Results from a Phase-IIΔ Trial of Pleconaril and Ribavirin

This clinical trial represents an attack on T1D slightly different than anything I've blogged on before.

Pleconaril and Ribavirin are both antiviral drugs.  The idea here is that viruses either cause T1D or contribute to it, and that attacking viruses during the early honeymoon period will do something good.   Maybe delay the onset, extend the honeymoon, or even allow the long term survival of more beta cells to lower long term complications of T1D.  

I want to stress that this "virus causes T1D" hypothesis is just that: a hypothesis.  It is held by some researchers, but is not the consensus cause of T1D.  However, these researchers are moving forward assuming it is true, and therefore testing a prevention technique that is likely to work if it is true.  They had previously found low grade enteroviral infection in the pancreas of people recently diagnosed with T1D, and that motivated them to run this study.  

The study participants were between 6 and 15 years old and within 3 weeks of diagnosis.  These were early honeymooners.  The drug combination was in liquid form and drunk daily for six months, and then the people were followed for an additional six months, which is reported here.  Although they reported results in October, the study will continue for two more years and so we should get more results in the future.

The key finding was "During the 12-month study period, the relative decrease in C-peptide was 11% in the Pleconaril and Ribavirin group and 24% in the placebo group" (paraphrased).  So both groups dropped, but the treated group dropped much less.  See here for more discussion of why these sorts of results do not excite me.

This study was supported by JDRF, INNODIA and others.

News Coverage: https://www.medscape.com/viewarticle/997094?form=fpf
Journal Article: https://www.nature.com/articles/s41591-023-02576-1

Clinical Trial Registry: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-003350-41

Earlier Report of Enteroviruses: https://www.frontiersin.org/articles/10.3389/fendo.2022.881997/full

 

Wikipedia Pleconaril: https://en.wikipedia.org/wiki/Pleconaril
Wikipedia Ribavirin: https://en.wikipedia.org/wiki/Ribavirin

Discussion

The idea that a virus causes T1D, or triggers it, or make it worse, is widely held.  Many parents remember that their kids were sick just before or as part of their T1D diagnosis.  However, the causality part has not been proven.  Viruses may cause T1D, or they might trigger it (i.e. the person was going to get T1D anyway, and the virus just caused it to manifest now rather than next month), or it may be that early T1D symptoms are similar enough to the flu so that people get them mixed up, or it might be that after a diagnosis of T1D, parents suddenly connect it to the last illness the child had.

On the other hand, Coxsackie B viruses (a type of enterovirus) have been associated with T1D in previous population studies, and enteroviruses are known to target pancreatic islets.  There is another clinical trial which attempts to use a Coxsackie B vaccine to lower the rate of T1D, and a third using flu vaccine on people in the honeymoon phase.  So the causal part is certainly possible. 

About these anti-virals specifically, I think it is important to note that Pleconaril was never approved for use by the FDA because of side effects.  It was evaluated in the early 2000s.  Ribavirin is approved, but use in T1D would be "off label" and its label includes two black box warnings.

To me, these results seem similar to the Teplizumab in honeymooners results, although with the obvious caveat that this result is in a 100 person phase-IIΔ study, and the Teplizumab study was a 300 person phase-III study.  The Teplizumab honeymoon trial reported a difference of 0.13 pmol/ml while this study reported 0.16 pmol/ml.

But also, this study only shows preservation of beta cells (and not even complete preservation), and I usually only get excited about beta cell regrowth in the honeymoon phase.

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.

 

 

 

Results From A Phase-IIΔ Baricitinib (Olumiant)

Baricitinib (trade name Olumiant) is a drug which targets the immune system, and is already approved for Rheumatoid Arthritis (since 2018) and Alopecia Areata (since 2022).  Since these two diseases are both autoimmune diseases, like T1D, it makes sense that this drug would be tried for T1D as well.  This drug is called a JAK inhibitor, and it blocks both JAK variants: JAK1 and JAK2.  JAK inhibitors have been an active area of research because of some case studies where they seem to impact T1D when people took them for other conditions.  I blogged on this once before:
https://cureresearch4type1diabetes.blogspot.com/2021/02/ruxolitinib-case-study.html

About This Study

People were recruited in their honeymoon phase, within 100 days of diagnosis.  A total of 91 people participated, 60 got treatment and 31 were in a control group.  The age range was 10 to 30, and about half were under 18 and half over.  They took a 4mg pill of Baricitinib (or placebo) once a day for 48 weeks.  The study was blinded for both participants and researchers.

The study was funded by JDRF and JDRF Australia.

Results

The key results for me are C-Peptide numbers, which are shown in the graph below.  The treated group (Baricitinib) actually rose in C-Peptide generation, going from 0.6 to 0.65, a rise of 8%.  That is not huge, but it is in the right direction, and it is not just "preserving" beta cells, it is growing them.  

Discussion

For me, these are good results in a first-in-T1D clinical trial, but it definitely needs follow-on work.  At this point, I think it is pretty clear that any treatment that helps C-Peptide numbers in the honeymoon phase should be tried in at-risk people.  To use TrialNet terminology, if it works in stage 3, it should work better in stage 2.    

You can see the confidence bars in the image above, they are the little horizontal bars above and below the measurements, and the same color.  Confidence bars represent the uncertainty in measurement, and the uncertainty in averaging a small number of data points.  We talk about an average as though it were one, exact number.  But an average is a statistical combination of many numbers.  Each one of those numbers has a measurement error (was it really 0.6 or was it 0.62 or maybe 0.59)?  Hopefully those errors cancel out as we measure more data points, but it is possible they combine to get worse.  Also, the average of a small number of data points might be different than the average of a large number of data points even if they are measuring the same thing.  Researchers summarize these uncertainties on their graphs with confidence bars.  Two data points within each other's confidence bars might be the same, even if they appear different.

