embryonic stem cells from a long-existing culture and treating them so they differentiate into pancreatic cells.  The cells that are inside the devices are these pancreatic cells.   (There are no "raw" stem cells in the device.)  This process is described on ViaCyte's web site here:

    The obvious question is, why would any person with type-1 diabetes choose to be in the VC-02 trial, if they could be in the VC-01 trial?  The immunosuppression required by VC-02 has known bad side effects, and there are known risks in taking those drugs for decades.

    First is that the VC-01 trial is not recruiting right now.  So if you want an encapsulated ViaCyte stem cell treatment right now, VC-02 is your only option.  I don't know if the VC-01 trial is completely enrolled, or if it will open up again, to gather a second group of patients.

    Second is this: The ViaCyte team believes that the reason some implanted beta cells work and some fail is "vascularization".  Vascularization is the body's ability to grow blood vessels into the new beta cells so that they can get oxygen, remove waste products, and generally integrate with the host person.   ViaCyte believes that the encapsulation used in VC-01 will allow this vascularization and therefore be successful.   However, they also believe that VC-02 will have even better vascularization, and therefore an even higher chance of success.  So if someone currently has type-1 diabetes, they may choose to have VC-02 because it has a higher chance of success (even if this is a trade off against a known higher risk from the treatment).

    The VC-02 Study

    Although there is only one official clinical trial of VC-02, there are two patient groups within this trial (which they call "cohorts"), and these cohorts are really separate phase-I and phase-II trials. It's just that one clinical trial registry covers both. The first cohort will be 15 patients, all of whom will get a low dose version of the treatment. The second cohort will be 40 patients, all of whom will get a higher dose version of the treatment. There is no control group. They expect to finish the second cohort in Dec 2020.

    They are collecting their primary safety data at 4 months post transplant, and primary effectiveness data (C-peptide data) at 6 months post transplant.

    They are recruiting at two sites:

    • University of California San Diego, San Diego, California, United States, 92121
      Contact: Study Coordinator    1-844-317-STEM (7836)
    • University of Minnesota Recruiting, Minneapolis, Minnesota, United States, 55455
      Contact: Study Coordinator    612-626-4993

    Clinical Trial Registry:
    ViaCyte's FAQs:

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

    Monday, August 14, 2017

    Possible Cures In The News (August)

    The blog posting is a collection of small updates to existing clinical trials.

    The TN20 (Oral Insulin) Phase-II Clinical Trial Completes Enrollment 

    TN20 is the name of a specific oral insulin clinical trial, which completed enrollment in March 2017. Since this study will follow people for one year, they should finish collecting data in March 2018.

    The following blog post:
    covers oral insulin in detail, describing why people think it might prevent type-1 diabetes, and the other clinical trials (and there are several) currently running.

    Clinical Trial Registery:

    T-Rex Study Is Half Enrolled

    I've previously blogged on the T-Rex study (sometimes under the name "Polyclonal T-Regs"):

    It is currently in a phase-II clinical trial, and that trial is now half enrolled (56 people out of 111).

    This study is unusual in that it can enroll kids as young as 8, and is recruiting people at over a dozen different sites in the US:


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

    Results from the previous phase-I trial found that this treatment preserved beta cells.  C-peptide levels remained constant in the treated group.  Since C-peptide levels drop during the honeymoon period, these treated people did better than untreated people would be expected to do.  The previous phase-I study did not have a control group, but the current phase-II study does.

    Results of Phase-I Clinical Trial of REMD-477 for T1D

    I probably will not cover this moving forward, because it is more treatment than cure. REMD-477 is a  Glucagon Receptor Antibody.  The hope is that giving this to people with type-1 will cause them to produce less glucagon and therefore use less insulin.   This was a 21 person trial, where half the people got the treatment and half did not.  The people spend a few days in a hospital, and then were followed for a few weeks "in the wild".

    They found that glucagon levels did go down (20-30%), insulin requirements did go down (about 10%), and people did spend more time in their target BG range (about 15%), for a few weeks after treatment.

