JDRF Funding for a Cure 2020

In the US, we are in the "Walking Season" when JDRF (Juvenile Diabetes Research Foundation) asks us to walk to raise money for a cure for type-1 diabetes. 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 T1D, which I track.

Let me give you the punch line up front: 71% of the treatments currently in human trials have been funded by JDRF. (And the number is 80% 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.  This message is even more important this year, when JDRF's donations have dropped precipitously due to the COVID pandemic.  This year, more than previous years, it is important to continue to fund research aimed at type 1 diabetes.

In Processes To Submit For FDA Approval
Summary: currently there is 1 drug in process of being submitted to the US FDA for approval for sale, and it was funded by JDRF.

• Teplizumab by Provention Bio (At Risk)

In the forth quarter of 2020, Provention Bio plans to submit Teplizumab for FDA approval.   This application will cover people who are "At Risk" (as described below) for T1D, and the aim will be to delay the onset of T1D by 2-3 years.

Phase-III Human Trials

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

• Oral Insulin (Preventative)
• Teplizumab by Provention Bio 

Note: Teplizumab is listed separately here, because it is being tested separately for people with honeymoon type 1 diabetes.

Phase-II Human Trials

Summary: there are 21 trials in phase-II, and 17 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)
• Stem Cell Educator by Zhao (Established) 
• Tocilizumab by Greenbaum/Buckner at Benaroya Research Institute 
• TOL-3021 by Bayhill Therapeutics 
• TOL-3021 by Bayhill Therapeutics (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-II? Human Trials
Summary: there are 14 trials in phase-II?, and 8 of them have been funded by JDRF, while 6 have not. Here are the treatments that have been funded by JDRF:

• Alpha Difluoromethylornithine (DFMO) by DiMeglio
• GABA by Diamyd
• Golimumab by Janssen
• Golimumab by Greenbaum (Established)
• Hydroxychloroquine by Greenbaum (At Risk)
• Intranasal Insulin by Harrison at Melbourne Health (Prevention)
• Iscalimab (CFZ533) by Novartis
  
• Rituximab by Pescovitz at Indiana University

Not funded by JDRF:

• Azithromycin by Forsander
• Ladarixin by  Emanuele Bosi of Dompé Farmaceutici
• Liraglutid (At Risk)
• NNC0114-0006 and Liraglutide by Novo-Norsk
• Rapamycin Vildagliptin Combo by IRCCS (Established)
• Visbiome by Medical College of Wisconsin

Phase-I Human Trials
Summary: there are 18 trials in phase-I, and 12 of them are funded by JDRF, while 6 are not. Here is the list funded by JDRF:

• AG019 and Teplizumab by ActoGeniX
• Alefacept by TrialNet 
• CGSF by Haller at University of Florida 
• Golimumab by (At Risk)
• MER3101 by Mercia (previously IBC-VS01 by Orban)
• 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:

• AVT001 by Avotres
  
• Baby Teeth Stem Cells by CAR-T Biotechnology
• 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 
• ProTrans by NextCell (Established)

Summary of all Trials
56 in total
40 funded by JDRF
So 71% 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
9 of these treatments (16%) are being tested on people with established T1D.
Of these, 6 are funded by JDRF.
So 66% of the trials recruiting people with established T1D are funded by JDRF.

Compared to Last Year
In 2019 there were 56 treatments in clinical trials, in 2020 there are 56 (no change).
In 2019 there was 1 treatment in process of approval to sell, in 2020 there is 1 (no change).
In 2019 there was 2 treatment in Phase-III trials, in 2020 there are 2 (no change).
In 2019 there were 21 treatments in Phase-II trials, in 2020 there are 21 (no change).
In 2019 there were 14 treatments in Phase-II? trials, in 2020 there are 14 (no change).
In 2019 there were 18 treatments in Phase-I trials, in 2020 there are 18 (no change).

The fact that there were no changes at all from last year is discussed below.

A Little Discussion
The big break through from 2019 was that Provention Bio expected to submit Teplizumab for approval in 2020.  Their most recent press release says they are still on that schedule.  They expect to complete their application to the US FDA in the 4th quarter.  

 

This year was unusual in that the total numbers did not change.  That has never happened before.  The studies were not static, a few clinical trials were removed and a few were added, but the overall counts were remarkably consistent from 2019 to 2020.  This might be because the COVID pandemic has slowed down research, but it might also be something else, or just random chance.

 
The money that we all donate is the thing that is going to move more Phase-II studies into Phase-III studies, the Phase-I studies to Phase-II, create more Phase-I studies, and so on.  If you don't like where we are on research, donating money is the way to make it better.  And if you do like where we are, then money is the way to push these things forward into the market.  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.)

Notes on How Trials Are Grouped

 

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

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.

 

How I Count Trials for This Comparison

• 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. 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. 

