Wednesday, November 16, 2022

Results from MultiPepT1De (Multi Peptide Vaccine) by Powrie at King’s College London

This is the most recent result from a long line of research led by Colin Dayan and Mark Peakman, at Cardiff University and King's College London. The goal here is to train the body's immune system not to attack itself, by using either one peptide (in the first trial) or several peptides (in the more recent trial).  A peptide is a small part of a protein, and these peptides are part of the insulin molecule.  The idea is vaguely similar to giving people tiny amounts of peanut protein to desensitize them from peanut allergies.  However, it is important to remember that type-1 diabetes is NOT a classic allergy; the analogy is not perfect, but gives the general idea. 

You can read my summary of the results of the first clinical trial, using one peptide, here:
https://cureresearch4type1diabetes.blogspot.com/2017/11/results-from-phase-i-clinical-trial-of.html

This study was done on adults, within 4 years of diagnosis.  This is a little unusual, as most studies either pull from "honeymooners" (within 1 year of diagnosis) or "established" (longer than that).  The average time after diagnosis for everyone in this study was about 20 months.  So while this study does contain a mix of honeymooners and established T1Ds, there are more people with established T1D.

Here is an image overview of the results. The line with the square is insulin production in the group that got the placebo, while the triangle covers everyone who got the treatment (in three different doses).  My summary is two fold: (1) the treated group did better than the untreated group (2) neither group actually got better, it is just that the treated group dropped less than the untreated group.  

Another way to view the results is this graph:

And notice that in the placebo group, everyone gradually lost C-peptide production during the 6 months of the study.  That is what we expect, since people gradually loose insulin production throughout their honeymoon.  However, the people who got the smallest dose, two of them actually went up.  They were generating more C-peptide after 6 months.  The official summery is "Taken together, these findings provide some encouragement for the evaluation of efficacy signals in future, well-powered studies."

Discussion

For myself, I consider C-peptide results to be successful when they go up, and unsuccessful when they go down.  Here, the C-peptide results for the treated people went down, so that is disappointing.   It is important to see that the study was successful because the treated group generated more C-peptide than the untreated group, and this difference was big enough to be statistically significant.  However, both groups (treated and untreated) actually went down in C-peptide production.  It is just that the treated group dropped less than the untreated group.  So even though this study was scientifically successful, I don't think of the results as successful.

But there is another issue here, which the researchers touched on: "responder vs. non-responder".  The overall results in the first chart, the average of everyone who got the treatment and compare this to the average of everyone who did not, and those were the disappointing results.  However, the second chart shows all people individually.  Certain people got noticeably better, while others did not, or even went down.  If you happen to be one of the people who's C-peptide numbers went up, you would be very happy with the results. 

So, when evaluating these results should we look at an average of everyone, or focus on specific responders?

It's a complex discussion, too complex to go into here.  However, one of the key questions is, do you know ahead of time who will be a responder?  Do they share some characteristic or test result, so you know they will be a responder?  If so, you can give the treatment only to the responders, and see some big results.  If that is the case, the responder result is the important one, and focusing on it is a reasonable thing to do.

However, if you do not know who will respond, or why they respond, then hyping the responder success is just an excuse to exclude data that makes your treatment look bad.  In this research, there is no indication of why some people respond and some don't, but the research is still in its early stages.  If they do discover why some people respond, while others do not, then suddenly this research could become very valuable to people who are "responders".

Abstract: https://pubmed.ncbi.nlm.nih.gov/35073398/
Full Paper: https://diabetesjournals.org/diabetes/article/71/4/722/140961/Immune-and-Metabolic-Effects-of-Antigen-Specific
Clinical Trial Record: https://beta.clinicaltrials.gov/study/NCT02620332

Thanks to ADA's "Diabetes" journal for making this article free, and thanks to all the people who pressured (and continue to pressure) all scientific journals to make these results freely available.

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.

