Diamyd Update

This is my first update on the Diamyd company in many, many years.  It is focused on their DIAGNODE-3 clinical trial, but before I discuss that one study, I cover Diamyd's history, and after I discuss the study, I've included a list of all the studies the company has done (which is a lot: about 19 studies in about 20 years).

But that is not all that Diamyd is active with.  In a future blog, probably in February, I'm going to discuss two more clinical trials which are important to applying Diamyd to at-risk people and people with LADA.  DIAGNODE-3 is focused on honeymooners.  That future blog will also include some interesting discussion of JDRF's funding of Diamyd.

The drug Diamyd is a form of GAD65.  GAD65 is an enzyme, which is common in the pancreas and is used to make GABA and it is also a target of the immune system which can cause type 1 diabetes.  The company Diamyd believes that the drug Diamyd works by teaching immune cells not to attack beta cells and therefore beta cells will not be destroyed at the onset of T1D.  The technical phrase for this is "antigen-specific tolerizing beta-cell preserving therapeutic".  It is also sometimes called a reverse vaccine, because it teaches your immune system not to attack a specific kind of cell (your beta cells), while a standard vaccine teaches your immune system to attack a cell (the attacking virus).

History

When I first started this blog, in 2006, Diamyd was already one of the potential cures most advanced in the research pipeline.  In 2008 they started two phase-III clinical trials in people in the honeymoon phase of T1D.  If successful, these could have led to government approval.  In January 2009, I considered the start of these clinical trials to be one of the "big-5" best news of the year.  At that time they were also running several phase-II trials to test out Diamyd in other situations.

However, in 2011 one of the phase-III trials ended  unsuccessfully ("did not meet the primary efficacy endpoint"), and in the next year, the other phase-III study was terminated.  In the years after that, several of the previously started phase-II were unsuccessful, and the company started a few more studies, but again none of these were particularly successful.

Later, in 2015 the company started the DIAGNODE clinical trial which involved injecting the Diamyd treatment directly into a person's lymph nodes.  Previous studies injected Diamyd right under the skin, much like insulin.  Results from that study were available in 2020 and the follow on DIAGNODE-2 had results in 2021.  I took a quick look at them, and they did not look successful to me.  (See the details below, the trial was unsuccessful, but also included some results that gave hope.)  So I never blogged on them.

Meantime, the company ran some meta analysis which pooled data from more than one of their studies.  They included some genetic subtyping and the results were successful and statistically significant for some genetic types.  I go into the details below.  This led Diamyd to a much more optimistic view of the results, and so they started the DIAGNODE-3 clinical trial.

The DIAGNODE-3 Trial

This phase-III trial will recruit 330 people in the honeymoon phase of T1D, within 6 months of diagnosis.  They will be between 12 and 29 years old and will have a specific gene called HLA DR3-DQ2.

Each patient will get three injections of Diamyd, one month apart, and also take vitamin-D for 2 months, and will be followed for 2 years.  The primary end points are C-peptides and A1c.  Secondary end points include time-in-range, insulin dose, and unexpected lows.

This study started recruiting in Europe in 2022, but the recent news is that in September 2023 it started recruiting in the United States.  This is a big study, with 60 recruiting locations all over Europe and the United States.  The trial has it's own web page here:
https://www.diagnode-3.com/
which includes a cool interactive map to find a clinic near you:
https://www.diagnode-3.com/Clinics.aspx
(Remember to select your country, if it starts off displaying a different country.)

Diatribe has a good article on this clinical trial as well:
https://diatribe.org/trial-investigates-promising-new-beta-cell-treatment

News Coverage: https://www.precisionmedicineonline.com/business-news/diamyd-medical-expand-phase-iii-diabetes-drug-trial-us
Clinical Trial Registry: https://clinicaltrials.gov/study/NCT05018585
Corporate Web Site: https://www.diamyd.com/

Discussion

For me, there are two areas of discussion for this clinical trial: (a) will it work, when previous research didn't, and (b) will the FDA approve it, based on successful results from this one study, or will more research be needed?

The big question is: will the current clinical trials be successful when the previous ones were unsuccessful?  As far as I can see, there are two differences.  The first is that for the recent studies, Diamyd is injected into a lymph node, while in the older studies it was injected under the skin, far from lymph nodes.  Because the lymph nodes are part of the system that educates immune cells to attack the foreign cells, getting more Diamyd closer to them could make it more effective.

The second difference is that they are only accepting people who have the HLA DR3-DQ2 gene (technically they must "carry the HLA DR3-DQ2 haplotype").  The gene is associated with autoimmune diseases, especially T1D, and it is involved in synthesizing GABA, so again, it makes sense that people with this gene would be more sensitive to the Diamyd treatment. About half the people with T1D have this gene.

Are these differences enough to create success?  The obvious way to measure this is to look at the phase-II DIAGNODE-2 study, which was published here:
https://diabetesjournals.org/care/article/44/7/1604/138800/Intralymphatic-Glutamic-Acid-Decarboxylase-With
https://academic.oup.com/jcem/article/107/9/2644/6602344

Unfortunately, the data is not clear.  This study recruited enough people to run the analysis in a statistically significant way looking at the whole population, but when it was designed the impact of the HLA DR3-DQ2 gene was not known.   After the study started a meta-analysis combining past studies suggested that people with the HLA DR3-DQ2 were much more likely to be helped by the treatment.  So the researchers added a HLA DR3-DQ2 analysis to the study while it was underway and still blinded, but they did not enlarge the study.  Once the study finished, they did their analysis separately: once for everyone and again for people with the HLA DR3-DQ2 gene.  Sure enough, the study was unsuccessful when everyone was analyzed together.  But when just the HLA DR3-DQ2 people were analyzed, the treated group did better than the untreated group.  However, it was not statistically significant.  There were not enough people with that gene in the study to get a statistically significant result.  

In summary, we have three pieces of data:

1. The phase-II study as a whole was unsuccessful.
2. The phase-II study looking just at the one genetype suggests success, but is not big enough to be sure.
3. A meta analysis combining previous studies was successful for the genetype.
   

The phase-III trial is only enrolling people with the HLA DR3-DQ2 gene, and is enrolling more people.  So I do expect a clear yes or no answer from this trial.

As for the question of FDA approval, that is much simpler to answer: no one knows, but the company is optimistic and plans to submit for FDA approval if the clinical trial is successful.  On paper, the FDA requires two phase-III clinical trials, and for T1D these trials involve about 300 people each.  So normally, I would say they need to run another study before getting approval.  

