Breakthrough T1D (formerly JDRF) Funding for a Cure 2024

Normally, sometime in October, I write a summary of all the clinical trials funded by JDRF.   However, this year I didn't, which was a mistake.  But late is better than never, so in this post I summarize the clinical trails that Breakthrough T1D (formerly JDRF) is funding as of October 1st, 2024.

I hope to remind everyone of how important Breakthrough T1D is to the human trials of potential cures for T1D, which I track.

Let me give you the punch line up front: 65% of the treatments currently in human trials have been funded by Breakthrough T1D, and this goes to 77% for the Phase-III and Phase-II studies!  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 trials that Breakthrough T1D has funded, and those Breakthrough T1D has never funded.  

 

The List, Divided by Phases

Below is the list of all treatments, divided into six phases: FDA Approved, In Process of Approval, Phase-III, Phase-II, Phase-IIΔ, and Phase-I.  Phase-II trials are "classic" phase-II trials, which are done after a Phase-I trial.  What I call Phase-IIΔ trials test treatments which never went through phase-I trials on people with T1D.  (I used to call those Phase-II? but I think using punctuation that way is confusing, so I'm using a delta instead: Phase-IIΔ.)  They've been shown safe in other diseases, so have skipped phase-I trials on people with T1D.  These Phase-IIΔ 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.

For T1D research, phase-I studies are usually about 10 people and test for both safety and efficiency.   In other diseases, phase-I trials are sometimes only done on healthy people, or only test for safety issues, but this is not the way T1D research is usually done.  Over 90% of phase-I studies are done on people with T1D, and over 90% test for both safety and effectiveness.

Phase-II trials are about 100 people, and phase-III about 300. After two successful phase-III trials, the FDA considers approval for general use.  These two studies can be run at the same time, and are often identical.  Occasionally, only one phase-III trial is required for approval. 

Approved or In Process of FDA Approval

In 2024, nothing was approved and nothing is in process of approval.

Phase-III Human Trials

Summary: currently there are 3 treatments in phase-III clinical trials.  2 are funded by JDRF:

• Diamyd by Diamyd 
• Oral Insulin (Preventative)
  

Not funded by JDRF:

• Ladarixin by Dompé
  

Phase-II Human Trials

Summary: there are 19 trials in phase-II, and 15 of them have been funded by Breakthrough T1D, while 4 have not. Here are the treatments that have been funded by Breakthrough T1D:

• ATG and GCSF by Haller at University of Florida (Established) 
• Abatacept in honeymooners and as a prevention by Orban at Joslin Diabetes Center and Skyler at University of Miami (Prevention)
• Aldesleukin (Proleukin) at Addenbrooke’s Hospital, Cambridge, UK 
• Diamyd in several combinations by Ludvigsson at Linköping University and Larsson at Lund University (Honeymoon and Prevention) 
• Difluoromethylornithine (DFMO) by Panbela
  
• Gleevec by Gitelman at UCSF 
• Gluten Free Diet: Three Studies  (Preventative)
• Rituximab and Abatacept by TrialNet
• Stem Cell Educator by Zhao (Established) 
• Tauroursodeoxycholic Acid (TUDCA) 
• Tocilizumab by Greenbaum/Buckner at Benaroya Research Institute 
• TOL-3021 by Bayhill Therapeutics (Honeymoon and Established)   
• 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 several research groups: Burt, Snarski, and 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)

Phase-IIΔ Human Trials
Summary: there are 19 trials in phase-IIΔ, and 10 of them have been funded by Breakthrough T1D, while 9 have not. Here are the treatments that have been funded by Breakthrough T1D:

• Alpha Difluoromethylornithine (DFMO) by DiMeglio
• Baricitinib by St Vincent's Institute of Medical Research
• GABA by Diamyd
• Golimumab by Janssen (Honeymoon and Established)
• Hydroxychloroquine by Greenbaum (At Risk)
• Intranasal Insulin by Harrison at Melbourne Health (Prevention)
• Iscalimab (CFZ533) by Novartis
  
• Influenza Vaccination at Aarhus University Hospital
• Pleconaril and Ribavirin by Oslo University Hospital
• Siplizumab by NIH and ITB-Med LLC

Not funded by JDRF:

• Abrocitinib or Ritlecitinib by NIH/Pfizer
• Azithromycin by Forsander
• BMF-219 by Biomea Fusion (Established)
• Fenofibrate at Warsaw Medical University
• Ixekizumab/Taltz by Vastra Gotaland Region
  
• Liraglutid (At Risk)
• NNC0114-0006 and Liraglutide by Novo-Norsk (Established)
  