Some Specific Notes:

• 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.  
• The PreventT1D study (Vitamin D and Omega-3s) is a "field study" so not included.
• A Rotavirus Vaccine study which was published this year was a population based study, so also not included.
• I've removed Dr. Faustman's BCG research from my list of potential cures, because it is no longer aimed at a cure.  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 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.

This is an update and extension to blog postings that I've made for the previous twelve years:

• https://cureresearch4type1diabetes.blogspot.com/2019/10/jdrf-funding-for-cure-2019.html
  
• https://cureresearch4type1diabetes.blogspot.com/2018/10/jdrf-funding-for-cure-2018.html
• https://cureresearch4type1diabetes.blogspot.com/2017/10/jdrf-funding-for-cure-2017.html
• https://cureresearch4type1diabetes.blogspot.com/2016/10/jdrf-funding-for-cure-2016.html
• https://cureresearch4type1diabetes.blogspot.com/2015/10/jdrf-funding-for-cure-2015.html
• https://cureresearch4type1diabetes.blogspot.com/2014/09/jdrf-funding-for-cure-2014.html
• https://cureresearch4type1diabetes.blogspot.com/2013/10/jdrf-funding-for-cure-2013.html
• https://cureresearch4type1diabetes.blogspot.com/2012/09/jdrf-funding-for-cure-2012.html
• https://cureresearch4type1diabetes.blogspot.com/2011/10/jdrf-funding-research-for-cure-2011.html
• https://cureresearch4type1diabetes.blogspot.com/2010/09/jdrf-funding-research-for-cure-2010.html
• https://cureresearch4type1diabetes.blogspot.com/2009/09/jdrf-funding-research-for-cure.html
• https://cureresearch4type1diabetes.blogspot.com/2008/10/jdrf-funding-of-cure-research-phases-ii.html

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. 

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 or JDCA news, views, policies or opinions. My adult 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.

Iscalimab (CFZ533) Starts a Phase-II? Clinical Trial

Iscalimab, also known by its "code name" of CFZ533 started a phase-II? trial last November, and is expected to finish in October 2022.  Although it has not previously been tested on T1D, it has been tested on other diseases.  A total of 11 clinical studies are either completed or currently underway, including several phase-I and phase-II trials. 

Iscalimab is being developed by XOMA and Novartis.  It blocks a specific type of immune cell, called CD40.  The drug has shown some success in clinical trials on Sjögren’s Syndrome, which is an autoimmune disease like T1D.  It has also shown some success in NOD mice (which are commonly used to test potential T1D cures), although there is some controversy about this result.

 

Iscalimab is a monoclonal antibody, which is created by cloning a single cell that attacks the cell you don't want.  You end up with a vast number of identical cells, all of which attack the cell you don't want.  By carefully choosing the starting cell, you can "target" the monoclonal antibody to attack a very specific type of immune cell.  So if a disease is caused by a specific type of bad cell, then using a monoclonal antibody to target that type of cell is a promising treatment. 

This Study

The study is enrolling 102 people into two groups.  Two thirds will get the treatment, while one third will get a placebo and be a blinded control group.  It is expected to finish in Oct-2022.  The trial is open to newly diagnosed (within 2-3 months of diagnosis) children and youth (aged 6-21). 

The primary end points are aimed at safety (adverse events, i.e. "side effects") and effectiveness as a cure (by measuring C-peptides).  There are a bunch of secondary outcomes most of which are focused on how Iscalimab moves through the body, but two are also focused on effectiveness as a cure: another C-peptide measure and a measure of people who go into partial or complete remission.

 

The study is recruiting at three different sites in Belgium (Edegem in Antwerpen, Jette in Brussel, and Montegnee).  You can contact the people running the study here:   +41613241111    novartis.email@novartis.com or clinicaltrial.enquiries@novartis.com

 

Discussion

One thing unique about this study is that the drug will be given in two different ways.  The first dose will be given "intravenously", meaning into the vein.  This generally must be done under the supervision of a medical professional.   However, after the first dose, all other doses will be given "subcutaneously", meaning under the skin.  This is how insulin is injected, and can be done by anyone at home.

This drug has already completed 5 studies in other diseases, so its safety is well understood, which is why it has skipped a phase-I trial in people with T1D and jumped directly to a phase-II study.   That is why I call this study a phase-II? study.  From a safety point of view it is a phase-II study, but from an effectiveness point of view, it is a phase-I study.

 

Iscalimab is the second T1D drug that XOMA has gotten into clinical trials.  Over 10 years ago, they started a phase-II trial into Gevokizumab (Xoma 052).  That was also a monoclonal antibody, but it targeted a different part of the immune system (called IL-1).  It was unsuccessful.