 

Sunday, October 16, 2022

JDRF Funding for a Cure 2022

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. (And the number is 78% for the later phase trials!) This is a strong impact; one that any non-profit should be proud of.  Below is a list of all the treatments, grouped by phase, and separated into trials that JDRF has funded, and those JDRF has never funded.  
 
I've made two big changes to how I track treatments this year.  
  • In the past, I counted each combination of treatments separately.  For example,  Diamyd, Etanercep, and Vitamin D was considered one possible cure and Diamyd alone was a separate possible cure, and Diamyd and Vitamin D was a third.  This year, I'm changing my methodology to group all of these possible cures together as one, since they are all really based on Diamyd.
  • In the past, I counted a possible cure separately if it was tested in different phases of type-1 diabetes.  For example, TOL-3021 was being tested on honeymooners, but also in people with established T1D, so it got counted twice.  This year, I'm no longer doing that.  Another example is Teplizumab.  It is in the approval process for at-risk people, but in phase-III trials for honeymooners, so it is listed in both phases but only counted once.

The List, Divided by Phases
Below is the list of all treatments, divided into five phases: In Process (of FDA Approval), Phase-III, Phase-II, Phase-II?, and Phase-I.  Phase-II trials are "classic" phase-II trials, which are done after a Phase-I trial.  What I call Phase-II? trials are done on treatments which never went through phase-I trials on people with T1D.  They've been shown safe in other diseases, so have skipped phase-I trials on people with T1D.  These Phase-II? trials might be Phase-II from the point of view of size and safety, but they are Phase-I in terms of effectiveness, so I'm putting them in their own category. 

In Process of FDA Approval
Summary: currently there is 1 drug which has been submitted to the US FDA for approval for sale, and it was funded by JDRF.
  • Teplizumab by Provention Bio (At Risk)
In the forth quarter of 2020, Provention Bio submitted Teplizumab for FDA approval.  Unfortunately, there have been some delays, but there is hope of an FDA decision in November  2022.  This application will cover people who are "At Risk" (as described below) for T1D, and the aim will be to delay the onset of T1D by 2-3 years.

Phase-III Human Trials
Summary: currently there are 2 treatments in a phase-III clinical trial.  Both are funded by JDRF:
  • Oral Insulin (Preventative)
  • Teplizumab by Provention Bio
Phase-II Human Trials
Summary: there are 16 trials in phase-II, and 12 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)
  • 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-II? Human Trials
Summary: there are 13 trials in phase-II?, and 7 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
Not funded by JDRF:
  • Azithromycin by Forsander
  • Ladarixin by Emanuele Bosi of Dompé Farmaceutici
  • 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 22 trials in phase-I, and 15 of them are funded by JDRF, while 7 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)
  • 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 
  • Gluten Free Diet by Carlsson at Lund University
  • Mesenchymal Stromal Cell by Carlsson at Uppsala University
  • NN1845 (Glucose Sensitive Insulin) by Novo Nordisk
  • PIpepTolDC at City of Hope Medical Center
  • ProTrans by NextCell (Established)
Summary of all Trials
52 in total
34 funded by JDRF
So 65% 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
 
12 of these treatments (23%) are being tested on people with established T1D.
Of these, 8 are funded by JDRF.
So 66% of the trials recruiting people with established T1D are funded by JDRF.

I'm not comparing these numbers to the 2020 numbers because I've changed the way I count potential cures, so the numbers are not equivalent.   However, I did do a quick comparison applying the older methodology to this year's data, and there was little change: 4 more phase-I trials, and 1 less phase-II trial. 

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 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. 
Some Specific Notes:
  • I only include intervention studies here, because those are the only type of study that the FDA will accept for the eventual approval of a new treatment.  
    • The PreventT1D study (Vitamin D and Omega-3s) is a "field study" so not included.
    • A Rotavirus Vaccine study which was published a few years ago was a population based study, so also not included.
  • 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 twelve years:
Please remember that my blog (and therefore this posting) covers research aimed at curing or preventing type-1 diabetes that is currently being tested in humans. There is a lot more research going on than is counted here.

