Thursday, April 24, 2025

Sana Biotechnology Reports First Results For Islet Transplants Without Immunosuppression

This blog post reports on some news that I consider exciting, for at least two different reasons: first because it might be an early milestone on a path that leads to a practical cure of established T1D.  The second because it could speed up research into similar cures.  However, it is important to understand what is actually new and unique about this news, and how it differs from previous news that sounds similar.




Background: Islet Transplants Without Immunosuppression

At least 50 years ago, it was pretty clear that the beta cells of people with T1D were destroyed, and that gave hope that transplanting in new beta cells might cure T1D in a straightforward way.  It did not happen, because the new cells were attacked by the body's immune system for two reasons: (a) they were foreign cells so the immune system attacked them "normally", as part of the healthy attack on foreign cells.  And (b) because the immune system is broken, leading to T1D in the first place, it attacked these new cells "abnormally" just as they had attacked the body's own cells to trigger T1D in the first place.

One way to solve both these problems is to modify the new cells so that they are invisible to the immune system.  That is, they don't present as foreign cells nor do they present as beta cells.  This is the solution that Sana Biotechnology has been researching, and that I'm reporting on here.

What Was Reported

In a very small clinical trial, they reported data on the first person transplanted with beta cells, after one month:
  • C-peptide data shows the transplanted beta cells were generating insulin, and were generating it in response to eating carbohydrates.  
  • MRI images suggest that the new beta cells are surviving.
  • No safety issues were seen.
  • The new cells appear to have avoided any immune attack ("evaded immune responses"). 
This is all good news, but notice what was not reported: no specific numbers on C-peptide generation, which means no specific numbers on insulin generation.  And similarly, no numbers on insulin usage, A1c, or anything else to show how well the new beta cells were operating.

Also notice the limitations of this reporting: one person and one month, and no scientific journal article, just a press release.

More Study Details

The entire study is a two person, phase-I study lasting a year, so not much bigger.   Donated beta cells are modified using Sana’s Hypoimmune (HIP) technology, and then implanted into the forearm of the person with T1D.   The procedure took 90 minutes.  The HIP technology is the "secret sauce" that Sana hopes will make the cells invisible to the immune system.  This protocol is identified as "UP421" and they are using it in another program aimed at cancer. 

This study was very much a proof of concept.  The researchers are implanting between 2% and 7% of the beta cells that will ultimately be needed, to see if they get any results at all.  They are measuring C-peptides, as well as various safety and immune system measurements.  But the summary is, even when the whole clinical trial is done, we will have very little information.  


Last Minute Update

Just as this blog was going out, Sana released a corporate presentation, which had some additional information.  The main updates are as follows, and I think they are all very positive:
  • Three months of data are included, and the c-peptide numbers continue to be strong for the entire time.
  • They include data (specific numbers) for fasting and mixed meal c-peptide data.  Considering how small the transplantation was, the results are very promising.
  • They include immunology data that supports their claims that the newly transplanted beta cells are not triggering an autoimmune response.  

Discussion

What To Look For In The Future (and When)

To me, this has the potential to be a huge breakthrough, as it could lead to a practical cure in the future.  The key words here are "potential" and "future".  For many people the next questions is, how likely is it or how long will it take.  But those are not my questions.  My questions are, what are the next reports we should expect to see, and what data from those reports will signal good news?

Unfortunately, we are not going to get a lot more information any time soon.  This data comes from a very small, phase-I clinical trial: only two people in total (both treated, no control group). That means that over the next year, the very best we can hope for is 2 people; no control group; a small dose; all published in a scientific journal.  That is not much (although one year is not long to wait).

The next data we should expect, would be the results of a phase-II or maybe a phase-II/III clinical trial.  But we should not expect that for 3 or 4 years.  And remember, no matter how successful the current  study is, and how successful the next study is, approval will still require an additional phase-III study (maybe two phase-III studies), which is more years.


Is it a cure?  The immune system is still broken!  

One comment I sometimes hear when I talk about transplants is that they are not cures, because the immune system is still broken.  They might stop the symptoms, but they do not cure the "real" disease, the flaw with the immune system.

This gets into the very emotional question of what is a cure.  After all, if someone's leg is crushed and you install a pin, have you cured them?  What if the pin means they can walk but not run?  On the other hand, if they crush a leg, and need a wheelchair for the rest of their lives, are they cured?  After all, the wheelchair means they can get around.  And so on.