Clinical Trial: https://www.clinicaltrials.gov/ct2/show/NCT04129528

Also registered in the EU: https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-004553-25/BE

NOD mouse results: https://link.springer.com/article/10.1007%2Fs00125-014-3342-5 

Controversy in CD40 NOD mice research: https://link.springer.com/article/10.1007/s00125-019-4893-2

Genetic Result for CD40: https://academic.oup.com/jes/article/4/Supplement_1/SAT-669/5833379

 

News (not T1D):  

• https://www.novartis.com/news/media-releases/novartis-presents-first-its-kind-histology-data-iscalimab-cfz533-suggesting-extended-survival-transplanted-organs-may-be-possible
• https://atcmeetingabstracts.com/abstract/cfz533-a-new-anti-cd40-mab-demonstrates-comparable-efficacy-and-better-renal-function-versus-tacrolimus-in-de-novo-cni-free-kidney-transplantation
  
• https://pubmed.ncbi.nlm.nih.gov/31512728/
• https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(19)30135-3/fulltext

 

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.

Update On Teplizumab

Here are three recent updates on Teplizumab.  You can read my previous summary of this drug here:https://cureresearch4type1diabetes.blogspot.com/2019/09/teplizumab-phase-ii-results-for.htmland all my Teplizumab postings here:https://cureresearch4type1diabetes.blogspot.com/search/label/Teplizumab

Updates from ADA 2020

The Teplizumab update from ADA 2020 contained several important pieces:

The average delay in onset of T1D rose from about 2 years in the previous reports, to 3 years.  This is based on following the same group of people but for a longer period of time.  My interpretation of this is that some people are simply not helped by this treatment, and they are later diagnosed with T1D.  However, for the people the treatment does help, it prevents T1D for a relatively long time, and as we follow these people for longer, that time gets longer too.  This is a good thing.

People treated with Teplizumab generated more C-peptide, in response to food, in the six months after treatment, then they had before.  This is important because usually, during this phase of the disease, C-peptide generation is slowly decreasing.  (And that was seen in the untreated group.)  C-peptide is generated by beta cells as part of their generation of insulin.  So generating more C-peptide means the beta cells are recovering or regenerating in some way.  Previous studies (in Teplizumab and other drugs) have sometimes shown preservation of insulin production by beta cells.  They stop decreasing.  But to the best of my knowledge, this is one of the few times a drug has shown increases in insulin production by beta cells in a human trial.

People in this study seemed to go through three phases: during the 6 months after treatment, their C-peptide numbers increased.  Then those numbered stayed mostly stable for months or years.  Some people continued to stay stable and were not diagnosed with T1D, while others started dropping and about 6 months after their C-peptide levels started dropping they were diagnosed with T1D.

Obviously, there are a couple of key questions that we don't know the answers to:

1. Will repeated dosing of Teplizumab continue to delay the onset of T1D?
   
2. Will dosing of Teplizumab in people with established T1D lead to increased insulin production, and therefore make their T1D easier to treat?  This study shows that increase for people who are at-risk of T1D, but we don't know about people who already have T1D.
3. Is there are some way to know ahead of time what sort of at-risk people will be helped by this treatment, and which will not?
   

Great write up from JDRF / Beyond Type-1: https://beyondtype1.org/teplizumab-updates-ada-2020/

Video from the researcher: https://www.facebook.com/watch/?t=42&v=264451347972017

Abstracts of the two ADA 2020 presentations:

    https://diabetes.diabetesjournals.org/content/69/Supplement_1/276-OR

    https://diabetes.diabetesjournals.org/content/69/Supplement_1/277-OR

Starting A Phase-II Trial In Honeymooners

The same group that ran the successful study to see if Teplizumab could delay the onset of T1D are now running a follow-up trial.  People previously treated with Teplizumab, but who later came down with T1D, are treated again with Teplizumab to see if it has any effect on the course of their T1D.   Remember, the previous effect was to delay the onset of T1D, so now we will learn if doses after diagnosis make for a slower onset or preserve some beta cells.

This is a 30 person study.  Everyone will get the treatment and will be followed for 18 months.  No control group.  The study's primary end points are safety related, but the secondary end points include C-peptide production (showing if the body is generating its own insulin) and several other measurements.  They started in March 2020 and hope to finish in August 2024.

This study is only open to people who took part in the earlier Teplizumab study titled Teplizumab for Prevention of Type 1 Diabetes In Relatives "At-Risk"  which is TrialNet study TN-10. The contact information for this study is Provention Bio Chief Medical Officer, 908-356-0514, eramos@proventionbio.com

Registration: https://www.clinicaltrials.gov/ct2/show/NCT04270942

Ongoing PREVENT Trial

There is also the ongoing PREVENT trial of Teplizumab.  This is a phase-III study being done on honeymooners.  Due to COVID-19, they have paused recruiting new patients into this study, but when the emergency is over, they will restart recruiting.  This study needs 300 people.  You can read the study's web page here: 

https://theprotectstudy.com/home/

and the trial registry here:

https://clinicaltrials.gov/ct2/show/NCT03875729

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.