If you look at the diagram, the placebo and treatment are within confidence interval of each other, until the last measure.  Even then, the treatment group is just barely outside the confidence interval of the placebo.  (And the placebo is clearly inside the confidence interval of the treatment.)  All this means, to me, that a bigger study is needed to get a strong signal.  I'm hoping that would also lead to more data on how much beta cell growth there is.

Finally, it is important to remember that, although Baricitinib is approved for use already, it comes with black box warnings, which are the most serious warnings that the FDA has.  These need to be considered before off-label use is considered, and right now, using Baricitinib on people with T1D is off label.

There are two other JAK inhibitors approved for use in the US: Tofacitinib (sold as Xeljanz) and Upadacitinib (sold as Rinvoq).

JAK inhibitors are very different medicines than Tzield (Teplizumab), or Diamyd, or Verapamil, so it is entirely possible that two or more of these treatments could be used together in the future.

Trialnet is running a clinical trial on JAK inhibitors (Abrocitinib and Ritlecitinib) which I will blog on in the future.  It is enrolling people between 12 and 35 year olds during the first 100 days of their honeymoon period.  You can read more about it here: https://trialnet.org/our-research/newly-diagnosed-t1d/jakpot-t1d

News Coverage: https://www.medicalnewstoday.com/articles/rheumatoid-arthritis-drug-shows-promise-as-type-1-diabetes-treatment
Journal Article: https://www.nejm.org/doi/full/10.1056/NEJMoa2306691

Clinical Trial Registry: https://www.clinicaltrials.gov/study/NCT04774224
Wikipedia: https://en.wikipedia.org/wiki/Baricitinib

A Note About Naming Drugs

In the medical world, it is common to capitalize the name brand of drugs, like Olumiant, but not capitalize the generic names for drugs, like baricitinib.  I have never understood this.  To me, they are both proper names of specific things, and both should be capitalized.  Therefore, I do capitalize both.

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.

 

 

 

What To Watch In 2024

At the start of a new year, some bloggers write a posting on the year that was, and a some write a posting on what they expect in the new year.  This posting is a little of each. 

The Big News From Last Year

Teplizumab! Which became the product Tzield.  Getting a drug approved that actually changed the course of T1D is a big deal.  I know it is for people at-risk, not people who have T1D.  I know it only delays the onset of T1D.  I know it is incredibly expensive.  Those things matter, especially in the short term, but in the long term this is still a huge breakthrough.  

And next year, it may well expand.  I recently reported on a phase-III clinical trial done on honeymooners:
https://cureresearch4type1diabetes.blogspot.com/2023/11/teplizumabtzield-reports-results-from.html
It is also being tested on younger kids, to expand the people who can benefit from it.  I'm also hoping that more widespread use will lead to more knowledge about how it works, and maybe even a realization that it delays T1D even longer than we know now.

Also, we have seen a few more clinical trials running in 2023 than in previous years.  I'm not sure if that is just a post-COVID bounce, or real and continuing growth in the human trial pipeline.  We are a little higher than our pre-COVID numbers (more clinical trials), so I'm hoping this is actual growth.  It is possible that previous research and Teplizumab's approval has laid a foundation that will accelerate future research.  I'm an optimist.

What I'm Watching In The New Year

Semaglutide (sold as: Ozempic, Wegovy and Rybelsus) had very strong results in a very small study of honeymoon T1Ds:
https://cureresearch4type1diabetes.blogspot.com/2023/09/strong-results-from-pilot-study-of.html
People who took the drug sometimes did not need to inject insulin for a year.  Other people had to inject long acting insulin, but did not need to inject at meal times (again, for the first year of their honeymoon).  I'm 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, that would be a huge win (and even more so if it could be combined with Teplizumab or other treatments).

Ladarixin is a drug being developed by Dompé.  Ladarixin targets two specific immune system chemicals: IL-8a and IL-8b.  I think it is the only research aimed at those targets, so it is a little unique.  I'm interested in this because it is a phase-III trial.  Those are large trials done only after results from phase-II trials.  This one is being funded by the same company that did the phase-II trial, so they are really (in American terminology) "putting their money where their mouth is". That is the good news.

The bad news is that it usually requires two phase-III studies to get approval, and (as far as I know) this is the only phase-III trial done so far.  Also, the results from the previous phase-II trial were not that strong.  And finally, this trial is not going to be quick.  They are gathering data for two years, which means the study will last at least two years after they finish recruiting, and they are still recruiting now.  Therefore, we should not expect results before the end of 2025.  However, even with all that, the company thought it was worth funding a large (300+ person) clinical trial, and that means that they have a realistic hope that it will be successful.

https://cureresearch4type1diabetes.blogspot.com/2023/05/dompe-starts-gladiator-phase-iii.html

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:
https://cureresearch4type1diabetes.blogspot.com/2022/02/verapamil-sr-starts-phase-ii-trial-ver.html

Diamyd is another drug in phase-III trials.  They hope to finish in 2025, but the news we can look for is that their clinical trial is fully enrolled in 2024.  If that happens, it puts them on track for results in 2025 or maybe 2026 in the worst case.  Diamyd has a long complex history, but in the end, all that matters is results, and the news from 2024 will tell us if results will be coming in 2025 or 2026.

https://cureresearch4type1diabetes.blogspot.com/2023/12/diamyd-update.html

My Biggest Hope (Over More Than A Year)

All four of these treatments target honeymooners or pre-honeymooners, and they all seem to have different reasons they work.  Therefore, it would be just wonderful if we could stack them.  Use 2, 3, or even all 4 to delay the onset of T1D and then delay the need for injections, for many years.

Of course, success in established T1Ds would be even better, but I don't see that on the horizon for the next few years.

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.

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.