My answer to this question is on my web page, just to the right of every blog posting I write: 
1. Blood sugar control without testing and with doctor's visits four times a year, or less. Any cure must result in an average lifespan close to normal.  
2. Does not require a lifetime of immunsuppressive drugs, so it is not trading one treatment for another. (but a couple of operations, or a short course of drugs is OK) 

 Obviously, this is my personal definition of a cure; yours may differ.

By that definition, this would be a cure, if it works.  The fact that the immune system is still broken does not change the fact that the person no longer needs to take insulin, count carbs, or wear a pump 24x7.

History and Complexities of Islet Transplants

You don't need to read this section to understand the research, or why it is important.  I'm putting it here for people who find it interesting.

The history and complexities of islet transplant research is a huge topic, far to big to fit in one blog posting, much less one section of a blog posting.  However, I will try to summarize both the history of transplant-based cures and the complexities that have prevented the research from succeeding:

Transplant History

In the 1970s and 1980s, it was commonly thought that type-1 diabetic's beta cells had been destroyed, and if they could just be replaced, their diabetes would be cured. This led to several attempts at transplants to cure T1D, especially whole pancreas transplants, beta cell transplants, and drug treatments designed to get beta cells to regrow (such as human growth hormone). 

These did not work because the new beta cells were destroyed by the broken immune system just as the old ones had been, and also because the properly working immune system attacked transplants as foreign cells.  

Starting in the 1980s, researchers tried encapsulating beta cells: they put beta cells inside a wrapper and then implanted the bundle in a person. The wrapper would need to be a very high-tech material that would allow nutrients and oxygen to flow in, wastes to flow out, insulin to flow out, and the chemicals which triggered insulin production to flow in. But if they succeeded, it would be like having a natural pancreas inside you, but protected from the immune system.

Many different companies and many different researchers tried to use encapsulated beta cells to cure T1D.  There were a lot of different options to try.  Every researcher needs to choose a source of beta cells, and an encapsulation technology.  Optionally, they might also add an unusual transplant location or a new drug protocol for the transplant itself.  Since there are many different sources of beta cells, and an almost unlimited number of encapsulation technologies, you can see how this would keep many researchers busy for many decades.

At different times, beta cells have been sourced from: pigs, genetically modified pigs, human cadavers, or live humans.  Plus, they have been grown from stem cells sourced from: the person with T1D themselves, other people's skin cells, placenta cells, or embryos.  Plus, I'm probably forgetting a few, since this research has been going on for 40 years!

As for encapsulation technologies, there are dozens of them, and I'm not even going to try to list them, but all kinds of modern material science has been applied to the problem.

However, to date nothing has worked.  I believe that there are several problems and solving one tends to make the others worse, and it is very hard (so far, impossible) to solve all of them at once.  The problems include: 
  1. Allowing nutrients to pass from the body into the new beta cells, and waste products to pass from the beta cells back out to the body.
  2. Not allowing immune cells to move from the body to the beta cells.
  3. Allowing sugar to pass in and insulin to pass out.
  4. Not having the body build up scar tissue around the beta cells, which blocks access to them.
You'll notice that solutions to problems 1 and 3 tend to make problem 2 worse, while solutions to problems 2 and 4, tend to make problems 1 and 3 worse.  Of course, all problems must be solved at the same time, for this to work.

Sana's Approach Is Different

Sana Biotechnology is not trying to encapsulate beta cells.  Instead, Sana is trying to alter them so that the immune system can not detect them.  This would solve both major transplant problems at once.  The "natural" attack on any foreign cells would not even see the new cells, and the "broken" attack on beta cells would not even see the beta cells to attack them.

The immune system identifies cells by identifying specific structures on the outside of cells.  MHC Class I and II are two such structures and the CD-numbers refer to other such structures.  So Sana is trying to remove these structures from the outside of their beta cells.  The hope is that then the immune system will not see the cells at all.

I'm not a researcher, so I have a lot of trouble evaluating the science behind Sana’s Hypoimmune (HIP) technology.  However, here are two summaries of HIP that I could find:

Sana's approach seeks to modify cells to evade both innate and adaptive immune responses by knocking out MHC Class I and II expression and over-expression of CD47.