Two New Clinical Trials (HCQ and Baby Teeth Stem Cells)

Hydroxychloroquine to Prevent Type 1 Diabetes

Hydroxychloroquine (HCQ) has been in the news recently because of claims that it may treat/cure COVID-19.  However, for this blog, I thought I'd update people on the clinical trials that are testing Hydroxychloroquine as a prevention of T1D.  (Note that HCQ has some T2D applications, which I'm not discussing here.)

Hydroxychloroquine is approved in the US for treatment and prevention of Malaria and some autoimmune diseases, such as Lupus and Rheumatoid Arthritis.  There are two reasons to think it might help with type-1 diabetes.  First, it helps with other autoimmune diseases.  Second, it is an anti-inflammatory and inflammation is seen in the pancreas of people with type-1 diabetes.

A large HCQ  trial started in Aug-2018 and is expected to run until Aug-2024.  The goal is to enroll 201 people who have tested positive for two autoimmune antibodies, but have not shown any symptoms of T1D.  During the study, people will take a pill, either HCQ or a placebo.  They will be followed for years to see how many are diagnosed with type-1 diabetes.  It is being run by the Type 1 Diabetes TrialNet, led by Carla Greenbaum, and JDRF is helping to fund it.

The study is double blinded, so publishing any information prior to completion in 2024 would be very difficult, and (to the best of my knowledge) no interim results have been published.

The study is recruiting people at 40 different sites all over the US.  You can read more about the study here:

https://www.trialnet.org/our-research/prevention-studies/hydroxychloroquine-hcq

the list of recruiting locations is in the Clinical Trial Registry:

https://www.clinicaltrials.gov/ct2/show/NCT03428945

to see the limitations due to COVID-19 read this:

https://www.trialnet.org/events-news/coronavirus

Personal note: I know there is a lot of interest in HCQ as a COVID-19 treatment.  I have not been systematically tracking every study done in that area.  However, I can boil down what I have seen into six bullet items:

1. In order to get a drug approved for use in the US, in normal times, there must be three high quality studies done which show safety and effectiveness (one phase-II study and two phase-III studies).
2. Right now, there are zero high quality studies showing HCQ's impact on COVID-19.  Zero.  And that covers trials which were successful and trials which were unsuccessful.  Every trial I've seen reported, in both the scientific literature and the popular press, has been low quality.  By low quality I mean either no control group, no randomization, or it is not an intervention study at all:  very basic stuff.  I'm not quibbling about size, protocol, or even publication.
   
3. There have been several low quality studies done on HCQ and COVID-19.  These studies show approximately a 1 to 2 to 1 ratio of good to bad to neutral outcomes.  So for each 4 low quality studies done, 1 has shown success (improved outcomes), 2 have shown failure (meaning higher death rates or other bad effects), and 1 has shown no difference.
4. Because high quality research is slower and more expensive than low quality research, under normal circumstances I would never expect anyone to fund a high quality clinical trial based on the terrible results of the low quality studies done so far.  However, these are not normal circumstances, so there might be a high quality study done.  If one is done, those results will carry more weight than the stuff published so far. 
   
5. Because of how clinical trials work, low quality research is far more likely to be positive than high quality research.  If you are getting unsuccessful results 3 out of 4 times with low quality results, you're not going to get successful results in higher quality studies.  That's just not the way it works.
   
6. The last gasp of the true believers in a situation like this is to point at the large number of unsuccessful results, and say that they are all low quality results.  (The same is true of the small number of successful results as well, but they will not dwell on that.)  Therefore the idea is not disproven, because a high quality result would carry the day, if it were done.  Notice the switch where they are requiring mainstream science to prove their idea wrong, rather than the scientific method where new ideas must be proven correct by the proponents.  However, in real life, no one will ever do the high quality study, because the low quality studies are failing.  The true believers will blame a conspiracy, and the matter will die. 
   

Stem Cells From Baby Teeth Starts A Phase-I Study

This study is of personal interest to me.  My daughter was diagnosed when she was 18 months old.  When she started loosing her baby teeth it was known that each one contained a tiny amount of adult stem cells and there were companies that could freeze the teeth for later use.  At the time, little was known about how to get adult stem cells or what they could do.  But since our daughter already had T1D it seemed like something worth doing.  So we had some of her teeth preserved.   However, a few years later, there were many more known sources of adult stem cells, and the uses of adult stem cells were better known and T1D had not shown any successes with these kinds of adult stem cells.  So we stopped paying our storage fees.

Now, many years later, this is the first clinical trial I have seen that attempts to use the adult stem cells in baby teeth.

This study started in January 2019 and is expected to finish in December 2020.  It enrolled 24 people who had either T1D or T2D.  There is no control group.  Each person will get three injections of stem cells from baby teeth and then be followed for a year.  Primary outcomes are insulin usage and C-peptides (which measures how much insulin the person is creating naturally).  Secondary outcomes include A1c, blood sugar numbers, and proinsulin generation (another measure of how much insulin the person is creating naturally).