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

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

Joshua Levy
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.

Friday, September 16, 2022

Research Dropped As A Practical Cure

Every year I have the sad job of removing some projects from my list of active research aimed at curing T1D.  In the perfect world, I would remove research when it was unsuccessful: when clinical trials testing it failed or the researchers working on it stopped.  However, in the real world, I often don't know that a clinical trial was unsuccessful because those results are not published.  Researchers sometimes continue working on a project long after it is clear that it has failed, or simply move on to something else without anyone noticing that their previous research has been dropped.

My policy is to stop following research 2 years after the end of the last active clinical trial aimed at curing T1D, even if there is no specific publication of failure.

These are the research projects which I have stopped covering recently:

AAT (Alpha-1 Antitrypsin) by Kamada 

AAT is an anti-inflammatory/immunomodulatory drug, which the body makes naturally, and which is already FDA approved for people who have a rare condition where they don't make enough of it on their own. Using AAT to treat type-1 diabetes is based on the idea that one of AAT's effects (lowering inflammation, immune modulation, or wound healing) can cure/prevent/treat the disease. 

The last results from an AAT study were two unsuccessful results published in 2018, and there are no ongoing studies now.  During the 2010s, there were a total of 7 studies done on AAT, and not one of them was a success.

The company producing the drug (Kamada) no longer even lists T1D as a "Therapeutic Focus Area" nor is it listed in their research pipeline.

Microvesicles (MVs) and Exosomes by Nassar at Sahel Teaching Hospital

The idea behind this research is that umbilical cord-blood derived stem cells microvesicles may reduce inflammation and hence improve natural insulin production (more β-cell mass) in people with T1D.

This referred to a Phase-I clinical trial started in 2014, which was expected to finish later in 2014.  As of 2020 a summary article reported no results had been published.  I also did a literature search and was not able to find any suggestion that results had been published, or that follow on research had been started.

References:
https://www.clinicaltrials.gov/ct2/show/NCT02138331
https://doi.org/10.3389/fcell.2020.00149

Alefacept / Amevive® by TrialNet

Alefacept is a drug that has been used to treat the skin condition, psoriasis. Psoriasis is generally considered to be an autoimmune disease, similar to type-1 diabetes, but with the body attacking its own skin cells, rather than its own beta cells. So trying a drug already approved for Psoriasis on type-1 diabetes seemed like a reasonable thing to do, and these researchers did it.  Back in 2016 I reported on the results of the phase-2 trials, which were OK, but not great:
https://cureresearch4type1diabetes.blogspot.com/2016/02/alefacept-reports-on-phase-ii-results.html

Unfortunately, in a certain sense, none of this matters.  The company that made Alefacept stopped production in 2011, so it has not been available for years.  I don't know of any planned clinical trials with Alefacept, nor any similar fusion proteins. 

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.

 

Monday, July 11, 2022

Provention Bio Update

Provention Bio is a small biotech company targeting several autoimmune diseases.  It has two drug candidates which target T1D: teplizumab (PRV-031) and a coxsackievirus B vaccine (PRV-101).  This blog is a quick update on both of them.

Teplizumab (PRV-031)

I've blogged many time before and you can read them here (which includes more details than are included in this blog posting):
https://cureresearch4type1diabetes.blogspot.com/search/label/Teplizumab

Clinical trials done to date suggest that Teplizumab will delay the onset of T1D (the first symptoms) by about 3 years.  For example, if someone has 3 autoantibodies, they have a 35% chance of having symptoms of T1D within 5 years.  However, treatment with Teplizumab will change their chances to 35% but only after 8 years.

Provention has submitted this drug for FDA approval to delay the onset of T1D when used after 2 autoantibodies have been detected, but before symptoms of T1D are detected.  This is the first drug to be considered for marketing approval which would change the course of T1D (insulin treats the symptoms but it does not change the underlying disease).