• Rapamycin Vildagliptin Combo by IRCCS (Established)
• Visbiome by Medical College of Wisconsin

Phase-I Human Trials
Summary: there are 21 trials in phase-I, and 13 of them are funded by Breakthrough T1D, while 8 are not. Here is the list funded by Breakthrough T1D:

• AG019 and Teplizumab by ActoGeniX
• DIMID1 (Faecal Microbiota Transplantation) at AMC Hospital 
  
• Diamyd by Diamyd (At Risk)
• CGSF by Haller at University of Florida 
• Golimumab (At Risk)
• MER3101 by Mercia (previously IBC-VS01 by Orban)
• Mozobil by University of Alberta (Established)
• PRV-101 (Coxsackie B Vaccine) by Provention Bio (Prevention)
• Semaglutide by Dandona at University of Buffalo
  
• TOPPLE T1D by Novo Nordisk (Established)
• VC-01 by Viacyte (Established)
• VCTX210A by Viacyte/CRISPR (Established)
  
• VX-264 by Vertex (Established)

Not funded by JDRF:

• AVT001 by Avotres
  
• Baby Teeth Stem Cells by CAR-T Biotechnology
• Extracorporeal Photopheresis by ADSCC
  
• Gluten Free Diet by Carlsson at Lund University
• NN1845 (Glucose Sensitive Insulin) by Novo Nordisk
• OPT101 by Op-T (Established)
• PIpepTolDC at City of Hope Medical Center
• ProTrans by NextCell (Established)

Summary of all Trials
62 in total
40 funded by JDRF
So 65% of the human trials currently underway are funded (either directly or indirectly) by JDRF. Everyone who donates to Breakthrough T1D should be proud of this huge impact; and everyone who works for Breakthrough T1D or volunteers for it, should be doubly proud.

Just Looking at Trials on Established Type-1 Diabetics

 
Of these treatments 14 (23%) are being tested on people with established T1D, of those, 9 are funded by Breakthrough T1D.  So 64% of the trials recruiting people with established T1D are funded by Breakthrough T1D.

Compared to Last Year
In 2023 there were 59 treatments in clinical trials, in 2024 there are 62 (growth of 5%).

In 2023 there was 2 treatments in Phase-III trials, in 2024 there are 3 (growth of 50%).
In 2023 there were 17 treatments in Phase-II trials, in 2024 there are 19 (growth of 11%).
In 2023 there were 14 treatments in Phase-IIΔ trials, in 2024 there are 19 (growth of 36%).
In 2023 there were 25 treatments in Phase-I trials, in 2024 there are 21 (dropped by 16%).

I think that the drop in Phase-I trials was mostly caused by me doing a good housecleaning to remove old, moribund trials, when I had not done that in several previous years.

A Little Discussion

 
The money that we donate does many things:

1. It finances more clinical trials (especially early clinical trials).
2. It finances making clinical trials (especially early clinical trials) larger and better designed.
   
3. It helps push possible cures to the next level of trial.  It finances moving phase-I trials to phase-II, and phase-II to phase III.

I like to say that there are two reasons for donating money for research into T1D.  People who like the research being done should donate money to move it forward, faster.  People who don't like the research being done should donate money to start up different research which (presumably) they will like more.  So no matter which group you are in, you should donate.  😀

  

Trial Populations

 

The list above uses the following marks to show the nature of the treatments, and if one treatment is being tested in different populations, then it will be listed more than once.
Honeymoon: Most trials are done on people within the first year of diagnosis.  All the studies listed above which are not Established, At Risk, or Prevention are in this Honeymoon category.

Established: One or more trials are open to people who have had type-1 diabetes for over a year. 
At Risk: 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.
If a trial is not marked, then it is for people in the honeymoon (first year) of T1D.

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.  

 

I also give credit if JDRF funds research indirectly, through another organization.  For example, JDRF funds nPOD, Immune Tolerance Network, and INNODA and so I give Breakthrough T1D credit for clinical trials based on their work.

 

How I Count Trials for This Comparison

• I don't count trials where the Breakthrough T1D funded some basic research, but not the research which lead to a specific clinical trial.  I'm sure this under estimates JDRF's impact.  For example OPT101 is an anti CD154 drug.  JDRF has funded many studies on CD154, but not the particular research that is being tested here.  Similarly with Ixekizumab, JDRF has funded related research on that drug, but not the clinical trial or the research immediately leading to the clinical trial here.
  
• 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. 
• 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.
• 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 only include intervention studies here, because those are the only type of study that the FDA will accept for the eventual approval of a new treatment. 
  