Clinical Trial Registry: https://www.clinicaltrials.gov/ct2/show/NCT03912480

The clinical trial record contains this note, and I've never seen anything like it before: "Note: at 1 month follow-up (V5) after the last transplantation of several cells, the subjects were still unable to discontinue insulin, and then began the second course of stem cell therapy. After the second course of treatment, the follow-up plan was resumed."

My interpretation of this is that the study is fully enrolled, and that (so far) no one has been cured.  This comment seems to imply that the researchers thought they might see some outright cures in the study, and these seems very optimistic to me.

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.

News from ADA 2020

June 12th to 16th was ADA 2020, the scientific sessions of the American Diabetes Association, which is the largest diabetes focused medical conference in the world.  This year, the scientific sessions were all on line.   As in previous years, I did not attend, but I did read publicly available information and watched the tweets and Facebook posts which discussed the talks.  Finally, I exchanged information with the JDCA as they covered the sessions as well.

There are scores of talks and 100s of posters; far too much for me to cover all of it.  Also, about 90% of the content was focused on type-2 diabetes.  After all, about 90% of the people who have diabetes, have T2D.  So what I've done is included a paragraph describing some of the bigger, more interesting news ideas, and after each paragraph some links which can tell you more about it.

I've divided the blog up into these sections:

1. Summaries
2. Cure Focused Research
3. Better Devices
   
4. Treatment News
5. Diversity and Diabetes Research
   

Summaries

Overall, I think that BeyondType1 has great summaries of the news from ADA 2020:

• https://beyondtype1.org/breaking-news-from-ada-2020/
• https://beyondtype1.org/ada-2020/

The JDRF did a video summary of each day:

• Friday: https://www.facebook.com/myJDRF/videos/280116049805425/
• Saturday: https://www.facebook.com/watch/?v=577045256556446   Last part of third speaker (low dose IL-2) is most important.  First speaker is slightly important.
• Saturday: https://www.facebook.com/watch/?v=577045256556446
• Monday: https://www.jdrf.org/blog/2020/06/16/adas-scientific-sessions-day-4/
• And this was JDRF's summary of the research they funded:  https://www.jdrf.org/blog/2020/06/17/ada-jdrf-funded-research-takes-center-stage-happy-hour-aaron-kowalski/

ADA

• Monday summary: https://youtu.be/htn0Yb7qjcw
• Tuesday summary: https://www.youtube.com/watch?v=kN76eMfjGbs&feature=youtu.be

diaTribe's Sunday summary: https://bit.ly/2YJh8yB

Cure Focused Research

I hope to write blog postings on each of these results in the future.

Teplizumab Gets Better

Teplizumab already had some of the strongest results seen in terms of being able to delay the onset of type-1 diabetes, and there was an update this year which showed longer, stronger results.  My previous blogging is here: https://cureresearch4type1diabetes.blogspot.com/search/label/Teplizumab

• https://twitter.com/BeyondType1/status/1272988512464375810
• https://beyondtype1.org/teplizumab-updates-ada-2020/
• https://www.facebook.com/watch/?t=24&v=264451347972017
• https://twitter.com/DUK_research/status/1272891016354422791

Anti-IL-21 and Liraglutide

The hope is that the first drug will stop the autoimmune attack and the second drug will regrow beta cells.  My previous blogging is here: https://cureresearch4type1diabetes.blogspot.com/2017/09/possible-cures-for-type-1-in-news.html

• https://twitter.com/CristobMorales/status/1272788910377140224
• https://twitter.com/CristobMorales/status/1272788112385728514
• https://twitter.com/CristobMorales/status/1272786985313329153

Combining Treg and anti-CD20

These two treatments have both been tried before, but this is the first time they have been tried together.

• https://www.diabetesdaily.com/blog/new-therapy-shows-promise-in-children-with-newly-onset-diabetes-ada2020-659034

Ladarixin

Looks like the results from a trial I've blogged on before: https://cureresearch4type1diabetes.blogspot.com/2016/08/ladarixin-starts-phase-ii-clinical-trial.html

• https://twitter.com/Cortellis/status/1272915415015055360

Golimumab

My previous summary of research is here: https://cureresearch4type1diabetes.blogspot.com/2018/10/golimumab-update.html.

