Monday, October 29, 2018

Golimumab Update

Golimumab (sold as Simponi) is an immune system modulator, which has been approved in the United States and many other countries for treatment of several autoimmune diseases, so testing it on type-1 diabetes makes a lot of sense.  Simponi has already been approved to treat rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and ankylosing spondylitis.

Golimumab is a monoclonal antibody, which is an artificially created antibody which targets one very specific molecule in the body.   If a disease is caused by that molecule (or a cell marked by that molecule), then using a monoclonal antibody to target it is promising.  Golimumab targets tumor necrosis factor alpha (TNF-α) which causes inflammation, and is well known to be involved with type-1 diabetes. 

There are three on-going clinical trials of Golimumab (Simponi):

T1GER: SIMPONI® to Arrest Beta-cell Loss in Type 1 Diabetes
Who: 84 people aged 6-21 with honeymoon type-1 (first 100 days)
What: 52 weeks of treatment
When: Started Aug-2016 and expects to finish May-2020 (fully enrolled in Aug-2018)
Where: 33 sites in the USA (but they are no longer recruiting)
Run by: Janssen Research & Development

SIMPONI (Golimumab) Therapy in Children, Adolescents and Young Adults With Pre-Symptomatic T1D
Who: 30 people aged 6-21 with two or more autoantibodies, but no "classical" symptoms of T1D
What: 26 weekly injections
When: Started Oct-2017 and hopes to finish July-2021
Where: Colorado, Finland, Sweden  (they are still recruiting new people)
Run by: Janssen Research & Development

Targeting Beta Cell Dysfunction With Liraglutide or Golimumab in Longstanding T1D
Who: 30 people aged 18-50 who have had type-1 for more than 3 years
What: 8 weeks of treatment
When: Started Aug-2018 and hopes to finish June-2020
Where: Idaho and Washington  (they are still recruiting new people)
Run by: Benaroya Research Institute

Summary
I like this as a complete program.  These three studies cover Golimumab from many different points of view: people before they are diagnosed, honeymooners, and people with longstanding type-1. Two of the studies are for children 6-21 years old, and one for adults 18-50.  All are reasonable size.

The downside, is that we have to wait until 2020 to see results.  The good news is that by 2021, we'll have results from three different studies to look at.

Discussion
Curing type-1 diabetes in people with established type-1 is generally thought  to require two successes.  First the autoimmune attack must be stopped, and second beta cells must be regrown.  Golimumab targets the autoimmune attack, but is not known to regrow beta cells.  By itself, such a treatment might cure presymptomatic or homeymoon type-1 (because those people still have some beta cells), but is unlikely to cure established type-1.

Clinical Trial References:
  * https://clinicaltrials.gov/ct2/show/NCT03298542
  * https://clinicaltrials.gov/ct2/show/NCT02846545
  * https://clinicaltrials.gov/ct2/show/NCT03632759

Drug Web Page: http://www.simponi.com/
Drug Wikipedia Page: https://en.wikipedia.org/wiki/Golimumab
TNF  Wikipedia Page: https://en.wikipedia.org/wiki/Tumor_necrosis_factor_alpha

Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com 
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF, JDCA, or Bigfoot Biomedical news, views, policies or opinions. In my day job, I work in software for Bigfoot Biomedical. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.
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Sunday, October 7, 2018

JDRF Funding for a Cure 2018

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: 69% of the treatments currently in human trials have been funded by JDRF. (And the number is 86% for the later phase trials.) This is a strong impact; one that any non-profit should be proud of.  Below is a list of all the treatments, grouped by phase, and separated into groups that JDRF has funded, and those JDRF has never funded.

Many of these treatments are being tested in more than one clinical trial.  For example, the "Polyclonal Tregs" treatment is running at least two trials, but since they are both 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 or 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.

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. The JDRF funds nPOD,  ITN, and several other organizations, so I include research done by these other groups as well.