Research Not Listed Here

I sometimes get asked why some piece of research is not listed here, and so here are some of those answers:

• VX-880 is a transplant study which requires life long immunosuppression.  Read here why I do not consider these to be cures.
• Levicure's Combination Therapy has only been tested in a retrospective study, not an intervention based clinical trial.

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 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.
  

This is an update and extension to blog postings that I've made for the previous fifteen years.  Below is a link to last year's, but you can search for "JDRF Funding for a Cure" for the rest of them:

• https://cureresearch4type1diabetes.blogspot.com/2023/11/jdrf-funding-for-cure-2023.html

Please remember that my blog (and therefore this posting) covers research aimed at curing, delaying, 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 Breakthrough T1D 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. 

Joshua Levy

http://cureresearch4type1diabetes.blogspot.com

publicjoshualevy at gmail dot com

All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid 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.

Fenofibrate Is Unsuccessful In A Phase-IIΔ Trial In Honeymooners

Fenofibrate (also spelled Phenofibrate) is commonly prescribed for high cholesterol and high triglycerides. In 2017, it was the 70th most commonly prescribed medication in the United States with more than eleven million prescriptions.  However, it is not approved for use in children under 18. It is also sometimes prescribed for diabetic retinopathy (eye damage from long term diabetes), and (off label) for gout.

However, it also showed some promise in NOD mice (an animal model for T1D), and so one person took it "off label" when they were diagnosed with T1D as a 19 year old.  They did not need to inject insulin for years after that, a huge result.  Still later, some researchers started a Phase-IIΔ trial.  These are my previous blog posts on Fenofibrate:

https://cureresearch4type1diabetes.blogspot.com/search?q=Fenofibrate&by-date=true

I had high hopes for this research.  I try not to become emotionally attached to specific research, because it clouds my judgement and because most research fails.  However, having one person go years without having to inject insulin was so good, and so unusual, that I was hopeful.  Unfortunately, this research did not pan out.

Results From the Phase-IIΔ trial

Here is the conclusion from the result's abstract:

Contrary to the beneficial effects of fenofibrate found in preclinical studies, this longitudinal, randomized, placebo-controlled trial does not support the use of fenofibrate for preserving beta cell function in individuals with newly diagnosed type 1 diabetes.

Since my initial excitement was based on a person who did not need to inject insulin after taking Fenofibrate, it makes sense to look at the insulin use and compare the people who got the drug (in red below) with the people who got the placebo (in blue).  You'll notice that the people who got the drug used a little more insulin.  This is the exact opposite of success, although the difference was not statistically significant.  Bottom line: it did not work.

Journal Article: https://www.researchgate.net/publication/385385677_Effect_of_fenofibrate_on_residual_beta_cell_function_in_adults_and_adolescents_with_newly_diagnosed_type_1_diabetes_a_randomised_clinical_trial/link/6722f02decbbde716b4c5777/download

This study used the same dose (160mg/day) that the successful "off label" used.  And that person stopped taking insulin after 19 days, so this study lasted much longer than needed to see the effect.  Also, the "off label" use started 7 days after T1D diagnosis, while this study started, on average, 22 or 24 days after diagnosis, with a standard deviation of 10 or 11 days.  The number of people who were "in remission" of T1D during their honeymoon was higher in the placebo group than in the treated group.  I put "in remission" in quotes because it is not what most people would consider remission.  They still used a little insulin, just not very much.  The researchers used a formal, technical definition of remission called the ADDRESS-2 definition, which is quite different than what you or I would call remission.

Joshua Levy

http://cureresearch4type1diabetes.blogspot.com

publicjoshualevy at gmail dot com

All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and has participated 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!

Fenofibrate Starts A Phase-IIΔ Trial

Fenofibrate (also spelled Phenofibrate) is commonly prescribed for high cholesterol and high triglycerides. In 2017, it was the 70th most commonly prescribed medication in the United States with more than eleven million prescriptions.  However, it is not approved for use in children under 18. It is also sometimes prescribed for diabetic retinopathy (eye damage from long term diabetes), and (off label) for gout.

However, it also showed some promise in NOD mice (an animal model for T1D), and so one person took it "off label" when they were diagnosed with T1D as a 19 year old.  They did not need to inject insulin for years after that, a huge result.  I blogged on this:
https://cureresearch4type1diabetes.blogspot.com/2020/06/strong-results-from-single-case-use-of.html
with an update:
https://cureresearch4type1diabetes.blogspot.com/2021/03/possible-cures-for-type-1-in-news-march.html

The Study 

The good news is that this study started in Sept-2022 and is scheduled to finish in July-2024.  However, the US registry lists them as still recruiting.  If this is true, completion will be delayed.  The European registry does not differentiate between recruiting and active, not recruiting.