• https://twitter.com/Ilmiodiabete/status/1272901764908486657
• https://ilmiodiabete.com/2020/06/16/ada2020-golimumab-preserva-la-funzione-delle-cellule-beta-in-bambini-e-giovani-adulti-con-diabete-di-tipo-1/

ATG

My previous posting on ATG: https://cureresearch4type1diabetes.blogspot.com/search/label/ATG

• https://twitter.com/DUK_research/status/1272895469501513734

Better Devices

There was a lot of news about new and improved devices.  Here are three summaries:

• https://beyondtype1.org/closed-loop-updates-ada-2020/
• https://www.healthline.com/diabetesmine/diabetes-tech-spectations-2020?utm_source=twitter&utm_medium=social&utm_campaign=diabetesmineom
• https://www.diabettech.com/uncategorized/more-commercial-aid-systems-what-do-the-trials-tell-us/

Medtronic

The big news was results of pivotal trials of the 780G (also called "AHCL") which just got approved in Europe and should be approved in the US soon.

• https://t.co/jU3TkK8tdT
• https://twitter.com/Drhja/status/1271549892582952960/photo/1
• https://twitter.com/_RomanHovorka/status/1271535984186982400

Insulet

Good results from a clinical trial.

• https://twitter.com/BeyondType1/status/1271544779357085696/photo/1
• https://www.businesswire.com/news/home/20200611005178/en/Insulet-Presents-Omnipod-Virtual-Care-Experience-Pre-Pivotal

Tandem

Mostly data on Control-IQ.

• https://www.tandemdiabetes.com/blog/post/general/2020/06/10/don't-miss-these-presentations-at-ada-s-80th-scientific-sessions-featuring-tandem-technology

Are Sets The Problem?

There was some belief that the next generation of Artificial Pancreas / Automated Insulin Delivery devices might be so good that the main barrier to use would be the sets, rather than them pumps:

• https://twitter.com/BeyondType1/status/1271546453958119424

DIY ("We are not waiting.")

There was a lot of buzz about various "do-it-yourself" devices.  I'm sorry I only saved this one reference, because there was a lot more going on:

• https://diyps.org/2020/06/13/poster-and-presentation-content-from-danamlewis-at-ada2020-and-ddata20/

iLet

• https://twitter.com/drfrasergibb/status/1271937794412351489

One Drop (Four Hour BG Prediction)

• https://beyondtype1.org/one-drop-ada-2020/

Treatment and General News

T2 Movie On PBS

There was a lot of excitement about this movie, although it focuses on T2 rather than T1:

• https://www.pbs.org/wgbh/blood-sugar-rising/

New, Faster Insulin

Patients like faster insulins because they lower BGs; companies like newer insulins because they are covered by patents for longer.  This Insulin is faster and newer.

• https://twitter.com/DiabetesMine/status/1272731367504216066

Weekly Insulin

There were phase-II results from a clinical trial on a weekly insulin.  This is a basal insulin (like Lantus) except that it only needs to be injected once a week, not once a day.  It was compared to Lantus and was just as effective.

• https://twitter.com/AmarPut/status/1272321339270070279
• https://www.medscape.com/viewarticle/932304?src=soc_tw_200616_mscpedt_news_mdscp_ada20&faf=1
• https://www.mdmag.com/conference-coverage/ada-2020/todd-hobbs-positive-results-once-weekly-insulin-vs-glargine
• https://diabetes.medicinematters.com/ada-2020/insulin-icodec/first-weekly-insulin-glargine-in-type-2-diabetes/18088110
• https://twitter.com/CristobMorales/status/1272888968430977026
• https://twitter.com/DanielJDrucker/status/1272244035726520321
• https://twitter.com/DrMoyaMendezE/status/1272308446537400321
• https://www.adameetingnews.org/live-updates/session-coverage/experts-will-analyze-the-potential-of-once-weekly-insulin/
  

TIR vs. A1c

Another debate which I expect to remain "hot" for the next few years is the Time In Range (TIR) vs. A1C debate.  Which is better for measuring the success of a new drug or device, and therefore which is better for patients?  Because better measurements in research lead to better treatments and hopefully cures in the future.

• https://twitter.com/dr_ralkhalifah/status/1271909577521614848
• https://twitter.com/RanjanAjenthen/status/1272189634387329024
• https://beyondtype1.org/pediatric-diabetes-care-success/
• https://www.ajmc.com/conferences/ada-2020/covid19-is-changing-the-a1c-vs-timeinrange-debate-expert-says
  
• https://www.adameetingnews.org/live-updates/session-coverage/a1c-is-a-critically-important-biomarker-kelly-west-award-lecturer-says/
• https://www.adameetingnews.org/live-updates/session-coverage/joint-symposium-to-examine-role-of-time-in-range-in-pediatric-diabetes/

I have two opinions on this debate:  First, I don't see how it is that important.  I have never seen a study where TIR led to a different conclusion than A1c.  Quite the opposite, in studies that measure both, if the TIR data shows one device is better than another, then the A1c data will show the same thing.  So arguing about which is "better" is pointless splitting of hairs.  Second, there are clear differences in how easy they are to use, and that is likely more important than one being "better" (ie. more predictive) than the other.  For example, TIRs can be measured at home, by the person with T1D.  But A1c is a single number with no ambiguity so easier to use in data analysis.   (A1c of 5.5 is better than 5.6, but if someone has BG way too high for 1 hour is that better or worse than being a little too high for 2 hours?)  But, it is a lively debate, and I don't think it will end soon.