The Difference Between Phase-II and Phase-II? Trials
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 on known safe treatments, 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 size and 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:
  • Oral Insulin (Preventative)
Cures in Phase-II Human Trials
Summary: there are 22 trials in phase-II, and 18 of them have been funded by JDRF, while 4 have not. Here are the treatments that have been funded by JDRF:
  • AAT (Alpha-1 Antitrypsin) by 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 
  • 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 
  • 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 12 trials in phase-II, and 7 of them has been funded by JDRF, while 5 have not. Here are the treatments that have been funded by JDRF:
  • Alpha Difluoromethylornithine (DFMO) by DiMeglio
  • GABA by Diamyd
  • GNbAC1 by GeNeuro (Established)
  • Golimumab by Janssen
  • Golimumab by Greenbaum (Established)
  • Intranasal Insulin by Harrison at Melbourne Health (Prevention)
  • Rituximab by Pescovitz at Indiana University
Not funded by JDRF:
  • Albiglutide by GlaxoSmithKline
  • 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 
  • Exsulin and Ustekinumab by Rosenberg at Jewish General Hospital, Canada (Established) 
  • Golimumab by (Presymptomatics)
  • IBC-VS01 by Orban at Joslin Diabetes Center  
  • Metformin by Littleford at The University of Exeter (Prevention)
  • MonoPepT1De by Cardiff University
  • Mozobil by University of Alberta (Established)
  • MultiPepT1De (Multi Peptide Vaccine) by Powrie at King’s College London
  • Nasal insulin by Harrison at Melbourne Health (Prevention)
  • Tauroursodeoxycholic Acid (TUDCA) by Goland at Columbia University
  • 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
  • IMCY-0098 by Imcyte
  • Mesenchymal Stromal Cell by Carlsson at Uppsala University
  • Microvesicles (MVs) and Exosomes by Nassar at Sahel Teaching Hospital 
  • Monolayer Cellular Device (Established) 
  • ProTrans by NextCell (Established)
  • Substance P by Vanilloid Genetics at Hospital for Sick Children Toronto (Established)
    Summary of all Trials
    59 in total
    41 funded by JDRF
    So 69% 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
    16 of these treatments (27%) are being tested on established type-1 diabetics.
    Of these, 9 are funded by JDRF.
    So 56% of the trials recruiting established type-1 diabetics are funded by JDRF.

    Compared to Last Year
    In 2017 there were 55 treatments in clinical trials, in 2018 there are 59 (growth of 7%).
    In 2017 there was 1 treatment in Phase-III trials, in 2018 there is one (no change).
    In 2017 there were 22 treatments in Phase-II trials, in 2018 there are 22 (no change).
    In 2017 there were 8 treatments in Phase-II? trials, in 2018 there are 12 (growth of 50%).
    In 2017 there were 24 treatments in Phase-I trials, in 2018 there are 24 (no change).

    A Little Discussion
    This year there are no phase-III trials aimed at curing type-1 diabetes, and that's been true for many years.  Indeed, since I've tracked research, there has never been a phase-III trial aimed at people with established type-1.  Back in the 2000s, there were a couple aimed at curing honeymoon type-1, but none were successful, and none have started for years.

    That's discouraging, because it means we are a long way from a cure.  However, for me, it's a reason to donate.  Money is the thing that is going to move the Phase-II studies into Phase-III studies, and the Phase-I studies to Phase-II, create more Phase-I studies, and so on.  And if we think "nothing looks promising in the next few years, so I won't give money" that results in nothing looking promising in the future, either.  If you're worried about your money going to non-research, then you can do what I do: fill out the attached form or go to the following website and send it in with your donation:  http://thejdca.org/good-giving-landing-page/  (Unfortunately I don't know how to do this for on-line donations.)

    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:
    • GNbAC1 by GeNeuro used JDRF's nPOD project.
    • NextGen's ProTrans product is a form of Wharton's Jelly, and JDRF has funded related research into Wharton's Jelly, but has not funded this program specifically, so it is listed as non-JDRF.
    • I'm removing Dr. Faustman's BCG research from my list of potential cures.  For more information read this blog:
      https://cureresearch4type1diabetes.blogspot.com/2018/09/every-year-in-september-or-october-i.html and for even more details
      https://cureresearch4type1diabetes.blogspot.com/2018/07/dr-faustman-publishes-follow-on-bcg.html
    • 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:
    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 than is counted 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. New this year, I'll be part of the Bigfoot Team.  Come by and say "hi", or strike up a conversation about research.  I love to talk about research!

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