The approval paperwork was submitted in Nov 2020.  In April 2021, the FDA identified a serious issue involving manufacturing changes impacting drug testing.  After much discussion between Provention Bio and the FDA, Provention submitted more data in Feb 2022 to address this issue.  The hope was that the FDA would approve it by Aug 2022.  However, in June 2022 the FDA announced that the decision would be made on 17 Nov 2022.  This was strictly a delay by the FDA; no additional data needs to be submitted.  In Oct 2022 there would be an announcement about required labeling and post-marketing studies (if required).

So the recent change is that we will now hear the decision on approval in Nov 2022 (with a strong hint in Oct 2022) instead of in Aug 2022 as we  had previously hoped.  From my point of view, this is a pretty small change.  There is no point in guessing if the FDA will approve it or not; in just 4 months we will know for sure.

Coxsackievirus B Vaccine Candidate (PRV-101)

Background: There is a theory that part of the trigger which causes the onset of T1D is infection by a virus.  Over the years, several common viruses have been investigated as possible triggers.  I've previously blogged on Polio family viruses and Rotaviruses as possible triggers for T1D.  Coxsackie B viruses are another family of viruses which might be a trigger.  If Coxsackie B viruses trigger T1D, then preventing infection might prevent (or delay) T1D, and we know that vaccines prevent infection.  So if this theory is correct, then a Coxsackie B vaccine could prevent or delay T1D.

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

Provention Bio is testing a Coxsackie B vaccine in the hopes that it will prevent or delay T1D, and in March 2022 they announced the results of their phase-I study.   The two key findings were:

  1. There were no major adverse effects (ie. no bad side effects).
  2. Six months after treatment, between 90% and 100% of the people who received a high dose of vaccine had strong immunity to Coxsackie B viruses.

This is the official word on the future of this research: "The Company is currently exploring partnership opportunities to further the clinical development of PRV-101."  My translation of this sentence is (very roughly) "The results were good, but we don't have enough money to run a phase-II trial for a vaccine, so we need to partner with someone who does."

 

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.

 

Wednesday, May 4, 2022

NN1845 (a glucose sensitive insulin) Starts A Second Phase-1 Clinical Trail

One approach to creating a "practical cure" for T1D is sometimes called "smart insulin", "glucose sensitive insulin", or "glucose responsive insulin".  This is insulin which is inactive if blood glucose numbers are low, but becomes active when those numbers are high. A person with T1D would inject a fixed amount of this insulin every day (or maybe every week), and it would become active only as needed.

This would not truly "cure" T1D, but it would result in a disease which did not require measuring blood glucose, counting carbs, or changing insulin doses based on food, exercise, hormones, etc.  It would make treating T1D much more like treating high blood pressure.  Some people (myself included) would consider this a practical cure.

Several different companies have attempted to create glucose responsive insulins, and several university researchers are also working on it.  However, most are still in animal testing.  Only one is being tested on people.  That one is being developed by Novo Nordisk and is called NN1845  (it used to be called NNC0363-0845).

The situation here is a little unusual in that Novo Nordsk has already run one phase-I clinical trial aimed very narrowly at safety and tolerability, and has recently started a second phase-I clinical trial, aimed at how well it works.

Results from the Previous Phase-I Clinical Trial

This is the summary of research results as published in a Novo Nordisk update:

During the third quarter of 2021, Novo Nordisk completed a phase 1 trial investigating safety, tolerability, pharmacokinetics and pharmacodynamics of subcutaneously administrated glucose-sensitive insulin (NN1845). In the trial, NN1845 appeared to have a safe and well-tolerated profile and demonstrated proof of principle of glucose-sensitive properties. Further development of glucose-sensitive insulin to optimize pharmacokinetic properties is now being evaluated.

First Phase-I Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT04569994

I want to stress that this is not a publication in scientific literature, and it does not include any actual data, just English phrases.  However, they are starting a follow-on clinical trial, which shows that they are optimistic about the results, and want to move forward with the research.