The study includes about 100 children (10 to 17 years old) divided into two groups: one gets 160 mg Fenofibrate and one gets placebo.  This is a once per day pill given for a year.  The study is randomized and blinded.  The primary result is C-peptide and secondary results include more C-peptide numbers, insulin usage, adverse events, A1c, and several immunology measures.

European Clinical Trial Record: https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-003916-28/PL
US Clinical Trial Record: https://clinicaltrials.gov/study/NCT05909800

Discussion

This is exactly the kind of study I want to see for Fenofibrate, and I'm very excited to see its results. 

There are two trials of Fenofibrate in people with T1D which are currently running.  The first is designed to prevent kidney function loss rather than cure/prevent/delay T1D itself and therefore I have not been following it.  It is NCT04929379.  They are enrolling 40 adults with T1D for at least 8 years and have diabetic kidney disease.  It started in 2022 and they hope to finish in 2025.  No intermediate results have been published, and I don't expect any.  But the bigger issue is that all their end points involve kidney function.  They are not measuring C-peptide, A1c, or insulin use at all.  So even if the medicine had a big impact, they would not see it.

The second is designed to prevent rather than cure/prevent/delay T1D itself, so I have not been following it, either.  It is NCT01320345.  They are enrolling 450 (!) adults with T1D and have eye problems.  It started in 2016 and they hope to finish in 2025.  No intermediate results have been published, and I don't expect any.  But the bigger issue is that all their end points involve eye function.  They are not measuring C-peptide, A1c, or insulin use at all.  So even if the medicine had a big impact, they would not see it.

Personal note: I try not to get excited about potential T1D cures.  I think treating all potential cures dispassionately is better for me and better for this blog.  (Plus, my child was diagnosed over 22 years ago, so getting excited would not have panned out.)  But I am human, and I do sometimes get excited.

I am optimistic about Fenofibrite potential to prevent T1D in the honeymoon phase.  I can't explain exactly why this honeymoon treatment and no other.  Maybe it is because it really seems to have worked for one person, for many years, and (as yet) there is no clinical trial results to dampen my enthusiasm. 

Joshua Levy

http://cureresearch4type1diabetes.blogspot.com

publicjoshualevy at gmail dot com

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

 

 

 

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

This posting is a collection of shorter news items. 

Fenofibrate Extends Cure Of T1D In Single Case Study

I originally reported on Fenofibrate in June 2019:
https://cureresearch4type1diabetes.blogspot.com/2020/06/strong-results-from-single-case-use-of.html
This was a single person case study (so not a clinical study), but the results were very strong.  The person was treated during her honeymoon phase, and has not needed to inject insulin since.

The update is that she has now gone about 31 months without needing injected insulin.  This is up from 21 months at the time of my previous report.  She continues to take one pill a day.  I know of nothing unique about this person or her type 1 diabetes, so there is every hope that this success can be tested and the used on others in the future.

Oral Insulin is Unsuccessful For At-Risk Patients (Pre-POINT-Early Study)

Rational: One of the autoantibodies that is associated with type-1 diabetes targets insulin.  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.  But I want to stress that T1D is not a classic allergy.  The mechanism for T1D is very different than the mechanism of classic allergies. 

Results: There were no statically significant results in the primary outcome.   "Immune responses to insulin were observed in children who received both insulin and placebo, and the trial did not demonstrate an effect on its primary outcome." (Quote from the abstract, but I've removed the numbers to make the English flow better.)  So from an effectiveness point of view, the study was unsuccessful.

Journal Article: https://link.springer.com/article/10.1007/s00125-020-05376-1

Trial Registry: https://clinicaltrials.gov/ct2/show/NCT02547519

Discussion: Oral Insulin has been tested as a possible cure or prevention for T1D for longer than this blog has existed.  In that time, several different clinical trials have been run.  All have been unsuccessful, like this one.   A few have been unsuccessful, but the researchers did extra analysis after the study was over, and found that maybe if they had tested oral insulin in a different subgroup of patients, then it might have worked.  That, in turn, has kept hope of oral insulin alive, and the cycle repeats.

There are three clinical trials of oral insulin which are currently running.  One is a 26 person study by a private company (Oramed).  Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT04150107

The other two are being done at Technische Universität München, and are called Fr1da and GPPAD-POInT.  Both are phase-II studies, of 220 and 1040 people, respectively.  The study reported above is a "proof of concept" version of the GPPAD-POInT. 