However, "in real life" (as opposed to the "on paper" requirements) the FDA did approve Teplizumab, which did not have two phase-III studies.  Instead, it had one phase-III and several older studies.   And Diamyd has a phase-III study and even more older studies than Teplizumab had.   Diamyd has a long history of safety in previous clinical trials, something like 15 trials covering over 1000 people.   Finally, Diamyd already has an orphan drug designation from the US FDA, and the company believes that will help get approval.

But no one except the FDA knows for sure what will happen if it were submitted for approval based on the phase-III trial currently underway.  The path to approval is clear: Complete the clinical trial, get a successful result, submit for approval, and then it is in the hands of the US FDA.

Diamyd More Generally

Diamyd has run 18 different clinical trials, which you can see here:

https://clinicaltrials.gov/search?term=diamyd

Below, I've organized them into five groups:

 

The DIAGNODE trials which enroll people with the HLA DR3-DQ2 gene and Diamyd is injected into the Lymph node.  These are aimed at getting government approval and turning Diamyd into a product for honeymooners.

More info:

https://clinicaltrials.gov/study/NCT05018585 "DIAGNODE-3" Recruiting honeymooners

https://clinicaltrials.gov/study/NCT05351879 "DIAGNODE-B" Extension to DIAGNODE-2

https://clinicaltrials.gov/study/NCT03345004 "DIAGNODE-2"

https://clinicaltrials.gov/study/NCT02352974 "DIAGNODE-1" 

DIAGNODE expansion trials.  These are using the same DIAGNODE technique, but the first is aimed at people who are at-risk of T1D, not honeymooners, and the second is aimed at people with LADA.  These are the studies I will discuss in a future blog posting.

More info:

https://clinicaltrials.gov/study/NCT05683990 "Diaprecise" Recruiting at-risk 

https://clinicaltrials.gov/study/NCT04262479 GADinLADA" Testing on LADA patients

The DIAPREVENT trials were supposed to get the data required for governmental approval, for what I would call "classic Diamyd", which is injected under the skin (not into the Lymph node), and given to any honeymooner (not just those with HLA DR3-DQ2).

More info:

https://clinicaltrials.gov/study/NCT00723411 Phase-III "DIAPREVENT-2" Unsuccessful 

ended in 2011

https://clinicaltrials.gov/study/NCT00751842 Phase-III "DIAPREVENT" Terminated in 2012

https://clinicaltrials.gov/study/NCT01129232 Phase-II 

https://clinicaltrials.gov/study/NCT00435981 Phase-II

These studies were "Diamyd And" studies, where the company Diamyd tested the Drug Diamyd and one or two other medicines, hoping for better results.  these are all "classic Diamyd" style clinical trails:

https://clinicaltrials.gov/study/NCT02002130 Diamyd and GABA

https://clinicaltrials.gov/study/NCT02387164 Diamyd and Vitamin D

https://clinicaltrials.gov/study/NCT01785108 Diamyd, Vitamin D, and Ibuprofen
https://clinicaltrials.gov/study/NCT02464033 Diamyd, Vitamin D, Vitamin D, and Etanercept 

Other Old Studies:

https://clinicaltrials.gov/study/NCT00837759 NIDDK

https://clinicaltrials.gov/study/NCT00529399 NIDDK (Trialnet?)

https://clinicaltrials.gov/study/NCT00456027 Diamyd on LADA
https://clinicaltrials.gov/study/NCT01122446 For at-risk people, not honeymooners.

https://www.diamyd.com/docs/pressClips.aspx?ClipID=4665003 Reanalysis of two previous studies.

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.

Islet Cell Transplantation Clinical Trails

In this blog I'm going to report on three different clinical trials involving transplantation.  The basic idea for all of these is to transplant beta cells into someone with T1D, and those new beta cells will produce insulin and cure the person.  As I describe below, this idea has been around for 40 years, but it has not been successful in the past because of two problems: First, the body's immune system attacks the transplanted cells because it is working properly and they are foreign cells.  Second, the body's immune system attacks the new cells because it is broken and mistakenly attacks beta cells.  Some people think there is a third problem: beta cell supply, but personally, I'm less worried about that.  These three trials all attack these problems in different ways.

VX-880

A lot of people are excited about this trial because it is generating headlines like "Vertex VX-880 Clinical Results Lead To Insulin-Independence".  This is not a lie, but it is highly misleading.  I discuss the problems with transplants which require immune suppression below (and VX-880 requires immune suppression).  However, it is important to understand that these are not recent improvements.  Transplantation trials have been getting results like this for a long time.

Another reason people are excited about this study, is because the beta cells used here are created from stem cells, and therefore there is an unlimited supply available, and a lot of control over how they are made.  Previous studies used beta cells harvested from cadavers or from pigs, each of which has its own problems of supply. 

For over 20 years islet transplantation  have led to many people not needing to inject insulin for many years (search for "Edmonton Protocol" with Google).  These are the same results seen in VX-880.  They are not seen as a cure, because of the bad effects of immune suppression drugs, which are required, and which must be taken for the rest of the person's life, and because they only work for a few years.  Typically, people do not need to inject insulin for 5 or 10 years, but then they do again.  So headlines reporting on no injecting insulin a year after a transplant are nothing new.

This trial is currently running, but I'm not covering it as a potential cure for T1D.  It requires each person to take a full suite of immune suppression drugs to support the transplant.  They will need to do this for their whole lives, even if the transplant only works for a few years.  Furthermore, the drug combinations used for transplants have significant bad long term side effects, causing health problems in their own right.

Therefore, I view transplants that require life long immune suppression to be trading one drug treatment (T1D) for another (Immune Suppression), and not a cure.  At this point, I'm not even sure which is more dangerous, more hassle, and has more side effects.  

Of course, in medicine, things change over time.  In the future immune suppression may become easier and safer and I might revisit this decision, but until then, for me transplants requiring immune suppression are not cures.  

Clinical Trial Record: https://www.clinicaltrials.gov/study/NCT04786262

VX-264 (Phase-I)

For me, VX-264 is much more interesting than VX-880, even though they both use the same cells, because it does not require life long immune suppression.  In VX-264, the islet cells are encapsulated in a special, high tech membrane.  The membrane allows nutrients and sugars in, and wastes and insulin out, but blocks immune cells.  This is possible because nutrients, sugar, waste, and insulin are all relatively small, while immune cells are relatively large.

This study will enroll 17 adults and everyone will get the treatment (no control group), so I consider this a phase-I trial.  Everyone will have established T1D for at least 5 years.

The outcomes of this trial are a little complex.  Early in the study they will focus on adverse events (side effects) for a total of 2 years after the transplants, but later they focus on C-peptides 3 months after the transplants.  The secondary endpoints include C-peptides, insulin use, and A1c numbers for 2 years after transplant.