Plans for the Next Phase-I Clinical Trial

They will recruit 30 adults who have had T1D for more than a year.  Participants will receive the "smart insulin" once every 4 hours up to 6 times daily for 3 days.  The study is blinded and has a cross over design.  Each person will be treated with the experimental insulin and Levemir® (at different times) and the results compared.

They will be followed about 6 weeks, up to a maximum of 14 weeks.  The primary end point is blood glucose levels in the hours after a simulated meal.  Secondary outcomes include adverse side effects and several additional measures of blood glucose levels during different time periods after a simulated meal.

This study is recruiting in Graz, Austria:
Contact: Novo Nordisk     (+1) 866-867-7178     clinicaltrials@novonordisk.com     

Second Phase-I Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT05134987

Discussion and Opinions

I like the fact that this study should be quick.  Classic cure-focused trials usually gather data for 2 years, but these researchers will gather data for 14 week at most.  Also, since they are recruiting people with established T1D, it should be easier and quicker to recruit the 30 people they need.  Together, these should lead to quick results.

Two things I don't like about this trial are the use of Levemir® and the lack of any background or fasting data.  Levemir is long acting insulin.  But is that the right comparison for effects after a meal?  It depends on Novo Nordsk's goal with this insulin.  If their goal is a better, safer long acting insulin, then this is a good comparison.  However, that is not a practical cure.  A practical cure would require the glucose sensitive insulin to cover a meal much like fast acting insulin.  I'm worried that this comparison telegraphs Novo Nordsk's opinion that this is not a practical cure, but just a better long acting insulin. 

Of course, the optimist in me thinks that even if this particular "smart insulin" is not fast enough to be a practical cure, maybe the next one will be.  Or maybe an improvement to this one will make it faster in the future.

Both of these studies are phase-I so an obvious question is: how are they different?  Let me summarize the major differences:  

  • The biggest difference is in end points.  In the first study people were only monitored for adverse effects and to see how the experimental insulin is absorbed by the body.  In the second study most of the monitoring is aimed at blood glucose results.
  • The first study includes 68 people in three parts, and each part is quite different.  The second study is 30 people all together, which is a much more common design.   Phase-I studies in T1D often have 10-20 people, so both of these studies are big for phase-I.
  • In the first study, people get treated once with the experimental insulin and once with the control.  In the second study, people will be treated for 3 days and given the control for 3 days.

Obviously, I'm excited to see this research progressing.  Unfortunately, because the research is run by a commercial company, there is no requirement that they publish results quickly, and so far, they have not published at all.  Therefore there is no way to know the results from the first phase-I study.  They think there is a chance of a product there (commercial success) and the evidence is strong enough for them to put more money into the research, to fund a second phase-I trial.  So that suggests good results, but there is no way to independently confirm it.

The Real Publication Requirement

A lot of people seem to think there is some rule that says you must publish the results of clinical trails.  Twenty years ago, the answer was simple: no.  There was no law saying anyone had to publish anything.  Sure, academics built their reputations by publishing, so there was pressure for them to publish.  But for commercial companies, there was no reason to publish anything that would not increase their profits.  Then the USA passed a law saying that any clinical trial that was part of a new drug application must be listed on the FDA's clinical trial registry.  That was enforced as part of drug approvals, so suddenly there was a trial registration requirement, but no requirement to publish results.  (Companies had to submit results for FDA approval, but not publish them in the scientific literature or make them available to anyone else.)  

Years later the law was updated to require results be added to the clinical trial registry.  However, there was no enforcement, and therefore few researchers did.  Even researchers who published results rarely added them to the clinical trial registry.  Years later, a news service published a series of articles describing the legal requirement, the fact that it was widely ignored, that there was no enforcement, and that most of this research was funded by US taxpayers via government agencies.  Finally, there was some movement.  Over the next few years many old clinical trial registries were updated with results, and now more results are posted when the studies are completed.  But the number is still low.

So the summery right now, in the US, is that there is a paper rule that researchers must make results of clinical trials public, but, in fact, this data is not available for many clinical trials, including many focused on T1D.  I think the situation is worse in the rest of the world, but I've never investigated in depth.