    Several Press Releases:
    Clinical Trial Registry:

    They have started a follow up study, which will enroll 75 people and last 24 weeks.  They hope to finish it in Sept-2018:

    I suspect that any treatment which lowers glucagon levels is going to have some impact on people who play sports, and anyone who has an unexpected low (especially if they need a Glucagon injection, but even if not).  This study did not address either of those issues, but I suspect that follow on studies will need to, if they want FDA approval for this as a treatment for type-1 diabetes.

    Diamyd Unsuccessful in Phase-II Clinical Trial on Presymptomatics 

    This study is another testament to the optimism of researchers.  Diamyd ("GAD Vaccine") has been tested for over 10 years.  None of these trials has been particularly successful.  They culminated in an unsuccessful Phase-III trial years ago.  You can read my previous blogging on Diamyd here:

    However, researchers are natural optimists.  And it is important that they are.  Society needs optimistic researchers so that they will repeatedly attack problems, and not give up, even in the face of adversity.  Previous Diamyd trials had been done on honeymooners, so this trial was done on presymptomatics. Unfortunately it failed.

    News Coverage:
    Press Release:
    Clinical Trial Registry:


    This trial reminded me that, in the world of type-1 diabetes, if the headline reads "new treatment shown safe" that really means "new treatment is not effective".  Almost all clinical trials aimed at type-1 diabetes measure both safety and effectiveness. This is especially true of phase-II trials, like this one, and phase-III trials. Since effectiveness data is obviously more news worthy than safety data, if the headline talks about safety, that means the treatment was ineffective.

    The headline for the press release above is classic that way "Autoantigen GAD-Vaccine is Safe for Children at High Risk for Developing Type 1 Diabetes", while the headline for the news coverage is much more accurate "ADA: Alum-GAD (Diamyd) Vaccine Fails to Prevent Type 1 Diabetes".

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

    Friday, July 14, 2017

    Update On Dr. Faustman's BCG Research

    There was some media buzz about Dr. Faustman's BCG research as reported on a poster at ADA 2017.  I can't link directly to it, but you can go to this page:
    and search for Faustman to see the poster and the abstract.

    Dr. Faustman's research has about 15 years of history, which I've blogged about before, here:
    And in several other blogs.

    But to summarize very quickly: Dr. Faustman's previous research was based on the idea that BCG (a Tuberculosis vaccine) increases the levels of TNF, and higher TNF levels could result in less autoreactive T cells, and this would lead to a cure for type-1 diabetes.  Unfortunately, this did not pan out.  Her phase-I trial showed that BCG did not change the levels of live autoreactive T cells in circulation.  However, using some non-standard data analysis, Dr. Faustman interpreted the phase-I study to show that there was an increase in T-reg immune cells.  T-reg cells get rid of the autoreactive T cells, so increasing the T-reg cell count could also lead to a cure for type-1 diabetes.

    What is the New News?

    The poster presented at ADA 2017 contained data on a possible mechanism whereby BCG could increase the level of T-regs in a type-1 diabetic.  This mechanism involved changes to how genes are used in the body (called "epigenetic changes").  These changes can be long lasting.  Obviously, a long lasting treatment is better than a short lasting one, so (if this finding is confirmed by more research) this is good news.

    Also, although not required, it is nice to have a theoretical basis for why a treatment should work, if you are going to test that treatment. This is particularly true of the BCG research, since the phase-I trial showed pretty clearly that the previous theory was wrong, so having a new theory is good.

    How Important Is This?

    In my opinion, it is not very important. Why not?  In a nutshell:
    1. It's a finding about a possible mechanism of how a cure works, not evidence of effectiveness, for a treatment where effectiveness is the important, unanswered question.
    2. It's based on data from 3 people.
    3. It's a poster, not a presentation (or a paper).

    1. It's a mechanistic finding so it is aimed at answering the question "how does BCG work?", but the important question is "does BCG work?"  That needs to be answered before the "how" question is important.  The results from the phase-I trial were not successful (see discussion below).  Therefore, for me, research into the mechanism of how it might work is less important until we get some evidence that it does work.

    2. Dr. Faustman's phase-I study gave BCG to only three people.  It is the smallest phase-I study I have ever covered in the field of type-1 diabetes.  This poster is based on data from those same 3 people, and that is not a large enough foundation to get me excited.