They expect to finish in mid 2026.

If successful, this would allow islet transplantation without immune suppression, and that would be a cure for T1D. 

They are recruiting at several locations in the US and Europe.  You can contact them at medicalinfo@vrtx.com or 617-341-6777, or look in the Trial Page or the "Contacts and Locations" section of the clinical trial record, which has an interactive map of the study locations.

Trial Page: https://clinicaltrials.vrtx.com/safety-tolerability-and-efficacy-study-vx-264-participants-type-1-diabetes
DiaTribe Article: https://diatribe.org/join-type-1-diabetes-trial-testing-encapsulated-insulin-producing-cells
News Article: https://investors.vrtx.com/news-releases/news-release-details/vertex-announces-fda-clearance-investigational-new-drug
Clinical Trial Registry: https://www.clinicaltrials.gov/study/NCT05791201 

Discussion

This idea of filtering out immune cells, but letting the smaller stuff in and out of the islet has a long history.  Research had already started in the 1980s, and the earliest clinical trials were running in the 1990s.  Obviously, none of those were successful, which suggests to me that the idea is a lot easier to think of than to actually implement.  The English language idiom is "The devil is in the details."  I'm not sure how many transplantation with high tech membrane type clinical trials have been run in the last 30 years, maybe 5 or 10, but certainly none was successful, so it is a hard problem that Vertex is trying to solve.

VCTX211 (Phase-I)

The VCTX211 clinical trial is also avoiding life long immune suppression. It is being run by CRISPR Therapeutics AG, and combines technology from them with stem cells and encapsulation technology from ViaCyte (since bought by Vertex).  CRISPR is powerful gene editing technology which is too complex for me to discuss here, so I don't, but you can see a list of all the different things they hope to do with it, here: https://crisprtx.com/pipeline.

This trial uses the CRISPR gene editing technique to modify the implanted cells so they are invisible to the immune system.  Therefore, they do not trigger the natural immune system rejection of transplanted organs, nor can the autoimmune attack which triggers T1D affect them.  No long-term immune suppression drugs are required. 

ViaCyte is part of a line of companies that has been trying a transplantation cure since the 1990s, the historical line is Neocrin -> Novocell -> ViaCyte -> Vertex.  

This study will enroll 40 adults who have had T1D for 5 years or longer.  They will be followed for 1 year.  Everyone will get the treatment; there is no control group.  The primary end points include side effects and C-peptide generation.  Secondary end points include several of insulin, A1c, and side effect measurements.

They expect to finish in mid 2025.

This trial is recruiting in two locations in Canada: Edmonton and Vancouver.  You can contact them at +1-877-214-4634 or MedicalAffairs@crisprtx.com.

Clinical Trial Registry: https://www.clinicaltrials.gov/study/NCT05565248

Discussion

This study is absolutely huge, both for T1D and for every other transplantation cure in the world.  Right now, most organ transplantation is a big deal, because it requires immune suppression, which has a whole raft of problems and issues associated with it.  If CRISPR can be used to avoid that, suddenly every form of transplantation is going to become a much better, much more common cure than it was before.

The idea that using CRISPR to make stem cells that could be transplanted to anyone has been an active area of research for years now, and here is an article that covers it from 2019:
https://www.ucsf.edu/news/2019/02/413311/crispr-gene-editing-makes-stem-cells-invisible-immune-system
Although I don't believe that this research was exactly the same as what is being tested in VCTX211.

Recent news on CRISPR based treatments of sickle cell disease:
https://www.statnews.com/2023/12/08/fda-approves-casgevy-crispr-based-medicine-for-treatment-of-sickle-cell-disease/
But it is important to note that for this disease, CRISPR is not used to make the cells invisible to the immunological system.  That is why the VCTX211 clinical trial is so important. 

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.

 

Teplizumab/Tzield Reports Results From A Phase-III in Honeymooners (PROTECT)

Teplizumab (sold as Tzield) was recently approved for use in people at-risk of diagnosis for T1D.  At risk meaning people who have two autoantibodies and abnormal blood glucose measurements, but not yet requiring insulin injections.  However, this phase-III study was testing its effectiveness on people after diagnosis; people in the honeymoon stage.  The goal is to get Tzield approved for honeymooners in addition to the current approval for at-risk people.

This was a large study: 328 people, 217 got the treatment and 111 were in the control group.  The people were all between 8 and 17 years old, within 6 weeks of diagnosis.  They got two treatments with each treatment being 12 days of Tzield infusions.  One treatment is 6 months after the other.

Results

The results are good but not great.  Perhaps a better way to say it, is that they are scientifically good, statistically significant and all that, but it is not clear how much they will matter to families with T1D.

The key result measured how much insulin a person was generating.  During the honeymoon period, it normally drops a lot.  In this trial, people who got the treatment did generate less insulin, but not as much less as people who were not treated.  And the difference was significant.  Untreated people insulin production dropped .21 (pmol/ml), while those who were treated dropped .09.  However, the other question is, does this .12 difference really mean anything?  They are still loosing the ability to generate their own insulin.

They also measured slightly lower insulin use, and slightly lower A1c numbers, but these were not statistically significant, nor were they clinically significant.  Clinically significant meaning important to the people with T1D or their families.  For example, a person who injected 4.6 units of insulin with treatment might have injected 5.8 units without.  That is a differences, but it is not clear how much it matters to the person doing the injection.  The A1c differences were about 0.1%, which is well below the 0.5 difference that is generally considered important.

Press Release: https://www.news.sanofi.us/2023-10-18-TZIELD-R-Phase-3-data-presented-at-ISPAD-shows-potential-to-slow-the-progression-of-Stage-3-type-1-diabetes-in-newly-diagnosed-children-and-adolescents-full-data-simultaneously-published-in-The-New-England-Journal-of-Medicine
Journal Article: https://www.nejm.org/doi/pdf/10.1056/nejmoa2308743
Clinical Trial Registry: https://classic.clinicaltrials.gov/ct2/show/NCT03875729

Discussion

For the company, the big question is: Is this one phase-III trial enough to get approval for an additional population?  I don't know the answer, but I suspect we will all find out in 2024.  Either the FDA will approve it, or they won't.  Once the FDA makes that decision, it will tell us a lot about how the FDA will make future decisions about similar treatments.  However, I don't think it is worth guessing about the decision; better to just wait for it.

For people living with T1D, the big question is: Is it worth it?  That is a decision every person (or family) must make for themselves.  It is a trade off of two 12 day series of infusions so that your body creates more of its own insulin for a longer period of time.  However, it is not clear to me how much this will matter in the long term.  You will still be injecting insulin, just a little less than otherwise.  Many people believe that generating more insulin for longer periods of time will lower the long term bad effects of T1D, and this would be a clear benefit.  However, this has never been measured and no one knows if the effect of this treatment is big enough to matter.