For example, in 2015 none of the research results previously funded by JDRF were available in the FDA's clinical trial registry.  The publication of this information by Statnews resulted in several JDRF funded clinical trials posting results to the clinical trial registry, in some cases years after the research finished.  I'm sure JDRF funded researchers are doing better now, but I don't have any more recent data.

As of 2019, the two local (to me) universities who do the most T1D research were University of California San Francisco (reporting less than 50% of results) and Stanford (reporting less than 75%).  These numbers are for all the clinical trials done at those universities, not just their T1D trials.

More to read:


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.

 

Tuesday, April 5, 2022

ViaCyte and CRISPR start a Phase-I Clinical Trial (VCTX210A-101)

For many years, it has been clear that one possible path to a cure is to transplant new beta cells and also in some way prevent the body from rejecting those new, transplanted cells.  Since the 1980s many different companies have tried encapsulated beta cells as a path to a cure.  The idea is that beta cells cure T1D and encapsulation means both that the person does not need to take anti-rejection drugs and that the person's autoantibodies cannot destroy the new beta cells.  Unfortunately, even after 40 years of research done by many different companies, this line of research has not been successful.

The JDRF has a good timeline of their support for stem cell therapies here:
https://www.jdrf.org/blog/2021/11/29/jdrf-timeline-stem-cell-therapies/
Note that they have funded several different research projects, and ViaCyte is just one of them. 

ViaCyte is one of these "old school" beta cell transplantation companies.  They have developed an infrastructure to grow large numbers of beta cells from stem cells.  However, recently they have partnered with a CRISPR company (called CRISPR Therapeutics).  CRISPR is a technology to edit genes.  In this case, they are editing genes in their newly grown beta cells, so that the beta cells are invisible to the patient's immune system.  The hope is that this is going to have two important effects:  First, the body will not reject the transplanted beta cells.  Second, the bodies' autoimmune attack will not be able to target the transplanted beta cells.

Obviously, either one of these effects would result in a huge step forward on the path to curing T1D, and both of them together could result in an outright cure.  This combination is what they have just started testing in a Phase-I clinical trial.

The Phase-I Clinical Trial

This is an open label (no blinding) clinical trial with 10 participants who are adults (18-65 years old) and have established T1D (diagnosed at least 5 years prior).  All 10 people will get the treatment; there is no control group.

The gene edited, stem cell derived beta cells are loaded into a device and then implanted into a person.  The person is then followed for 6 months.   The trial's end points involve safety and several scientific measures of transplant success.  The researchers will check for bad side effects, if the body is generating antibodies against the transplanted cells, and new autoantibodies related to T1D.  They will also see if the stem cells are growing properly.  However, none of the end points measure success in treating or curing T1D.  There are no measures of C-peptides (the body generating its own insulin) or lowered requirements of insulin, or improved A1c. This study is really focused on testing safety and ability to be tolerated, not effectiveness.

Because patients are only followed for 6 months, they hope to run this study from January 2022 to December 2022.  This includes the time needed to recruit the patients and the time to actually run the study on each patient.

This trial is being run in Canada, and you can get more information on participating here:
Contact: Clinical Trials     +1 (877) 214-4634     MedicalAffairs@crisprtx.com

The study locations include:

  • University of Alberta,  Edmonton, Alberta, Canada
    Contact: Parastoo Dinyari    +1 (780) 407-1501    parastoo@islet.ca   
  • University of British Columbia, Vancouver, British Columbia, Canada    
    Not yet recruiting
  • LMC Manna, Toronto, Ontario, Canada
    Enrolling by invitation

Clinical Trial Record: https://www.clinicaltrials.gov/ct2/show/NCT05210530

Discussion and Opinions

I'm very happy that a company is testing a combination cure, which (in theory) will both generate new beta cells and prevent the autoimmune process from destroying the new beta cells.  This is something I've been hoping for for 10 years. 