TP-399 (treatment, not cure)

This drug is being tested as therapy that you take for T1D in addition to insulin.  The study found that it could lower A1c by .32 or raise your time in range by 2 hours.

• https://vtvtherapeutics.com/wp-content/uploads/2020/06/Simplici_T1-_Part-2_ADA_ePoster1_Final-draft-for-Submission_6-5-2020.pdf
• https://vtvtherapeutics.com/pipeline/ttp399/

One Hormone vs. Two

I suspect that the next big debate in devices will be between Artificial Pancreas devices which use insulin vs. those that use insulin and Glucagon.  The current trade off seems to be an average of 10 points lower BG numbers vs. the added hassle of two drugs as opposed to one. 

• https://twitter.com/T1DExchange/status/1272247346433269762
• https://twitter.com/BeyondType1/status/1272258669841793024
  

TrialNet Talks
https://www.adameetingnews.org/live-updates/session-coverage/trialnet-continues-to-advance-type-1-diabetes-research/?utm_source=twitter&utm_medium=social&utm_campaign=ADA-2020-Issue7-medmtg.news&utm_content=link-share

Microbiome based prevention:

The idea that bacteria in the gut might cause T1D or impact it's severity is comes up most years at ADA.  This is a summary of some JDRF funded research looking into it:

• https://twitter.com/emmahwlab/status/1271933990757269504
• https://twitter.com/JDRF/status/1271867170524364801

TEDDY

TEDDY is a large, long term study aimed at finding causes and environmental triggers for T1D.

• https://www.healio.com/news/endocrinology/20200616/teddy-data-early-type-1-diabetes-signals-environmental-triggers-and-diet-associations
• https://www.adameetingnews.org/live-updates/session-coverage/teddy-study-providing-insight-into-the-type-1-diabetes-disease-process-in-children/

Two T1Ds or One?

This is another topic which might turn into a larger debate.  It is generally understood that people who get T1D when they are younger have faster onsets (shorter honeymoon phases) and generally stronger disease symptoms.  But is this because younger people are struck by a different (and stronger) form of the disease, or does everyone get the same form of the disease, it is just that people diagnosed younger have the disease for longer?  Are there two forms of type-1 diabetes (younger onset and older onset), or just one form (which varies in strength from person to person)?

• https://twitter.com/PracDiabetes/status/1272833143008104449

Hiding Cells from the Immune System

Something about beta cells is targeted by the immune system.  This research is attempting to change beta cells, so that the immune system can not target them:

• https://twitter.com/DUK_research/status/1271488267783938048

Diversity In Diabetes Research

This ADA conference was held against the backdrop of Black Lives Matter.  I've included some of the more eye-opening research on race and diabetes below.  (Personal note: I tried to write a short introduction to racism and diabetes research for this section.  However, the subject is too complex and too impactful to be summarized so briefly, at least with my writing skills.  I hope to blog on it in the future, giving it the space it deserves.)

Black vs. White Gestational Diabetes

One tweet on the difference, and one on part of the cause.

• https://twitter.com/diaTribeNews/status/1271546920943726598
• https://twitter.com/diaTribeNews/status/1271542282941063170

Lack of diversity in device design:

• https://twitter.com/KyleJacquesRose/status/1271931686150799361
• https://twitter.com/AaronNeinstein/status/1271930476404465664
• https://twitter.com/KellyRawlings/status/1271927510381416450

Other diversity issues:

• https://twitter.com/diaTribeNews/status/1271884744645582856

AP with Different Starting Points

When companies test new devices they often end up testing them on "good diabetics" by which I mean people who already have good management, already see their doctors regularly, and have the money to buy good medicine in the US.  So the tests end up showing that someone who is already in good shape will be even better with the new device.  But that excludes people who are not doing well to start (who arguably need new devices more), and does not give a realistic whole-population view of the new device.

• https://twitter.com/drfrasergibb/status/1271559840754798592

Protest Notes

• Protest Safety from Stanford:  https://images.squarespace-cdn.com/content/v1/5a138c2df6576e7fb23868e8/1591385230753-Y29ET2BJV6N64N2RPRSS/ke17ZwdGBToddI8pDm48kNbVcG6eoqiDW377nMeQfaZZw-zPPgdn4jUwVcJE1ZvWQUxwkmyExglNqGp0IvTJZamWLI2zvYWH8K3-s_4yszcp2ryTI0HqTOaaUohrI8PI8PJ9KihTSnTM1L1doN1MMYzJemeN8RIdEQJIGd6NIK0KMshLAGzx4R3EDFOm1kBS/DW+Guide+to+Protesting+with+Diabetes.jpg?format=1000w
• Protest Dangers: https://www.facebook.com/NowThisNews/videos/vb.341163402640457/269053317631403/?type=2&theater

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.