One question I'm sometimes asked is "will doctors be able to play around with the dosing to get better results?"  My answer to that is yes they will be able to, but I don't think they will, at least not aggressively.  Why not?  It is an infusion treatment, which is not going to encourage experimentation.  Also, the drug sometimes has side effects over the 14 days of infusion (things like rashes and decrease in white blood cells), which is not going to encourage experimentation with higher doses, either.  More generally, since the benefit is basically a statistical delay in onset of T1D, if a doctor wanted to experiment, they would not see the results for years, and would only see them in a statistical sense after they had done the experiment on many patients.  I just don't see that happening.

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.

 

JDRF Funding for a Cure 2023

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: 65% of the treatments currently in human trials have been funded by JDRF.  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 JDRF has funded, and those JDRF has never funded.  

 

As a reminder, last year I changed the way I counted treatments in two ways: First, treatments which are subsets of other treatments are counted only once.  For example, if drug X is being tested, and there is a separate test of a combination of X and Y, these are only counted once.  If a third test is testing  X, Y, and Z, then it is still only counted once.  Second, treatments being tested in two different phases of the disease (such as honeymoon and established) are only counted once.

 

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 about 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!

Summary: there is 1 drug approved by the US FDA to delay the onset of T1D symptoms, and it was funded by JDRF:

• Teplizumab by Provention Bio (At Risk)

This is big news!  It is the first drug approved which changes the course of T1D, rather than just treating the symptoms, like insulin.  I'm looking forward to reporting its progress to see how usage expands moving forward.

In Process of FDA Approval

Nothing is in process of approval right now.

Phase-III Human Trials

Summary: currently there are 2 treatments in phase-III clinical trials.  1 is funded by JDRF:

• Oral Insulin (Preventative)
  

Not funded by JDRF:

• Ladarixin by Dompé
  

Phase-II Human Trials

Summary: there are 17 trials in phase-II, and 13 of them have been funded by JDRF, while 4 have not. Here are the treatments that have been funded by JDRF:

• 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)
• Stem Cell Educator by Zhao (Established) 
• 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 14 trials in phase-IIΔ, 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 (Honeymoon and Established)
• Hydroxychloroquine by Greenbaum (At Risk)
• Intranasal Insulin by Harrison at Melbourne Health (Prevention)
• Iscalimab (CFZ533) by Novartis
  
• Rituximab by Pescovitz at Indiana University
• Influenza Vaccination at Aarhus University Hospital

Not funded by JDRF:

• Azithromycin by Forsander
• 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 25 trials in phase-I, and 16 of them are funded by JDRF, while 9 are not. Here is the list funded by JDRF:

• AG019 and Teplizumab by ActoGeniX
• DIMID1 (Faecal Microbiota Transplantation) at AMC Hospital 
  
• CGSF by Haller at University of Florida 
• Golimumab (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)
• PRV-101 (Coxsackie B Vaccine) by Provention Bio (Prevention)
• Semaglutide by Dandona at University of Buffalo
  
• Tauroursodeoxycholic Acid (TUDCA) by Goland at Columbia University
• TOPPLE T1D by Novo Nordisk (Established)
  
• Pro insulin peptide by Dayan at Cardiff University 
• VC-01 by Viacyte (Established)
• VCTX210A by Viacyte/CRISPR (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
• Mesenchymal Stromal Cell by Carlsson at Uppsala 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
59 in total
39 funded by JDRF
So 66% 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

 
Of these treatments 12 (20%) are being tested on people with established T1D, of those, 9 are funded by JDRF.  So 75% of the trials recruiting people with established T1D are funded by JDRF.

Compared to Last Year
In 2022 there were 53 treatments in clinical trials, in 2023 there are 59 (growth of 11%).

In 2023, one treatment was approved by the FDA!
In 2022 there was 2 treatments in Phase-III trials, in 2023 there are 3 (growth of 50%).
In 2022 there were 16 treatments in Phase-II trials, in 2023 there are 17 (growth of 6%).
In 2022 there were 13 treatments in Phase-IIΔ trials, in 2023 there are 14 (growth of 7%).
In 2022 there were 22 treatments in Phase-I trials, in 2023 there are 25 (growth of 14%).

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 both nPOD and Immune Tolerance Network and so I give JDRF credit for clinical trials based on their work.

 

How I Count Trials for This Comparison

• I don't count trials where the JDRF 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. 
  

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 fourteen years:

• https://cureresearch4type1diabetes.blogspot.com/2022/10/jdrf-funding-for-cure-2022.html
  
• https://cureresearch4type1diabetes.blogspot.com/2020/10/jdrf-funding-for-cure-2020.html
  
• 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, 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 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

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.

DFMO Starts A Phase-II Clinical Trial (TADPOL)

Difluoromethylornithine (DFMO), also known as Eflornithine, is FDA approved since 1990 as an injection to treat African Sleeping Sickness (trypanosomiasis) and since 2000 as a cream to prevent excessive hair growth in women.  DFMO has also been approved, for clinical trial use only, as an oral solution to treat certain cancers. 

I have blogged on a previous Phase-IIº  study for this treatment here: https://cureresearch4type1diabetes.blogspot.com/2018/06/alpha-difluoromethylornithine-dfmo.html

This drug lowers polyamine synthesis in beta cells.  Polyamines are a class of chemicals used in beta cells to regulate the production of insulin.  The researchers believe that too many polyamines in beta cells that also have inflammation, is part of the process that leads to type-1 diabetes.  They hope that lowering polyamine synthesis will preserve β-cell insulin production and delay the onset of type-1 diabetes.

The New Study

This study will enroll 70 people, aged 6 to 40, who are within 100 days of T1D diagnosis.  They started in March 2023 and hope to finish in December 2027.  The study chair is Emily K Sims, and funding comes from JDRF and Cancer Prevention Pharmaceuticals.

This is a randomized, placebo controlled study.  About 2/3 of the people will get a dose of 1000mg/m2 (see dose note below) because this was the most successful dose from a previous, small study.  This is two pills per day which they will take for 6 months.  There are two primary end points: C-peptide in response to a meal and side effects.  Secondary end points include more C-peptide numbers and measurements of beta cell stress.

If this study is successful at recruiting, it could be finished much more quickly than scheduled.  They only need to gather data for a total of 12 months (6 while taking the drug, and then 6 more).  That means if they can recruit 70 people in 2 years, the study would be done in 3 years, rather than the 4 years they expect, and even faster if they can recruit 70 people in a year.