The goal of Sana’s hypoimmune (HIP) platform is to eliminate the need for immunosuppression by cloaking cells from immune recognition while at the same time generating the manufacturing scale and reproductibility of allogeneic cells. The challenge for the field to date in generating immune cloaked cells has been turning off both the adaptive and innate immune system concurrently. Sana’s platform includes disruption of major histocompatibility (MHC) class I and MHC class II expression to hide cells from the adaptive immune system, which includes antibody and T cell responses, as well as overexpression of CD47 to inhibit activation of the innate immune cell system, in particular macrophages and natural killer (NK) cells. 

As with all research approaches, it doesn't matter if it sound good or if it makes sense.  It only matters if it works in clinical trials.  



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 BreakthroughT1D or JDCA news, views, policies or opinions. My kid has type-1 diabetes and has participated in clinical trials, which might be discussed here.  I am obese and right on the boarder of T2D and therefore may be taking drugs for those conditions.  My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog!
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Tuesday, March 18, 2025

TIXIMED Starts a Phase 1 Study of TIX100


TIX100 is a protein which inhibits the action of TIXNP (thioredoxin-interacting protein).  It is being developed by the TIXIMED company.  TXNIP is elevated in pancreatic islets of people with type-1 diabetes and causes beta cell death and dysfunction.  The hope is that inhibiting that protein will protect beta cells and therefore delay or prevent T1D.

Anath Shalev, a researcher at the University of Alabama, Birmingham is leading this research effort, first at UAB and now also at TIXIMED.  She first identified TXNIP in 2002 in human islets exposed to high glucose and then later showed that it played a role in glucose toxicity and diabetic beta cell loss.  Research has shown that inhibiting TXNIP protects beta cells and promotes beta cell health and function.

Recently she has run clinical trials for Verapamil, which lowers TXNIP and is already approved in the USA for the treatment of high blood pressure, migraines, and heart problems.  I have blogged several times on those studies, but especially the results from a phase-II trial here:
I also listed it as a drug to watch in 2024:
because there is another phase-II study ongoing in Europe, but it is now scheduled to finish in 2025 or 2026.

TIX100 is an oral medicine, and a "small molecule", but I have not found any other public information on what it actually is.  It has been tested in animals for T1D, T2D, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).  For example: 
https://diabetesjournals.org/diabetes/article/72/Supplement_1/97-OR/150782/97-OR-Antidiabetic-TIX100-Improves-NAFLD-NASH-in

This Study

This is a blinded dosing study done in healthy people.  They are recruiting 35 people, none of whom have T1D, and giving them 6 different doses ranging from none to 200 mg of TIX100.   The goal is to make sure all potential doses are safe.  

This is a single dose study, follow up is after one week, and they expect to be done by May.  Because the end points are all safety and side effect related, we will not know anything about efficiency (if it actually works against T1D), but "the trip of 1000 miles starts with a single step".  Good results here will presumably enable an efficiency focused phase-II study.

The good things about this study are that it is quick and easy to participate in.  They are recruiting in one location:

Chula Vista, California, United States, 91911
ProSciento, Inc.  619-427-1300   hello@myproscientostudy.com

Corporate Web Page: https://tiximed.com/

To see a longer history of research into curing type-1 diabetes by targeting TIXNP, you can read this article: https://www.news-medical.net/news/20240731/FDA-clears-UAB-startups-TIX100-for-clinical-trials.aspx




Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and has participated in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog!
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Friday, March 7, 2025

Combination of Harmine and GLP-1RA Completes Phase-I Clinical Trial (In Healthy People)

This is the most fun I have had writing a blog in a long time.  It is not often I can blog about psychedelics and curing type-1 diabetes at the same time!  I hope it is as fun for you to read as it is for me to write.  Do not skip the "Discussion" section.

These researchers are testing Harmine as part of a long term project, which started by doing a quick screen of many chemicals, which identified Harmine as a possible way to help the body grow more beta cells.  This screening process involved cell cultures (i.e. biology not computer simulation). They then tested it in mice, and found strong beta cell growth.  They cured the mice of diabetes, but those mice did not have autoimmune diabetes.  Their pancreases were destroyed with a toxin to give them diabetes.  A different research group cured mice who were overfed into diabetes. These are both positive results, but neither involved autoimmune diabetes.

You can read about the mice research here:

This blog reports on their first test in people, but they did not have T1D.  The researchers hope to move on to people with T1D in the future.
  