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

This blog posting is a summary of four small updates.  Unfortunately, they include research delay, two unsuccessful trials, and one trial unreported for so long that I'm now assuming that it failed.

Tianhe Delays Phase-II Trial of Stem Cell Educator

You can read my previous blogs on Tianhe's Stem Cell Educator here:

https://cureresearch4type1diabetes.blogspot.com/search/label/Stem%20Cell%20Educator

The quick summary is that the stem cell educator is a machine which takes the immune cells from a person's blood, exposes them to various organic molecules which change their behavior so they learn not to attack beta cells. The cells are then returned to the body.

Unfortunately, the new news is that clinical trials for the Stem Cell Educator have been delayed by three months because of the COVID-19 pandemic.  You can read the announcement here: https://www.facebook.com/tianhecell/posts/1149765802041857

I suspect that some other clinical trials are getting delayed as well, but since there is no central clearing house for these kinds of announcements, it is hard to know for sure.

Also new (to me) is that Dr. Zhao has a fund raising page through the hospital where he does his research.  So if you want to fund his research directly, you can do it here:

https://secure2.convio.net/humc/site/Donation2;jsessionid=00000000.app20058a?4622.donation=form1&DONATION_LEVEL_ID_SELECTED=1&NONCE_TOKEN=F031AB361B3FAE40A58FDBF166E9EE74&df_id=4622&idb=0&mfc_pref=T&fbclid=IwAR0fYn6E7Y--EzfHeoR5rcNLKdQK-3WWUrgywEZH6zPZEVx2EI8N87tg6Xo

Unsuccessful Phase-II? Study of Albiglutide

Albiglutide (tradenames Eperzan and Tanzeum) is a GLP-1 inhibitor, similar to Byetta, Victoza and other drugs commonly used by people with type-2 diabetes.  GlaxoSmithKline tested it in people with type-1 diabetes, to see if it had the potential to delay T1D or cure them.

Unfortunately, it was not successful.  Their conclusion was:

In newly diagnosed patients with type 1 diabetes, Albiglutide 30 to 50 mg weekly for 1 year had no appreciable effect on preserving residual β-cell function versus placebo.

I previously blogged about this research here:

https://cureresearch4type1diabetes.blogspot.com/2016/01/research-in-news-january.html

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02284009
Wikipedia: http://en.wikipedia.org/wiki/Albiglutide

Unsuccessful Phase-II for Low-dose IL-2

Interleukin 2 (IL-2) is a protein that the body's immune system uses for communications.  It is part of the system that helps the immune system identify the body's own cells from foreign cells.  Since the root cause of type-1 diabetes is a failure in this process, IL-2 is a possible cure.

This study enrolled 24 children in their honeymoon phase into 4 different groups: one placebo group and three different treatment groups.  The primary outcome was higher levels of a specific immune cell called a Treg cell.  Higher levels of Tregs are thought to help prevent T1D.  Secondary outcomes included direct measures of T1D: how much insulin the person produced naturally (as measured by C-peptides) and A1c numbers.

The study showed that treated honeymooners did generate more Tregs. This result was statistically significant and was higher in the higher dose treatments.  However, the secondary outcomes (which measured effect on T1D symptoms) were not statistically significant.

In 2016, I published a blog which was a summery of the 6 clinical trials using IL-2 at that time:

https://cureresearch4type1diabetes.blogspot.com/2016/05/general-update-on-il-2-research.html

You can read all my blogging on IL-2 here:

https://cureresearch4type1diabetes.blogspot.com/search/label/IL-2

My informal summary of all this research is that IL-2 causes more Tregs to be generated, but does not cause more insulin to be made, or impact A1c.  The key measure of progress to a cure is how much insulin a person is naturally creating and (so far) IL-2 is not increasing that.

Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT01862120

Abstract: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3384899

Whole Paper: https://poseidon01.ssrn.com/delivery.php?ID=292084092121074084075006078065124119003088025016027009096102007033048103037118051096057092059036018012018012106018002009032090052021085105123103112121126100107039085023106102024117103092096081021001102126003094018118025077005022012013064085005024&EXT=pdf

Unsuccessful Phase-I Study of Ustekinumab and INGAP: No Results After Three Years

My policy is that any study which has not published within two years of completion is unsuccessful.  My experience has always been that studies that are successful are published quickly: within one year.  So when a study goes three years, as this one has, without publishing its results, I'm very comfortable assuming that it was unsuccessful.

I have tried, more than once, to contact the researchers involved to get an update, but never got a reply.

Previous Blogging: https://cureresearch4type1diabetes.blogspot.com/2016/01/exsulin-ustekinumab-combo-starts-phase.html

Clinical Trial Registry: https://www.clinicaltrials.gov/ct2/show/NCT02204397

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.