More information on the study:

https://medicine.iu.edu/research-centers/pediatrics/research/diabetes/clinical/tadpol https://finance.yahoo.com/news/first-patient-enrolled-jdrf-funded-121500059.html
Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT05594563 

Dose Note

This drug is dosed as mg/m2, meaning milligrams per meter squared.  The dose is based on the skin area of the person getting it.  This is the first time I've seen a drug dosed like that.  I suspect it has to do with the drug's use as a hair growth preventative.

Recruiting

They have already started recruiting in Indiana, and will soon be recruiting at the rest of these sites:

Overall Contacts:
      Maria L Spall     317-278-7034     malnicho@iu.edu    
      Operations Manager     317-278-8879     tadpol@iu.edu

Barbara Davis Center, Aurora, Colorado, United States, 80045
Contact: Lexie Chesshir    303-724-1755    lexie.chesshir@cuanschutz.edu   
     
University of Chicago, Chicago, Illinois, United States, 60637
Contact: Triniece Pearson    773-359-7556    tpearson1@medicine.bsd.uchicago.edu   
        
IU Health Riley Hospital for Children, Indianapolis, Indiana, United States, 46202
Contact: Ellie M Ryan    317-278-7037    elmryan@iu.edu   
Contact: T1D Research    317-278-8879    tadpol@iu.edu   
        
Children's Mercy Hospital, Kansas City, Kansas, United States, 64108
Contact: Heather Harding        
        
University of Michigan, Ann Arbor, Michigan, United States, 48109
Contact: Sheree Nicholson    734-232-4213    nsheree@med.umich.edu   
       
Medical College of Wisconsin, Milwaukee, Wisconsin, United States, 53226
Contact: Joanne Kramer    414-955-8486    jkramer@mcw.edu   

Discussion / Previous Study

The same researcher had previous run a Phase-I clinical trial.  the results of this were published as a poster at IDS 2023.  The key quote on results was: 

An exploratory secondary analysis showed that at the two highest dose levels, treatment with CPP-1X stabilized C-peptide areas under the curve compared to placebo.

However, when I look at the poster results (especially Fig 4A) it looks to me like the placebo group dropped over time (as expected), and the treated group stayed flat.  This does lead to a statistically significant difference at 6 months, but it is not clear to me that it will lead to a cure, treatment, or delay onset, especially when given during the honeymoon when patients are already injecting insulin.  Even if the drug stops loss of beta cells, at that point, the people are already injecting insulin, so I'm not sure it will help much.

On the other hand, for the 1000mg dose group only (the biggest dose given), there is a slight increase in C-peptide generation between 3 and 6 months.  I don't think it is statistically significant, but if we are going to cure T1D, we are going to need to increase C-peptide generation, not just hold it constant in the honeymoon phase.  These are the types of results we are going to need to see, and bigger, in the follow-on study if this line of research is to be successful.

This study also shows the problems we (as a society) face in terms of diversity in clinical trials.  The study involved 41 people.  38 were White, 1 was Black, and 2 are listed as Multiple.   None were listed as Asian, or Hispanic.  They were recruiting in Indianapolis, Buffalo, and Wauwatosa, Wisconsin, and I would think they could do better than that.

Press Release: https://www.biospace.com/article/releases/panbela-announces-poster-presentation-at-immunology-of-diabetes-society-meeting-evaluating-the-potential-of-cpp-1x-eflornithine-in-recent-onset-type-1-diabetes/
The poster itself: https://panbela.com/wp-content/uploads/2023/06/ENDO2023poster.pdf 

 More Information: https://en.wikipedia.org/wiki/Eflornithine

Discussion / Compassionate Use (Right Now)

In the past, I've often said there were two ways to get access to a drug in the USA.  Either through FDA approval for your illness, or through "off label" use if the drug is approved for a different illness.  However, since 2016, there is a third way, called "Compassionate Use".  This is authorized by the 21st Century Cures Act.  I bring it up here, because Orbus, the company developing DFMO has an official Compassionate Use policy, which you can read here:
https://www.orbustherapeutics.com/s/Orbus-Expanded-Access-Policy.pdf

It is quite limited, and completely at the discretion of the company to approve.  Patients (and their parents) can not even request Compassionate Use.  Instead, their doctors must request it.  They will need to fill out an FDA form 3926.

I'm sure there are many rules and requirements for this, but the key ones are that the drug is in active clinical development (phase-II or phase-III), and the patient must have a serious or life-threatening disease or condition. 

I expect to see more of this in the future, as companies (and even later, doctors) get more comfortable with this aspect of the 21st Century Cures Act.  I want to stress, that I'm not mentioning it here because I think this particular drug is a good candidate to ask your doctor to ask the company for Compassionate Use.  As I hope I made clear in the "Previous Study" section, the results so far are not so good that they suggest to me that pre-approval treatment with DFMO is worth the uncertainty and risk.  However, I do think it is important for everyone to understand their options before the situation comes up where they might need to use those options.

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 Pilot Study of Semaglutide in Adult Honeymooners

I've been blogging on research aimed at curing type-1 diabetes for over 15 years, and in that entire time, rarely have I rushed to blog on a new piece of research.  That is because research progresses slowly, and it rarely matters if findings become public this month or next month.  However, the results of this research initially felt so good, that I started rushing.  However, as I've worked more on the posting, I've become less sure of how important it is.  I do think that adults who are in the early part of their honeymoon may want to discuss this with their endocrinology team and consider taking action quickly.  The big, open, unknown question is, should teenagers and children do the same?

The drug in question is Semaglutide, which is sold under several trade names: Ozempic, Wegovy and Rybelsus.  It was approved for use by people with type-2 diabetes in 2017 and for overweight people in 2021.  It is widely prescribed for both of these conditions.  Semaglutide is an example of a class of drugs called Glucagon-like peptide-1 (GLP-1) receptor agonists.  As a receptor agonists it attaches to the same part of the cell as glucagon.  This class includes seven approved drugs, sold under at least twelve different brand names by several "big pharma" companies.

Semaglutide is thought to work in four different ways: beta cells generate more insulin in response to food, the liver releases less sugar, digestion is slowed down, and appetite is suppressed.  The last three can be expected to help anyone with T1D, and the first one to help T1D honeymooners.  Of course, Semaglutide could have other actions in addition to these.

This was not a randomized, controlled, clinical trial.  Rather several endocrinologists knew that Semaglutide had good results in causing beta cells to generate more insulin, and thought this would help their patients, especially those in the early honeymoon phase.  So therefore, they chose to prescribe it "off label".  After having done this for 10 patients for a year, they went back and reviewed their charts.  The data was very positive and they published a correspondence in the New England Journal of Medicine.  There was no external funding for this; they spent their own time. 