Fr1da: https://clinicaltrials.gov/ct2/show/NCT02620072

GPPAD-POInT: https://clinicaltrials.gov/ct2/show/NCT03364868

 

I'm often asked "If the proof concept Pre-POInT-Early study was unsuccessful, why then continue with the much larger, much more expensive GPPAD-POInT study?"  A detailed answer to that question would not fit here, but two things to remember are:

1. There is no requirement of a successful small study in order to run a larger study.  Running a clinical trial requires a safety document (called an IND), money, and interest.  You do not need good results from previous studies, if you already have money.  There is never any regulatory review that previous studies were "successful enough" to start another study.  If the researcher is committed, and has the money, and the safety document, bad results from previous studies don't matter.
2. Researchers are naturally optimistic, and we want them to be.  Most research fails, but we cannot let that stop research in general, or there would be no new breakthroughs.  So we need optimistic (even overly optimistic) researchers to push forward even in the presence of some bad news.  Of course, we don't want to waste money on research which has a history of failures, either, and so it is a tough judgement call.

More Bad News from a BCG Meta Analysis

Years ago, there was a lot of hope that BCG might cure type-1 diabetes, and this lead to several clinical trials.  All of those were unsuccessful.  The only BCG trial still ongoing is aimed  aimed at lowering A1c numbers (so treatment rather than a cure).  Recently a group of researchers, who were not previously involved in BCG research, published a meta analysis which combined data from four different clinical trials of BCG.  Each trial involved giving BCG to people with established T1D and measuring A1c and C-peptides.  The results did not show statistically significant improvement for people treated with BCG:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139880/

So even as a treatment, it appears that BCG is unsuccessful.

Joshua Levy

http://cureresearch4type1diabetes.blogspot.com

publicjoshualevy at gmail dot com

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

 

Ruxolitinib Case Study

Note: this blog reports on a Ruxolitinib case study, it is different than my report last year on a case study of Fenofibrate.  These are different case studies on different drugs; don't mix them up.

 

This blog is different from most of my blogs because I'm reporting on a case study rather than a clinical trial.  A case study is the experience of one person who got a treatment, as reported in a medical journal.  Even the smallest (phase-I) trials usually have 10 or more people enrolled.  But this journal article reports on a single person's experiences with a new treatment.

I'll discuss exactly what happened in more detail below, but the summary is that: In a teenager who has many different health issues including type-1 diabetes, genetic testing found an unusual STAT1 gene which led to a diagnosis of STAT1 Gain-Of-Function Disease (SGOF).  Ruxolitinib is a known treatment for SGOF.  Using it improved the symptoms of many of the issues he faced.  His need for injected insulin gradually decreased until he stopped using it and has been insulin free for over a year as of Oct-2020.

More Details

The person involved had chronic immune triggered yeast infections, chronic diarrhea, oral and rectal ulcers, recurrent infections (otitis, tonsillitis, sinusitis, and bronchitis), and an immune problem causing underproduction of immunoglobulins (called hypogammaglobulinemia). Two years later he was diagnosed with T1D.  Nine months later genetic testing found the unusual STAT1 gene, and he started Ruxolitinib.  This led to some of his previous symptoms resolving, while others improved, including his T1D.  He used less injected insulin and his A1c improved.  After 12 months of Ruxolitinib (21 months after diagnosis of T1D) he stopped using injected insulin completely.

Ruxolitinib is a JAK1/JAK2 inhibitor.  It has been approved for use in the US since 2011, but its use for SGOF is "off label" because its approvals are for cancer and graft vs host disease.  

The STAT1 gene mutation was "c.1154C→T, pT385 M".

The letter was written by these researchers in Houston and San Francisco:
Baylor College of Medicine, Houston, TX: Lisa R. Forbes (lisa.forbes@bcm.edu), Natalia S. Chaimowitz, Sophia J. Ebenezer, I. Celine Hanson
University of California, San Francisco, Medical Center, San Francisco, CA: Mark Anderson

Discussion

The obvious question is: Did Ruxolitinib cure his T1D specifically or did it cure SGOF in general and cured the T1D as a side effect of curing the SGOF?  Or, put more simply: will it work on people who have T1D but not SGOF?

My gut feeling is that this patient has a very different version of T1D than the vast majority of people with T1D.  Something much closer to "MODY", an unusual form of diabetes described here:
https://www.diabetesgenes.org/

However, I'm still interested in testing Ruxolitinib in a clinical trial.  Actually two: one for people who have T1D but not the STAT1 gene mutation, and another for people who have T1D and an unusual STAT1 gene.  A relatively small (10 person/one year) trial would immediately tell us if more research is worthwhile or not.  (And some researchers in Australia have already filed the paperwork to start one of these trials.  See below.)