    3. As a poster, this is a lesser form of publication, than a journal article or a presentation.  That is not fatal, of course, but it is a handicap.  For comparison, Gleevec and Oral Insulin both merited presentations, so the organizers of the ADA scientific sessions clearly thought that those studies were more important than this BCG result.  (And I agree with them.)

    Some Discussion on The Results From the Phase-I Trial

    Obviously, Dr. Faustman considers the phase-I trial to be a success, which is why she has started a phase-II trial, so why do I consider it unsuccessful?  For two reasons:

    First, the normal definition of success for a clinical trial is successful results from the primary outcome.  Her phase-I trial's primary outcome was autoreactive T cells, and there was no difference between the the treated group and the control group.  So that's an unsuccessful result.

    She did report two tiny successful outcomes in her secondary results.  But to get those, she had to do two different data manipulations.  I discussed those in detail in 2012 when the original results were published:
    See the section called "Weaknesses in Data Analysis".

    A very short summary is:
    1. She shifted 1/3 of her control group to be analysed as though it were in the treatment group, after she had seen the results, and saw that would change the outcomes.
    2. She did not use a single control group.  Rather, she used different control groups for different outcomes, including (in some cases) pulling data from other studies.

    My older blog posting describes in detail how damaging these are to her analysis.  But suffice it to say, if the data shows success, there is no reason to do those manipulations.  And if the data is successful (even at a tiny level), only after those manipulations, then how real is it?

    Now, if her phase-II study (which is expected to enroll about 150 people) is successful using standard data analysis techniques, then she can rerun this poster study with data from those 150 people.  She will then have more people and a successful treatment and at that point, a mechanistic study would be interesting. The phase-II study is expected to end around 2023.

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

    Phase-III Results from an Oral Insulin Clinical Trial In Presymptomatics

    A Quick Introduction to Oral Insulin to Prevent T1D

    Obviously, all type-1 diabetics need to take insulin in order to process carbohydrates. This insulin must be injected, because if it were taken orally it would be digested into smaller pieces and would not work as insulin [d1]. Injecting insulin in this way does not cure or prevent type-1 diabetes, it just treats it.

    However, one of the autoantibodies that is associated with type-1 diabetes targets insulin molecules[d2]. Therefore, there is a theory that giving insulin to people with T1D might prevent or delay the onset of type-1 diabetes by training the body not to produce this autoantibody. The process is vaguely similar to giving small amounts of peanut proteins to people with peanut allergies[d3]. Insulin pills may work for this purpose even though they would not work as a treatment for type-1.

    The Phase-III Study (Structure and Results)

    These researchers started with 10,000s of TrialNet participants, and enrolled 560 people who were "presymptomatic". They showed two autoimmune markers, but no symptoms of type-1 diabetes. All of these people tested positive for one particular autoantibody associated with T1D (micro insulin autoantibody) [d2], but they were further subdivided into four groups based on the other autoantibodies they tested positive for, and how much insulin they were producing.

    Each subgroup was split in half. One of these halves got oral insulin twice a day, and the other half got a placebo. They were followed for a year or longer to see how many people in each group developed type-1 diabetes as measured by "classic" symptoms.

    If you look at the entire study, oral insulin did not have a statistically significant effect. However, if you looked at one subgroup specifically [d4], that subgroup did show a statistically significant effect. For that one subgroup, about 18% of the treated group came down with T1D, while 34% of the untreated group did. The researchers viewed this as delaying the onset of type-1 diabetes by 2.5 years (on average) for this subgroup.

    Presentation Slides:

    News Coverage:

    Clinical Trial Record:

    Discussion Of This Study

    The results of this study are clearly "bad news on one hand, good news on the other". If you look at the study as applied to all presymptomatics, it was not successful. On the other hand, if you look at it for one specific subgroup, then it was successful. So the obvious thing to do is to try to replicate the results on the specific subgroup where it was previously successful. If so, this could turn into a delaying or preventative treatment for the 10% of patients who fall into this group. Since this subgroup had a specific combination of autoantibodies, it is straightforward to test ahead of time, and give oral insulin to people with this same combination, but not other combinations (where it did not work).