The Study


This study is unusual in that it enrolled people without T1D ("healthy people", in medical terminology) and only looked for bad side effects ("adverse effects") in the medicine and not effectiveness.  Almost all T1D studies that I've blogged about over more than 10 years, even the earliest phase-I trials enroll people with T1D and have end points that cover both safety and effectiveness.  But not this study.

This is an open-label, no control group, dose escalation study which enrolled 27 people.   Each person goes through the following doses: 100 mg, 200 mg, 300 mg, 500 mg, 700 mg, 900 mg and 1200 mg, stopping when they experience side effects.  The researchers are trying to find the largest does that has minimal side effects.

The results are summarized like this:  Harmine HCl can be orally administered to healthy participants in doses <2.7 mg/kg with minimal or no adverse effects. Doses >2.7 mg/kg are associated with vomiting, drowsiness, and limited psychoactivity.   So a 50kg person (110 lb.) can have a dose of 135 mg with minimal adverse effects, and a 91kg / 200 lb. person can go up to 270 mg.

This is good news, because it opens the way for clinical trials on people who have T1D, and tells the researchers what is the maximum dose they can use without bad side effects.


Discussion


Dose Comparison to Mice Work


The important finding of this clinical trial is that doses less than 2.7 mg/kg are safe and well tolerated.  ("well tolerated" being medical jargon for "In our judgement, the side effects of this treatment are small enough so that people would be willing to get them in order to also get the benefits of the treatment".)  For comparison, two previous research projects targeted curing T2D in mice with 30 mg/kg and targeted T1D mice with 3 mg/kg.  Together, this trial in people with T1D and the previous trial in mice suggests that the 3 mg/kg is a "sweet spot" dose: high enough to work and low enough to avoid bad side effects.

However, there was another difference.  People in this study were given Harmine in a single pill, but the previous mice study gave Harmine using a subcutaneous pump (like an insulin pump) and continually dosed throughout the day.  For comparison, the T2D mice were given 30 mg/kg daily with an injection.  So if we compare the people to the T1D mice, they got a similar dose, but the people got it once in a pill and the mice got it infused daily for months.  Since pills are generally easier to take than injections, this is good news, if pills are as effective as injections.

Obviously, an important target of future research is going to be if pills are an effective way of delivering this medicine, or if a continuously dosing pump is required.


Psychedelics


Harmine is found in several species of plants (esp. wild Rue) and animals (esp. butterflies), but it is famous as a component of Ayahuasca, a South American psychoactive folk medicine and religious sacrament.

It is being tested for psychiatric uses (suicide prevention, treating depression, PTSD, etc.) in several clinical trials, some of which have completed and some of which are ongoing.  

My favorite quote is from one of the researchers: 
no psychoactive properties have been identified in animal studies at the doses we are employing, but animals can’t tell you if they’re hallucinating

Obviously, this is why they are carefully doing a phase-I trial on healthy humans, looking specifically for psychedelic adverse effects.  I suspect it is also the reason the study was done at the Depression and Anxiety Center at Mount Sinai Hospital in New York city.  They have more experience with this kind of clinical trial.

I'm sure the association of Harmine with Ayahuasca is going to cause some regulatory complications, even after this study shows that it is not psychoactive at the doses they are giving.  The American DEA has a long history of aggressively opposing any potential medical use associated with psychoactive drugs.  

Wikipedia article on Harmine: https://en.wikipedia.org/wiki/Harmine
Wikipedia article on Ayahuasca: https://en.wikipedia.org/wiki/Ayahuasca

What Next?


In my mind, the obvious next step is to run a phase-I or phase-II trial on people who actually have T1D, but that is not the direction these researchers are going in.  As described below they are looking for a patentable drug (which they hope will be even more effective).

And then there is the issue of bringing these discoveries to people with diabetes. Because harmine is a natural product, it can’t be patented. “If you can’t patent it, no drug company is going to make it because clinical trials are expensive,” he notes.

So, going forward, the team has turned its efforts toward other new small molecule compounds they have designed and synthesized, along with computer modeling. “Some of these are as good as harmine, and several are substantially better. Mount Sinai has patented these, and we’re now working to move them along via Mount Sinai’s Innovation Partners Program,” Dr. Stewart says.