I do think that people who have T1D and other symptoms related to STAT1 gain-of-function disease should either discuss this treatment with their doctor(s) or get in touch with these researchers.

This patient has already gone over a year without using insulin, so I'm totally comfortable saying that his T1D is in remission.  If others want to call him cured (or maybe temporarily cured), that is reasonable to me as well.  I do hope we get updates to see if this continues.

Sources and Extra Reading

The Letter: https://www.nejm.org/doi/full/10.1056/NEJMc2022226
News: https://medicalxpress.com/news/2020-10-treatment-reverses-young-diabetes.html
Here is some research from mice:  https://pubmed.ncbi.nlm.nih.gov/28292965/
Wikipedia on Ruxolitinib: https://en.wikipedia.org/wiki/Ruxolitinib

Related Research

 

There is an Australian, 83 person, phase-II clinical trial which was registered in February 2020, but has not yet started recruiting.  This study will use Baricitinib which is a different JAK1/JAK2 inhibitor.  This trial will recruit people in the honeymoon phase of T1D.  No STAT1 gene testing will be done, so this it the "T1D with normal STAT1" clinical trial described above.  As is my policy, I'll blog more fully on this once it starts recruiting.

https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=379220&isReview=true

https://mdhs.unimelb.edu.au/research/2018/medical-projects-by-theme/student-research-project/using-the-jak1jak2-inhibitor-baricitinib-to-treat-new-onset-type-1-diabetes

https://researchdata.edu.au/repurposing-jak-inhibitors-1-diabetes/1320460

https://en.wikipedia.org/wiki/Baricitinib

 

A case study of Baricitinib on a person with T1D (and other autoimmune diseases) is described here:

https://www.hindawi.com/journals/crirh/2019/5293981/

The results included "Regarding the influence on slowly progressive type 1 diabetes, the required daily dose of insulin decreased rapidly after the start of treatment (17⟶11 units), and the HbA1c level also decreased (7.4%⟶6.4%)".  No data on C-peptide changes were reported.  

 

Joshua Levy

http://cureresearch4type1diabetes.blogspot.com

publicjoshualevy at gmail dot com

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

Strong Results from a Single Case use of Fenofibrate and Start Of A Clinical Trial

This blog is different from most of my blogs because I'm reporting on a case study rather than a clinical trial.  A case study is the experience of one person who got a treatment, as reported in a medical journal.  Even the smallest (phase-I) trials usually have 10 or more people enrolled.  But this journal article reports on a single person's experiences with a new treatment.

I'll discuss exactly what happened in more detail below, but the summary is that a 19 year-old woman was diagnosed with type-1 diabetes.  She quickly started taking Fenofibrate, which is an FDA approved drug usually used to reduce cholesterol and triglycerides (fatty acids) in the blood.  The results were shocking: her need for external insulin quickly dropped to zero.  After approximately 14 months she stopped testing her blood glucose daily.  She did not need to inject or inhale insulin for 21 months, at which time she still was not using external insulin. (!)

Results

The table below shows two separate data points on each day after treatment started.  The blue line is injected insulin levels per day, and use the blue numbers on the left.  The red line is blood glucose numbers, and use the red numbers on the right.  For blood glucose, they use European units, but the 5 is about 90 in American units, 10 is 180, and 15 is 270.

Image is from the journal article and is presented for educational purposes only.

Starting on day 19, she stopped taking any insulin at all, with one exception: while backpacking in Sri Lanka she was admitted to a hospital with a high fever.  The doctors told her to take insulin as a precaution, and she took 2 units.  You can see that on the 133rd day. 

Prior to treatment, her blood glucose numbers were high, as would be expected of someone newly diagnosed.  Her A1c was 13.5 at diagnosis.  However, her blood glucose numbers rapidly normalized.  After she stopped taking insulin, her blood glucose averaged about 90, with A1c around 5.7%.

As you look at this data, which is amazing, it is important to remember that it is from just one person.

Background on Fenofibrate

Fenofibrate is commonly prescribed for high cholesterol and high triglycerides. In 2017, it was the 70th most commonly prescribed medication in the United States with more than eleven million prescriptions.  However, it is not approved for use in children under 18. It is also sometimes prescribed for diabetic retinopathy (eye damage from long term diabetes), and (off label) for gout.

With a 45+ year history of use in Europe and 25+ years in the US, my assumption is that Fenofibrate is a safe and well understood drug.  As with all drugs, it has side effects, some serious.  However, this drug has been in use for a long time, by a lot of people, who typically use it for a long period of time, so it starts out with as good a reputation as you could hope for.  It has no black box warnings, which are the most serious FDA warnings.  To the best of my knowledge, it has no safety controversies (no class action law suits, no exposés on 60 minute, etc). 