This blog is long because the research has many implications, but also some weaknesses, all of which require discussion.

• What Was Found: The Good News
• What Are The Weaknesses: The Bad News
• What Should Honeymooners Do Now
• Next Research Steps
  

What Was Found: The Good News

Semaglutide was given to 10 adults (18 years or older: average age 27) during the first 100 days after they were diagnosed with T1D ("stage 3" in Trialnet terminology).  This was a weekly injection.  They also got standard treatment for T1D in the honeymoon phase.  For this practice, that included daily injections of long acting insulin, short acting insulin with meals, and general advice to eat fewer carbs.  The key results were (these are all quotes from their publication, which I have edited slightly):

• Mealtime insulin was eliminated in all the patients within 3 months.
• Long acting insulin was eliminated in 7 patients within 6 months. 
• These doses were maintained until the end of the 12-month follow-up period. 
• The mean A1c level fell to 5.9 at 6 months and to 5.7 at 12 months. [Normal for non-T1D is below 5.7]
  
• The fasting average C-peptide level increased from 0.65 at diagnosis to 1.05 [Normal for non-T1D is between 0.5 and 2.0.]
• The time-in-range was 89% according to continuous glucose monitoring. 

Obviously, these are some big results.

During the honeymoon phase, people with T1D continue to generate some insulin, so it is quite common to have fluctuating insulin requirements during this time.  Some people go weeks, even months, without needing to inject insulin, and this is even more true of adults.  The results above are much better than seen on average in teenage honeymoons, but I'm not sure how they compare to average adult honeymoons.  I discuss this much more below, in the "weaknesses" section.

I do think it is important that the fasting C-peptide numbers went up for the year of the honeymoon.   (Remember that C-peptide is generated by the same process that generates natural insulin.  So generating more is better because it means the body is also generating insulin.)  In the past, I have seen honeymoon studies where treatments would stop the decline of C-peptide.  The researchers would then compare them to the control group where the C-peptide number did decline, and see a statistically significant difference.  They would say that their treatment "preserved beta cell function".  That's true, but these people already had T1D, and so preserving that did not help them much, and these treatments have not entered widespread use.

But these C-peptide numbers show improvement, not just preservation.  At the end, these people were generating 61% more fasting C-peptide than when they started, they went from 0.65 up to 1.05.  For comparison, non-T1Ds are typically between 0.5 and 2.0.

This study was published as a correspondence in the New England Journal of Medicine (NEJM), which is an important medical research journal.  The authors all work at the University of New York at Buffalo, and the authors have worked on dozens of clinical trials.

What Are The Weaknesses: The Bad News

This study has several weaknesses.  I want to stress that none of these show a mistake or invalidate the results.  They do show the need to run a larger clinical trial, and also more/different clinical trials.  Larger trials validate that this was not just an accidental result and more/different trials show more about who is likely to be helped and exactly what part of the treatment is helpful.

Small Study Size: This study has 10 people, which is common for a phase-I or pilot study, but larger studies are needed to be sure of the results.  Phase-II studies are often 100 people, phase-III studies for T1D cures are usually 300 people, and in other diseases, they are often even larger.

No Control Group: This study has no control group.  That is common for a phase-I trial (especially the first phase-I trial, a "pilot" trial), but it is still a weakness.  The researchers did compare their treatment group to the control groups from 5 recently completed clinical trials, 4 of which were done in adults.  You could say they "borrowed" control groups from these other studies.  

They compared A1c data from their treatment group to the other study's control groups.  This technique is better than nothing, but it is not a true control group, and (for me) using A1c data is a second choice to using C-peptide data.  (Because C-peptide means the body is making insulin, but A1c numbers are influenced by how much people eat and how careful they are in injecting insulin.)  With all those limitations, basically they found that A1c numbers in all the groups dropped for the first 6 months, but then went up in the the control groups.  However, in their treated group, it continued to go down (slightly) for the whole year.

Retrospective: This was a retrospective study, meaning the researchers gathered the data, and then realized there was something important in it, and created the study "backwards" while already holding the data.   Most clinical trials that I follow are prospective.  The researchers design the study, and then recruit the patients, gather the data, and analyze it according to the design done at the start.   There are a large number of potential problems which can occur in a retrospective study that are avoided with a prospective design.  It would take a book chapter, or maybe a whole book, to describe all the potential problems, so I can't even list them here.   In any case, there is no way for me to know if this study actually encountered any of them, and therefore no reason to worry about them.  But this is why a prospective study confirming these results is important.

Impact of LADA: This study enrolled people between the ages of 18 and 49 (average age was 27 and standard deviation was 6 years), so many of these people probably had LADA rather than classic type 1 diabetes.  LADA stands for Latent Autoimmune Diabetes in Adults; you can think of it as juvenile diabetes diagnosed in adults, but we don't call it juvenile diabetes any more.  LADA has a honeymoon, just as T1D does, but it is not the same.  It is well known to be longer and stronger.  Since there was no control group, the researchers compared their patients to patients in other studies of adults in their honeymoon phase of T1D.   I think that is the best comparison available, but it is important that people not compare these results to standard T1D honeymoons seen in teenagers or younger kids. That is not a good comparison.

Correspondence vs. Article: This publication was not a journal article.  Instead it was a correspondence, a shorter work.  I don't know what the NEJM's review and editorial processes is for correspondence and how it differs from other articles.  I don't know how much peer review NEJM correspondence get, if any.

Only Fasting C-peptide Data: I would have preferred to also have C-peptide data from after a meal, but this data was never collected because it is not part of standard care, and these patients were mostly getting standard care (just with Semaglutide in addition).  I like to see both fasting and meal based C-peptide data, because the fasting number just measures the body's ability to make insulin "at rest".  The meal number measures the body's ability to make insulin in response to eating food.  They are both important in different ways, which is why I like to see both.  

No Clinical Trial Registration: This study was not registered with the FDA.  That is normal for this kind of "chart review" / retrospective style of research.  But it still means I don't have as much data on the study as I usually have before blogging.

Restricted Carb Diet: The letter stated "Carbohydrate intake was restricted in all the patients" which initially made me very nervous, because carb restrictions can significantly lower insulin requirements, especially if taken to extreme.  However, in a discussion with one of the authors, I was told that this was simply part of "standard of care" for newly diagnosed T1Ds at their practice.  That all such people are told not to eat excessive carbs.  They were not told to limit carbs to X grams per day, or Y grams per meal, or anything like that.  It was just suggested that they eat fewer carbs as part of a healthy T1D diet.