These two paragraphs come from this article:

Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and has participated in clinical trials, which might be discussed here.  I am obese and right on the boarder of T2D and therefore may be taking drugs for those conditions.  My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog!
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Friday, January 31, 2025

Denosumab Starts A Phase-I Trial In People With Established T1D

Denosumab is a monoclonal antibody, which is already approved for several bone related diseases and is sold under the names Wyost, Xgeva, Prolia, and Jubbonti.  A research team has found that the pathway that Denosumab targets also has effects on beta cells. Animal studies suggest that Denosumab may protect and/or increase the number of beta cells and improve how well they work.  It was first approved in 2010 after being developed by Amgen.  There is a biosimilar available from Sandoz.

Denosumab is a subcutaneous (under the skin) injection, much like insulin.  It is taken every month or every six months, depending on the bone disease being treated.

This Study

This is a phase-I trial in 45 adults who have had T1D for between 1 and 5 years. It is blinded, randomized and has a control group.  People will get one injection every 3 months for one year.

There are two primary end points.  For safety, they will track adverse events and for effectiveness they will measure C-Peptide levels. There are secondary end points for more C-Peptide measures and also for A1c measurements.  There are tertiary end points for time-in-range and insulin sensitivity.

The trial started in September 2024 and should run until April 2026.

This study is funded by JDRF and is run out of City Of Hope.  Contact information is:

Name: Arthur Riggs Diabetes & Metabolism Research Institute at COH
Phone: 1-866-44-ISLET(1-866-444-7538)  
Email: Islets@coh.org

And the three sites recruiting are:

University of Alabama-Birmingham Comprehensive Cancer Center
Anath Shalev, MD
205-996-4777 ashalev@uabmc.edu

City of Hope Medical Center, Duarte, California, United States, 91010
Fouad Kandeel, MD, PhD
866-444-7538 Islets@coh.org

Indiana Univ Med Ctr, Indianapolis, Indiana, United States, 46202
Carmella Evans-Molina, MD
317-278-3177 cevansmo@iu.edu

Discussion

This study is being done on people with established T1D, not honeymooners.  However, I'm not sure why.  The researchers state specifically that "Lab studies suggest that Denosumab may protect and/or increase the number of beta cells and improve how well they work."  For me, that suggests that this treatment would work much better during the honeymoon, when people with T1D still have some beta cells that work.  It is a mystery to me why they chose established T1Ds rather than honeymooners.

One large population based study, done in Taiwan, showed that people using Denosumab for Osteoporosis had a significantly smaller chance of being diagnosed with type-2 diabetes, than those who where not taking the drug.  That is an interesting finding, but those people all had plenty of working beta cells, so it is not clear to me that this finding is useful for people with established type-1 diabetes.  That study is published here: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2814873

If this treatment is found effective, it could be used off label immediately, without FDA approval, since it is already approved for a different disease.

Clinical Trial Registry: https://www.clinicaltrials.gov/study/NCT06524960 
Denosumab: https://medlineplus.gov/druginfo/meds/a610023.html


Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and has participated in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog!
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Sunday, January 19, 2025

What To Watch In 2025

Last year, at the start of the year, I published a blog of four research projects I was looking forward to updates in the new year.  This year, I'm doing the same thing.  I'm also including an update of the project from last year.

What I'm Watching In 2025

Vertex VX-264 is an encapsulated beta cell transplant that does not require immune suppression.  The trial is expected to run until 2026, but the company has said that they expect to have some data to report in 2025.  I hope so!


VCTX211 is another encapsulated beta cell transplant that does not require immune suppression.

Biomea BMF-219 is a drug that the company hopes is "a brake on beta-cell turnover and growth, supporting the notion that [it] could lead to the regeneration of normal, healthy beta cells".  It is in the middle of a clinical trial which started in 2023 and is expected to finish in Sept-2025.  I'm looking forward to data in 2025.  I previously blogged on it here:


Ladarixin is a drug being developed by Dompé. It inhibits activity on parts of the immune system called the IL-8 receptor (which has two subtypes: IL-8a and IL-8b).  Dompé hopes that this will stop the progression of type-1 diabetes.  Ladarixin is in the middle of a phase-III trial, and they expect results in 2025.  This is a big study.  They have enrolled 327 people and 2/3s of them will get the treatment; with only 1/3 controls who get the placebo.