The Clinical Trial

Obviously, the women described in this case study has had the onset of her type-1 diabetes delayed for 21 months (and counting), or possibly it has been entirely prevented, as long as she keeps taking Fenofibrate.  So the key question is: how common is this result?  Is this one person a fluke, or is this the result we should expect from treatment with this drug soon after T1D diagnoses?  The only way to answer that question is through a clinical trial.

A phase-I clinical trial has already (as of 16-April-2020) been started.  It is being run by Dr.     Flemming Pociot at the Steno Diabetes Center in Copenhagen, Denmark.  This trial will enroll people between 16 and 46 years old who are within 6 weeks of their first injection of insulin (ie. just diagnosed).  The primary end point is how much natural insulin the person is creating, as measured by C-peptides.  Secondary end points include A1c numbers and insulin use.  Patients will be followed for 2 years.  There are expected to be 10 children and 48 adults in this study.

Discussion

This follow up clinical trial is exactly what I would expect.  It has more than enough people and they will be followed long enough to get a good feel for the treatment.  It's a randomized, controlled, double blind trial, so the highest quality.  This trial is a safe and conservative way to be sure, in three years, if this treatment is worth an even larger study or not. 

Normally, I would be all in favor of a rigorous study like this.  And I am in favor of doing this study, but I also think it is time to be more aggressive.  The results from this single case study are so strong and so unexpected, that I think we should also start a quicker, smaller  trial, so we can get some data in 6 months rather than 3 years.

The bottom line, is that (because of the 3 year duration and the double blinding), we will not know if this works for 3 years.  However, in the case study, the patient stopped using insulin after only 19 days, and that is a huge, good effect that would benefit honeymooners immediately, and would be obvious if it happened even in a smaller trial.

So I hope that another research team does a second study, starting right now, and running at the same time as the slow, careful, high quality study described above.  This second study would be about 20 people, run maybe 3-6 months, and be open label / no control group.  The advantage of this study is speed.  If this study (which I'll call a "pilot study") is as successful as the case study, then it will be plenty big enough and long enough to show an effect.  In this case study, the patient's insulin use stopped at 19 days, so even a 90 day trial (which is short) would have more than enough time to see that effect.

It is important to remember that some people naturally go through a period during their honeymoon where they don't have to inject insulin (called "spontaneous remission"), or who need to inject very little insulin ("spontaneous partial remission").   I have not been able to find a paper that has a specific number of how often it happens, but it is described in the literature.  This period lasts for a few weeks or a few months, so is much shorter than the 19 months seen in this case study.  However, since it is seen, it is important that the pilot study be large enough to make sure we are seeing a result of the treatment, and not this "spontaneous remission".

Furthermore, the drug is inexpensive and safe.  Even if the drug has no effect at all, the danger of taking a common drug for a few months is tiny.  On the other hand, if the drug has a good effect, it is already approved for use, and could start having that good effect for people with honeymoon T1D years before the slower study would complete.

This is a sort of "fail fast" plan which is common in Silicon Valley web startups.  I'm usually not in favor of "fail fast" for medical research because of the impact on safety.  However, in this case, the drug is well known, and the advantage of a quicker result is large (for honeymooners).  Indeed, I would argue that the fast plan is safer, because if it doesn't work, the people will have gotten the drug for a shorter period of time, and if it does work, they can continue with an "off label" prescription knowing that it does work.

And I want to emphasize, that this plan is not extreme.  With the publication of a (very) successful case study, the next obvious step is a pilot or phase-I study.  For T1D, such studies are commonly about 20 people, commonly 3-6 months, and often don't have control groups.  So they are exactly what I am proposing.  The difference here is that the original researchers are running a larger, longer, more complex study: something closer to a phase-II study.

Questions and Answers About The Case Study

Are we sure she had type-1 diabetes?

It is a good question.  Since all our data comes from one person, if her diagnosis is a mistake, then we have nothing.  When she was diagnosed, her A1c was 13.5% and her max blood glucose level was around 540.  When a 19 year old shows up with those numbers, I don't think anyone would fail to diagnose type-1 diabetes.  In addition she had "minor diabetic ketoacidosis", "polydipsia" (drinking a lot) and "polyuria" (peeing a lot), all of which are classic T1D symptoms.  She tested positive for two T1D autoantibodies.  Although none of her 1st or 2nd degree relatives had type-1 diabetes, her mother had a different autoimmune condition.

Are we sure she did not have MODY diabetes?