Inclusion Criteria: The publication does not say how these 10 people were selected to be included in this study.  However, in discussion with one of the authors, I was told that the 10 people included everyone who had been treated with Semaglutide at the practice and followed for a year.  There was no "selection" of people.  Everyone who they had data for was included.  Of course, it is still possible that something about the people who agreed to take Semaglutide or something about how the doctors decided to prescribe it, impacted the findings. 

What Should Honeymooners Do Now

I think that adults (especially those with LADA) who are early in their honeymoon phase have two choices:

The first is to do nothing.  I think that is a reasonable thing to do in response to a 10 person, no control group, pilot study such as this one.  I've gone over the pros and the cons of this treatment above, but it is also important to remember that most research is not successful.  In fact, less than 1% of the successful phase-I clinical trials ever become successful treatments.  So the long term odds of this being successful are low, and doing nothing is a reasonable course of action.  There are some risks both because Semaglutide has known side effects, but also because it has not been fully tested in people with T1D.

The second is to talk to your endocrinologist about it.  Semaglutide is a prescription medicine, so if you want to use it, you will need a doctor to write you a prescription.   For people in the early part of their honeymoon (the first 100 days) it is a very reasonable conversation to have with your doctor.  New medicines and treatments are one of the reasons you have a doctor (and not only a pharmacist).   Semaglutide has been widely used for many years, so there is a lot of safety data available.  However, it is not approved for type-1 diabetes, so a discussion with your doctor about off label use is appropriate.  Doctors have the discretion to use medicine off label.  They have the knowledge of T1D in general and the information about their patients in particular to make good decisions even with uncertainty.

Obviously, one major question is: this study was done on adults, does it apply to teenagers or children?  No one knows the answer to this with certainty, and that is why I would talk to your endocrinologist if you are considering it.

What about non-honeymooners?  Semaglutide has been given to people with T1D for years, usually to treat being overweight.  There is no question it helps lose weight, lowers the amount of insulin used, and generally improves A1c and time in range numbers for most people who use it.  You can read about cases here:

https://t1dexchange.org/semaglutide-type-1-diabetes/
https://www.diabetes.co.uk/diabetes-medication/semaglutide.html
https://www.oatext.com/impact-of-adding-semaglutide-in-a-person-with-type-1-diabetes-a-case-report.php

Next Research Steps

For me, there are several different research programs that this study should motivate, and I think we (as a society) should work on all of them at the same time.

Follow Those 10 People For Years

One of the big questions is, how long will these people avoid injecting insulin.  Obviously a year delay is valuable to some people.  The Teplizumab value proposition is based on a 2-3 year delay.  By simply following these 10 people for years in the future, we can get some data on the longer term effects of this treatment. 

I was able to learn that a couple of the people in the study were no longer being followed because they had moved out of the area or out of the practice.  Also, a few more had stopped taking Semaglutide because they had continually lost weight on it, to the point where they needed/wanted to stop.  But even with this shrinking study size, I'm still interested in what happens to people in the coming years.

One of the worries of a treatment like this is that it is somehow "burning out" beta cells early and that people who get it might do better in the short term, but worse in the long term.   That is the kind of fear that can be removed (or confirmed) by following people for more years.  With less than 10 people, the data will be approximate, but I'm a big believer that some data is better than none.

Run A Larger Phase-II Study on Semaglutide In Honeymooners

I listed a bunch of weaknesses in this research, but the three biggest weaknesses are (a) small size, (b) no control group, and (c) only adults were included.  All of these issues could be resolved by running a larger, randomized, controlled, clinical study which included younger people.  The authors are looking into doing this.  The first step is (always) getting the money.

JDRF: are you listening?  Fund this larger study! 😁

Run A Study On Semaglutide In People "At Risk" of T1D
(By "at risk" I mean "stage 2" in Trialnet terminology.)

One thing that came through very clearly is that C-peptide levels improved with this treatment.  Therefore, it makes sense to try the treatment earlier, when people are still generating more C-peptide naturally.  This is the same progression that Teplizumab went through, and TrialNet is perfectly set up to run a similar clinical trial for Semaglutide.

TrialNet: are you listening?  Organize this longer, stage 2 study! 😁

Survey Honeymooners Taking Semaglutide "Off Label" Now

Finally, I suspect that some younger people are going to get Semaglutide "off label" during their honeymoon in the hopes that they will see results like those seen in this study of adults.  I have no idea if that will be successful or not, but I hope that the doctors who prescribe it in this situation publish the results.  That would be very valuable no matter if it is successful or not.  One of the things I'm worried about is that many people try it, it does not work, but no one publishes the negative results, so people continue to try it. 

Of course, if someone runs the larger phase-II study discussed above, that would give better results than a survey, but a survey might be quicker to organize.  Of course, we could do both, a quick survey and a slower but more definitive phase-II clinical trial.

Lots More To Read

https://www.cnn.com/2023/09/08/health/ozempic-diabetes-semaglutide-study/index.html
https://www.buffalo.edu/news/releases/2023/09/UB-research-semaglutide-Type-1-diabetes-insulin.html
https://www.nejm.org/doi/full/10.1056/NEJMc2302677
https://en.wikipedia.org/wiki/Semaglutide
https://www.novomedlink.com/semaglutide.html

...and you might want to read my previous blogging on Teplizumab, too.

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.

 

T1D Research News (Quick Bits for July)

This blog is a collection of smaller news items about T1D.

COVID Not Likely to Increase T1D in Children

From the beginning of COVID there has been an expectation that T1D rates would go up because COVID would either "cause" or "trigger" T1D.  

(I might be splitting hairs by separating "causing" and "triggering",  but in my mind, these are two different things.  If X causes Y, that means that if the person avoids X they will never get Y.  That X takes a healthy person and they get Y.  On the other hand, X triggers Y, means that the person was always likely to get Y, and X changed the timing so that the person got Y right then, but they still would have gotten Y eventually, even if X had not happened.  I think there is widespread agreement that many illnesses "trigger" a diagnosis of T1D, but the question of weather they "cause" T1D is very much open.)

In any case, this research suggests that T1D diagnosis rates did go up, but not because of COVID, but rather because of changes in behavior due to the lock down.

Source: https://www.news-medical.net/news/20230322/SARS-CoV-2-not-likely-to-increase-the-incidence-of-type-1-diabetes-in-children.aspx

From the article:

More children and adolescents than usual developed type 1 diabetes in Finland in the first 18 months of the coronavirus pandemic. According to a recently completed study, the cause was not the novel coronavirus, but altered environmental factors.