Siplizumab is a monoclonal antibody targeting CD2, which is part of the immune system.  This study finished recruiting in Oct-2024, so I would expect results in late 2025.  I blogged on this here:


Sana UP421 is a last minute addition.  It is a no-immunosuppression beta cell transplant.  In early January, they announced very positive 1 month data from 1 person.  They are currently running a 2 person study (so really tiny pilot study).  I'm not sure if they will have final data in 2025 or not, but if they continue to publish early data, I'll be following.

https://www.clinicaltrials.gov/study/NCT06239636

What I Watched In 2024

The quick summary of 2024, is that, of the four research projects I focused on:
    1. Semaglutide is big in T2D/Obesity, but did not make progress as a T1D cure.
    2. Ladarixin progressed as expected, but the real news is expected in 2025.
    3. Verapamil completed enrollment in 2024, so should have results by 2025, but has already led 
        to important follow-on work.
    4. Diamyd was hoping for full enrollment, but did not make that milestone.
So overall, I would say 1 project did better than expected, 1 project did as expected, and 2 projects did worse.  

Semaglutide (sold as: Ozempic, Wegovy and Rybelsus) had very strong results in a very small study of honeymoon T1Ds:

I was hoping to read about more research starting up in 2024 to confirm these results.  Because Semaglutide is widely used to treat T2D and for weight loss, I think just one or two confirmation studies will be required to enable widespread use.  If that gets us a year or two delay starting injections for newly onset T1D, that would be a huge win (and even more so if it could be combined with Teplizumab or other treatments).

Unfortunately, none of that happened.  Semaglutide continues to blow up (in a good way) for T2D/Obesity, but does not move forward for T1D.

Ladarixin is a drug being developed by Dompé.  I'm not sure why I put it in the 2024 list, because there was no expectation of results until the end of 2025.  Nothing happened, but it is on my 2025 list.


Verapamil is another interesting "off label" drug.  This is a drug which is already approved (since 1981) and widely used (3 million prescriptions a year) for high blood pressure.  It is being tested on honeymooners.  Therefore, if clinical trials show that it helps, it should be available quickly, especially for aggressive doctors who are willing to prescribe it off label.

Unfortunately, the ongoing study which was going to finish in 2024 is now going to finish in either 2025 or 2026, so we'll be waiting longer for results.  I blogged about the start of this study here:

However this line of research has already led to the creation of the company TIXIMED working to start clinical trials on their drug TIX100, which is sort of a follow on to Verapamil.  They have gotten FDA approval for the clinical trial, but have not yet started it.

Diamyd is another drug in phase-III trials.  They hope to finish in 2025, but the news I was hoping for was that their clinical trial was fully enrolled in 2024.  Unfortunately, it looks like that did not happen.  The trial is still not fully enrolled, so I would not expect results in 2025.



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.
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Tuesday, December 31, 2024

Breakthrough T1D (formerly JDRF) Funding for a Cure 2024

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

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

Let me give you the punch line up front: 65% of the treatments currently in human trials have been funded by Breakthrough T1D, and this goes to 77% for the Phase-III and Phase-II studies!  This is a strong impact; one that any non-profit should be proud of.  Below is a list of all the treatments, grouped by phase, and separated into trials that Breakthrough T1D has funded, and those Breakthrough T1D has never funded.  
 
The List, Divided by Phases

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

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

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

Approved or In Process of FDA Approval

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

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

Not funded by JDRF:

Phase-II Human Trials
Summary: there are 19 trials in phase-II, and 15 of them have been funded by Breakthrough T1D, while 4 have not. Here are the treatments that have been funded by Breakthrough T1D:
  • ATG and GCSF by Haller at University of Florida (Established) 
  • Abatacept in honeymooners and as a prevention by Orban at Joslin Diabetes Center and Skyler at University of Miami (Prevention)
  • Aldesleukin (Proleukin) at Addenbrooke’s Hospital, Cambridge, UK 
  • Diamyd in several combinations by Ludvigsson at Linköping University and Larsson at Lund University (Honeymoon and Prevention) 
  • Difluoromethylornithine (DFMO) by Panbela
  • Gleevec by Gitelman at UCSF 
  • Gluten Free Diet: Three Studies  (Preventative)
  • Rituximab and Abatacept by TrialNet
  • Stem Cell Educator by Zhao (Established) 
  • Tauroursodeoxycholic Acid (TUDCA) 
  • Tocilizumab by Greenbaum/Buckner at Benaroya Research Institute 
  • TOL-3021 by Bayhill Therapeutics (Honeymoon and Established)   
  • Umbilical Cord Blood Infusion by Haller at University of Florida 
  • Ustekinumab by University of British Columbia
  • Verapamil by Shalev/Ovalle at University of Alabama at Birmingham
Not funded by JDRF:
  • ATG and autotransplant by several research groups: Burt, Snarski, and Li 
  • Dual Stem Cell by Tan at Fuzhou General Hospital 
  • Stem Cells of Arabia (Established)
  • Vitamin D by Stephens at Nationwide Children's Hospital (Prevention)
Phase-IIΔ Human Trials
Summary: there are 19 trials in phase-IIΔ, and 10 of them have been funded by Breakthrough T1D, while 9 have not. Here are the treatments that have been funded by Breakthrough T1D:
  • Alpha Difluoromethylornithine (DFMO) by DiMeglio
  • Baricitinib by St Vincent's Institute of Medical Research
  • GABA by Diamyd
  • Golimumab by Janssen (Honeymoon and Established)
  • Hydroxychloroquine by Greenbaum (At Risk)
  • Intranasal Insulin by Harrison at Melbourne Health (Prevention)
  • Iscalimab (CFZ533) by Novartis
  • Influenza Vaccination at Aarhus University Hospital
  • Pleconaril and Ribavirin by Oslo University Hospital
  • Siplizumab by NIH and ITB-Med LLC
Not funded by JDRF:
  • Abrocitinib or Ritlecitinib by NIH/Pfizer
  • Azithromycin by Forsander
  • BMF-219 by Biomea Fusion (Established)
  • Fenofibrate at Warsaw Medical University
  • Ixekizumab/Taltz by Vastra Gotaland Region
  • Liraglutid (At Risk)
  • NNC0114-0006 and Liraglutide by Novo-Norsk (Established)
  • Rapamycin Vildagliptin Combo by IRCCS (Established)
  • Visbiome by Medical College of Wisconsin
Phase-I Human Trials
Summary: there are 21 trials in phase-I, and 13 of them are funded by Breakthrough T1D, while 8 are not. Here is the list funded by Breakthrough T1D:
  • AG019 and Teplizumab by ActoGeniX
  • DIMID1 (Faecal Microbiota Transplantation) at AMC Hospital 
  • Diamyd by Diamyd (At Risk)
  • CGSF by Haller at University of Florida 
  • Golimumab (At Risk)
  • MER3101 by Mercia (previously IBC-VS01 by Orban)
  • Mozobil by University of Alberta (Established)
  • PRV-101 (Coxsackie B Vaccine) by Provention Bio (Prevention)
  • Semaglutide by Dandona at University of Buffalo
  • TOPPLE T1D by Novo Nordisk (Established)
  • VC-01 by Viacyte (Established)
  • VCTX210A by Viacyte/CRISPR (Established)
  • VX-264 by Vertex (Established)
Not funded by JDRF:
  • AVT001 by Avotres
  • Baby Teeth Stem Cells by CAR-T Biotechnology
  • Extracorporeal Photopheresis by ADSCC
  • Gluten Free Diet by Carlsson at Lund University
  • NN1845 (Glucose Sensitive Insulin) by Novo Nordisk
  • OPT101 by Op-T (Established)
  • PIpepTolDC at City of Hope Medical Center
  • ProTrans by NextCell (Established)
Summary of all Trials
62 in total
40 funded by JDRF
So 65% of the human trials currently underway are funded (either directly or indirectly) by JDRF. Everyone who donates to Breakthrough T1D should be proud of this huge impact; and everyone who works for Breakthrough T1D or volunteers for it, should be doubly proud.

Just Looking at Trials on Established Type-1 Diabetics
 
Of these treatments 14 (23%) are being tested on people with established T1D, of those, 9 are funded by Breakthrough T1D.  So 64% of the trials recruiting people with established T1D are funded by Breakthrough T1D.

Compared to Last Year
In 2023 there were 59 treatments in clinical trials, in 2024 there are 62 (growth of 5%).
In 2023 there was 2 treatments in Phase-III trials, in 2024 there are 3 (growth of 50%).
In 2023 there were 17 treatments in Phase-II trials, in 2024 there are 19 (growth of 11%).
In 2023 there were 14 treatments in Phase-IIΔ trials, in 2024 there are 19 (growth of 36%).
In 2023 there were 25 treatments in Phase-I trials, in 2024 there are 21 (dropped by 16%).