MODY, also called monogenic diabetes is a group of rare diabetes which are caused by specific genetic defects.  It is not one disease (like "type-1" or "type-2") but a class of related diabetes.  By some estimates, 1% of the people who think they have type-1 diabetes, actually have a form of MODY diabetes.  These people sometimes need insulin to treat their diabetes, but sometimes oral drugs can be used instead, and sometimes no drugs are needed, except in times of stress (such as pregnancy or flu).  The journal article did not discuss any genetic testing for MODY diabetes.

Has this happened before?

There have been a few cases over the years where someone diagnosed with type-1 diabetes went into remission for a long period of time.  None of them involved Fenofibrate.  You can read three examples below:

https://care.diabetesjournals.org/content/26/4/1314

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612476/

https://edm.bioscientifica.com/view/journals/edm/2014/1/EDM14-0072.xml

For me, these show why a clinical trial is needed.  There is always the chance that this remission was just a random happening, and had nothing to do with the Fenofibrate she was taking.

Might This Cure People with Established Type-1 Diabetes?

I think it is premature to discuss this at all.  The case study was someone who starting taking Fenofibrate within days of diagnosis, so was very much a honeymooner.  But in terms of guessing about the future, there is both positive and negative information.  On the positive side, when it was tested on NOD mice, it cured about half of the mice who already had T1D, and that is a hopeful sign.  On the negative side, because this is a widely used drug, I'm sure it's been used by people with long established T1D, and I would think that someone would have noticed if it cured them.  Similarly, it is surely used on many people who have type-2 diabetes (who often have  high cholesterol or high triglycerides), and it's not known to help their blood glucose levels.

Even more on point: there is a long running clinical trial where people with established type-1 diabetes are given Fenofibrate to stop the progression of retinopathy (eye problems).  This study started in 2016, and is expected to run until 2025.  Blood glucose, A1c, and amount of injected insulin are not end points for this study, however, I would expect that if many patients started using much less insulin (and especially stopped taking insulin at all) someone would have noticed.

But, as with honeymooners, the only way to know if Fenofibrate will work on established T1Ds is to test it in a clinical trial specifically designed to look at this result as a primary end point.  Right now, no such clinical trial has been registered.

Why did this person start taking Fenofibrate right after being diagnosed?

Basically, the woman's father saw a paper which showed that Fenofibrate had good results when used on NOD mice in their honeymoon phase, and so she started taking it.  After 19 days she had this wonderful result, and never stopped taking it.  My understanding is that this was done under the Danish version of "off label use".  The family contacted the researchers who had done the NOD mice study and they wrote up this case study.

Can I take Fenofibrate if I have been recently diagnosed with Type-1 Diabetes?

No.  And yes.  (And this is not medical advice!)  Fenofibrate is a prescription medicine, so you cannot just go out and buy it.  However, it is approved for use in the US since 1993 (and longer in Europe), so your doctor can prescribe it for any purpose.  In the US, this is called "off label use".  I am in no way suggesting that anyone should take Fenofibrate.  That is a question that only your medical team can answer.

Is this for real?

I don't usually discuss researchers when I discuss clinical trials.  My opinion has always been that it is the results of the research that matters and not the previous achievements of the researchers.

However, when I report on especially good results from early research, I am often asked "are these guys for real?"  Of course, "for real" means different things for different people.  However, the three authors of this case study are all at the Copenhagen University Hospital in Denmark.  The have published 200+ 25+, and 10+ papers respectively.  One is a full professor, another the chief of endocrinology.  The person running the clinical trial (who is not one of the authors of the case study), has published over 190 papers, and is at the Steno Diabetes Center, which is world famous. 

In short, these researchers are very much "for real" by my standards.  But the real question is, and always will be, will they be successful?  Will the results from this single person case study be replicated in clinical trials?

More Reading

Short Article: https://asweetlife.org/did-a-common-cholesterol-drug-reverse-one-teens-type-1-diabetes/

Paper: https://www.hindawi.com/journals/crim/2020/6865190

Drug label: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021350s013lbl.pdf

Wikipedia: https://en.wikipedia.org/wiki/Fenofibrate

European Clinical Trial: https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004434-41/DK

Australian Clinical Trial (for retinopathy): https://clinicaltrials.gov/ct2/show/NCT01320345

Background Material:

    https://www.karger.com/Article/Fulltext/479030

    https://www.longdom.org/open-access/remission-in-type-diabetes-whats-new-2327-4972.1000150.pdf

    https://onlinelibrary.wiley.com/doi/full/10.1046/j.1365-2796.1999.00426.x

    https://pubmed.ncbi.nlm.nih.gov/16629716/

Joshua Levy

http://cureresearch4type1diabetes.blogspot.com

publicjoshualevy at gmail dot com

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