According to the study, the incidence of type 1 diabetes increased in children in Finland by 16% in the first 18 months of the pandemic. However, very few children or adolescents who developed type 1 diabetes had SARS-CoV-2 antibodies indicating a past infection.

According to the researchers, the increase in the incidence of type 1 diabetes in the early stages of the pandemic is not likely to have been caused directly by coronavirus. Instead, it may be related to the society-wide lockdown in the pandemic period and the resulting social isolation.

"According to what is known as the biodiversity hypothesis, microbial exposure and infections in early childhood can boost the protection against autoimmune diseases. The reduction in contacts in connection with the societal lockdown significantly reduced acute infections in children, which may have increased the risk of developing diabetes," Knip [one of the paper's author's] explains.

Combination of GABA and GAD Unsuccessful in Phase-II Trial

I previously blogged on this study here: https://cureresearch4type1diabetes.blogspot.com/2018/08/gaba-starts-phase-ii-clinical-trial-in.html

Summary of results from the abstract:

The primary outcome, preservation of fasting/meal-stimulated c-peptide, was not attained. Of the secondary outcomes, the combination GABA/GAD reduced fasting and meal-stimulated serum glucagon, while the safety/tolerability of GABA was confirmed. There were no clinically significant differences in glycemic control or diabetes antibody titers. ... although GABA alone or in combination with GAD-alum did nor preserve beta-cell function in this trial.

The paper: https://www.nature.com/articles/s41467-022-35544-3
The Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02002130

Discussion

This is a classic example of "slow publishing means bad results".  The study finished in 2019, but the results were not published until 2022.

Also, this is not good news for GAD, which Diamyd has been testing for many years.  One group of this study got GABA and GAD, but did no better than the control group.  If GAD were effective, you would expect to see some good effect in this group.

Abatacept Unsuccessful at Preventing the Onset of T1D

I previously blogged on this study here: https://cureresearch4type1diabetes.blogspot.com/2020/04/possible-cures-for-type-1-in-news-april.html

Summary of results:

This trial of 1-year treatment with abatacept in participants with stage 1 type 1 diabetes did not show a statistically significant effect on progression to stage 2 or stage 3 type 1 diabetes.

This was a 200 person study (half got Abatacept, half got a placebo), for people at-risk of T1D (called "stage 1").  These are people with two or more autoantibodies, so the assumption is that they will move to abnormal blood glucose tests ("stage 2") and then diagnosis of T1D ("stage 3"), as the disease progresses.   The goal was to delay this progression. 

News Article: https://www.hcplive.com/view/abatacept-misses-mark-for-preventing-type-1-diabetes-in-phase-2-trial
Journal Article: https://diabetesjournals.org/care/article/doi/10.2337/dc22-2200/148547/Abatacept-for-Delay-of-Type-1-Diabetes-Progression
Note to the T1D Community: https://www.trialnet.org/our-research/completed-studies/abatacept
Trial Registry: https://clinicaltrials.gov/ct2/show/NCT01773707

Discussion

Abatacept has been tested in several different clinical trials going back at least 15 years.  In a case of unfortunate timing, researchers in Australia started a new Abatacept study about 3 weeks before the unsuccessful results of this study were announced:
https://www.clinicaltrials.gov/ct2/show/NCT05742243
The Australian study is enrolling people who have been diagnosed with T1D, while the earlier study was enrolling people who had 2 autoantibodies, but no abnormal blood sugar tests, and no other symptoms.  So it is possible that one would be successful even though the other has failed, but I think it is a "long shot". 

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.

CELZ-201 Starts a Phase-I Trial (CREATE-1)

CELZ-201 is a stem cell product, where the cells are isolated from the umbilical cord, Wharton’s jelly, placenta, amniotic membrane, and/or amniotic fluid and then treated in a proprietary way.  (I have not found any information on how the cells are treated.)  These cells are used to create a cell line, which is then used to treat everyone who gets the therapy.  This is not the kind of stem cell treatment where a person gets their own cells.  The cells are injected into the dorsal artery of the pancreas.  No immune suppression is required.

The Study

This is a pilot study / phase-I clinical trail, called CREATE-1, which will enroll 18 people within 6 months of diagnosis, who are between 18 and 35 years old.  2/3s will get the treatment and 1/3 will be a control group.  This study is open label / not blinded.

The people enrolled will get one dose of the stem cell product infused into an artery.  They will then be followed for two years.  The primary end point is adverse effects after 6 months, and the most important end point (for me) is a C-peptide measure after one year, which they track as a secondary endpoint.

They started recruiting in April 2023, and are expecting to finish the trial in January 2026. The company involved is Creative Medical Technology Holdings Inc, specifically their AlloStem program.  The study is being run by the Diabetes Research Institute (DRI).

Recruiting

Creative Medical Technology (480) 399-2822
clinicaltrials@creativemedicaltechnology.com
Diabetes Research Institute, University of Miami Miller School of Medicine
Miami, Florida, United States, 33136
Contact: Camillo Ricordi, MD    305-243-6913          

News of IND approval: https://creativemedicaltechnology.investorroom.com/2022-11-03-Creative-Medical-Technology-Holdings-Announces-FDA-Clearance-of-Investigational-New-Drug-IND-Application-for-AlloStem-TM-,-a-Novel-Cell-Therapy-for-the-Treatment-of-Type-1-Diabetes

Clinical Trial Record: https://www.clinicaltrials.gov/ct2/show/NCT05626712

Discussion

This research fits into a long line of research trying to cure T1D in a similar way.  It is a classic "stem cell" cure.  For it to work, the stem cells that they are implanting will need to integrate into the pancreas (to absorb food and oxygen and shed waste products), produce insulin, not be attacked by the body's regular immune system, and avoid being targeted by the immune system (the same immune reaction which triggered T1D originally). 

Creative medical Technologies is a holding company that has several different technologies "in house".  The CELZ-201 treatment comes from their AlloStem line.  But another line of research they are working on is called ImmCelz, and they are currently testing two treatments from that line: CELZ-101 for brittle Type 1 Diabetes and CELZ-001 for Type 2 Diabetes.    Both AlloStem and ImmCelz are cellular treatments (i.e. not chemical drugs, not specific proteins or peptides, but whole cells), and they both have CELZ numbers for identification.  However, they come from different lines of research.

Their Type 2 Diabetes application (CELZ-001) recently had good results in a small trial: 

Researchers released early clinical trial results on an innovative cell treatment for people with type 2 diabetes. After one year, 93% of those who received the treatment safely reduced their insulin doses by at least 50%.

You can read more about it at DiaTribe: https://diatribe.org/positive-results-new-type-2-diabetes-cell-therapy-trial

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.