    This trial was the size of a phase-III trial. However, the success was only seen in a subgroup, and that subgroup was the size of a phase-II trial. So I would not think of this as a successful phase-III trial, but rather as a successful phase-II trial (meaning that at least two phase-III trials should be expected before it becomes commonly available) [d5].

    It is also important to remember that as group size gets smaller, the chance for accidental correlation gets bigger. With these sorts of subset analysis, it is always possible that the effect seen is cause by luck rather than effect. In this particular case, the results were statistically significant even for the smaller group, which is a good sign, but only larger studies will be conclusive.
    The History of Oral Insulin

    Oral Insulin has a long, complex history of clinical trials, and the results are very mixed (like this study). Just before I started my blog (so 10+ years ago), the results of an oral insulin for prevention trial were announced, and the trial was unsuccessful. However, the researchers analysed the data in more depth after the study concluded, and realized that it had worked for one subgroup (sound familiar?) That was the micro insulin autoantibody subgroup, and that's why everyone in this study had that antibody.

    But the idea that oral insulin might prevent/delay type-1 is a popular one, and there are at least three clinical trials running right now. All three of these studies are similar, except for size: the first is 44 people, the second is 220, and the third is 92.

    Oral Insulin Starts a Phase-II Trial In Germany (pre-POINT Early)
    Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes der Technischen Universität München, München, Germany, 80804
    Started in Aug 2015 and expected to finish in Aug 2017
    News: Vaccination against type 1 diabetes may soon be available to young children:
    Clinical Trial:

    Phase-II Oral Insulin Trial In Germany (Fr1da)
    Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes, der Technischen Universität München, München, Deutschland (DEU), Germany, 80804
    Anette-G. Ziegler, Prof. Dr., MD +49 (0)800 464 ext 8835
    Started in Dec 2015 and expected to finish in June 2021
    Clinical Trial:

    Phase-II Oral Insulin Trial In The US (TN20)
    Not recruiting.
    Started in Jan 2016 and expected to finish in Dec 2017.
    Clinical Trial:
    Extra Discussion

    [d1] To complicate things, several researchers are working on creating a form of insulin which could be eaten, but which would avoid digestion, so that it could be used to treat type-1 diabetes. This is also called "oral insulin" research. In this blog posting, I'm talking about oral insulin as a cure or preventative for T1D, not as a treatment.

    [d2] Autoantibodies are the malfunctioning antibodies which cause the immune system to attack beta cells. There are five autoantibodies associated with type-1 diabetes, and there may be more that we haven't discovered yet. The five we know about are:
    * micro insulin autoantibodies (mIAA or just IAA)
    * islet-cell antibodies (ICA)
    * glutamic acid decarboxylase (GAD) antibodies
    * islet antigen-2 (IA-2) antibodies
    * zinc-transporter 8 (ZnT8) autoantibodies
    The last one was not used in this study, possibly because it tends to show up later in the disease process.

    [d3] It is important to realize that type-1 diabetes is NOT a conventional allergy to insulin. It is similar to allergies in that it is the body's immune system overreacting to something that it should not react to, but other than that, is quite different. Allergies involve the immune system overproducing histamines. These histamines attempt to get physical irritants, like pollen, out of your body. You can counter this histamine reaction by taking antihistamines. Type-1 diabetes involves the immune system overproducing malfunctioning killer T-cells (or perhaps under producing regulatory T-cells). These malfunctioning killer T-cells mistakenly kill beta cells, thinking they are foreign cells (ie. living creatures like viruses, that have invaded the body). So the mechanism is different (histamines vs. T-cells), and the mistaken target is different (physical things, like pollen or wheat vs. living organisms, like viruses).

    [d4] The subgroup that showed the effect was the micro insulin autoantibody (which everyone in this study had), and either the ICA autoantibody or both the GAD and IA-2 antibodies, and also low insulin secretion at the start of the study.

    [d5] As far as I can tell, oral insulin is not approved for the treatment of any disease in the US, and is not available either by prescription or "over the counter". Therefore, it will need to go through full US FDA approval, which requires two phase-III trials. I don't know if the FDA would consider this a phase-III trial for approval purposes.

    Joshua Levy
    publicjoshualevy at gmail dot com

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