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

A Little Discussion
 
The money that we donate does many things:
  1. It finances more clinical trials (especially early clinical trials).
  2. It finances making clinical trials (especially early clinical trials) larger and better designed.
  3. It helps push possible cures to the next level of trial.  It finances moving phase-I trials to phase-II, and phase-II to phase III.
I like to say that there are two reasons for donating money for research into T1D.  People who like the research being done should donate money to move it forward, faster.  People who don't like the research being done should donate money to start up different research which (presumably) they will like more.  So no matter which group you are in, you should donate.  😀
  
Trial Populations
 
The list above uses the following marks to show the nature of the treatments, and if one treatment is being tested in different populations, then it will be listed more than once.
Honeymoon: Most trials are done on people within the first year of diagnosis.  All the studies listed above which are not Established, At Risk, or Prevention are in this Honeymoon category.
Established: One or more trials are open to people who have had type-1 diabetes for over a year. 
At Risk: One or more trials are open to people who have 2 or more autoantibodies, but have not yet started showing symptoms of type-1 diabetes.
Prevention: This treatment is aimed at preventing type-1 diabetes, not curing it.
If a trial is not marked, then it is for people in the honeymoon (first year) of T1D.

I give an organization credit for funding a treatment if they funded it at any point in development; I don't limit it to the current trial.  
 
I also give credit if JDRF funds research indirectly, through another organization.  For example, JDRF funds nPOD, Immune Tolerance Network, and INNODA and so I give Breakthrough T1D credit for clinical trials based on their work.
 
How I Count Trials for This Comparison
  • I don't count trials where the Breakthrough T1D funded some basic research, but not the research which lead to a specific clinical trial.  I'm sure this under estimates JDRF's impact.  For example OPT101 is an anti CD154 drug.  JDRF has funded many studies on CD154, but not the particular research that is being tested here.  Similarly with Ixekizumab, JDRF has funded related research on that drug, but not the clinical trial or the research immediately leading to the clinical trial here.
  • I mark the start of a research trial when the researchers start recruiting patients (and if there is any uncertainty, when the first patient is dosed). Some researchers talk about starting a trial when they submit the paper work, which is usually months earlier. 
  • For trials which use combinations of two or more different treatments, I give funding credit, if the organization in the past funded any component of a combination treatment, or if they are funding the current combined treatment.
  • I have made no attempt to find out how much funding different organizations gave to different research. This would be next to impossible for long research programs, anyway. 
  • Funding of research is not my primary interest, so I don't spend a lot of time tracking down details in this area. I might be wrong on details. 
  • I only include intervention studies here, because those are the only type of study that the FDA will accept for the eventual approval of a new treatment. 
Research Not Listed Here

I sometimes get asked why some piece of research is not listed here, and so here are some of those answers:
  • VX-880 is a transplant study which requires life long immunosuppression.  Read here why I do not consider these to be cures.
  • Levicure's Combination Therapy has only been tested in a retrospective study, not an intervention based clinical trial.

Some Specific Notes:
  • Oral Insulin: This trial was a phase-III trial, meaning that it was large and designed to provide enough information so that, if successful, the treatment could be widely used. However, as it turned out, only part was successful, and that part was phase-II sized, so I don't think we will see widespread use based on this trial alone. You can think of this as a phase-III trial with phase-II results.
This is an update and extension to blog postings that I've made for the previous fifteen years.  Below is a link to last year's, but you can search for "JDRF Funding for a Cure" for the rest of them:
Please remember that my blog (and therefore this posting) covers research aimed at curing, delaying, or preventing type-1 diabetes that is currently being tested in humans. There is a lot more research going on than is counted here.

Please think of this posting as being my personal "thank you" note to all the Breakthrough T1D staff, volunteers, and everyone who donates money to research a cure for type-1 diabetes:
Thank You!

Finally, if you see any mistakes or oversights in this posting, please tell me! There is a lot of information packed into this small posting, and I've made mistakes in the past. 

Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.
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Monday, December 23, 2024

Fenofibrate Is Unsuccessful In A Phase-IIΔ Trial In Honeymooners

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

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

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

Results From the Phase-IIΔ trial

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

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



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


Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and has participated in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog!
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