Normally, I'd would be happy with the speed of this trial.  Finishing this year means we will get our first data very quickly.  However, this clinical trial is only measuring safety outcomes, not effectiveness results.   Although phase-I trials are sometimes safety only, in T1D research it is normal to include some effectiveness outcomes.  They can give an early signal of success.  Not having effectiveness measures makes the short duration and quick results of this study less important, because (at best) it can only show us the treatment is safe, and not that it actually works (much less, works well).  We might need to wait to the end of the phase-II trial to see if it works, which will be very frustrating. 

Here are two very good articles which cover this clinical trial:

And here is the official press release:

Some notes on names and terminology:

  • ViaCyte refers to this product as PEC-QT, but CRISPR Theraputics calls it VCTX210 in the press release and VCTX210A in the clinical trial record.
  • The stem cells are created using CRISPR/Cas9, which is an improved form of CRISPR gene editing.
  • The clinical trial is called VCTX210A-101 by the companies running it, and has the clinical trial registration number NCT05210530.
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. 

Monday, March 21, 2022

Update On Teplizumab from Provention Bio

Teplizumab is a proposed treatment which, if given to someone at-risk for type-1 diabetes (T1D), can delay or possibly prevent the onset of T1D symptoms.  At-risk has a specific meaning here: it is someone who has tested positive for two or more autoantibodies for T1D, but has not yet shown symptoms of T1D (i.e. a lack of blood glucose control).  These are people not yet in their honeymoon phase.  In TrialNet terminology, they are in stage 1 of T1D.  Teplizumab works by targeting one specific part of the immune system which is involved in the attack on beta-cells which leads to T1D.

Scientifically, Teplizumab is a monoclonal antibody targeting CD3.  What does that mean?  It means Teplizumab starts out as an antibody aimed at neutralizing a specific part of the immune system called CD3.  Because CD3 is part of the process that leads to type-1 diabetes, the hope is by neutralizing it, T1D can be delayed or maybe even prevented.  Provention Bio starts out with one of these cells, and clones it repeatedly to create a large number of cells, all of which target CD3 (and only CD3) in exactly the same way.  This is a very common way to create new medicines.  Roughly 1/3 of the new medicines approved in recent years have been monoclonal antibodies.  If you see a treatment with a generic name ending in "mab" that is a Monoclonal AntiBody.

The full history of Teplizumab is long and complex, and I covered it in a previous blog:
https://cureresearch4type1diabetes.blogspot.com/2019/09/teplizumab-phase-ii-results-for.html

As very quick summary is as follows: Teplizumab was developed in the 1990s, and had its first clinical trial 1999-2005.  In 2008 it started a phase-III trial, which could have led to approval, but was unsuccessful, and was stopped in 2010.  A similar treatment, also targeting CD3, was also in phase-III trials at the same time and was also unsuccessful.  Other clinical trials on Teplizumab continued however, and in 2018 a different company, Provention Bio, restarted clinical trials.  Provention believed that the previous phase-III trials had failed because of a poor choice of primary end point (i.e. they measured the wrong thing to prove success).

In 2019, Provention Bio announced plans to submit Teplizumab for FDA approval based on three sets of data: 1. from the long ago completed studies. 2. from the long running, recently completed study, and 3. from their own recently completed study.

Recent History
  
November 2020 
Provention Bio finished submitting their application to sell Teplizumab.  This was (and is) huge news.  It is the first time, to my knowledge, a company has asked for FDA approval for a drug that will fundamentally change the course of type-1 diabetes [d1].  It is not a cure, or a preventative, but it is (potentially) able to delay the onset of T1D.  Obviously, this treatment will not directly help people who already have type-1 diabetes, but it will directly help their younger relatives, and I'm hopeful it will lead to better treatments over time which may lead to a cure.

Press Release: http://investors.proventionbio.com/2020-11-02-Provention-Bio-Completes-Rolling-Submission-of-the-Biologics-License-Application-BLA-for-Teplizumab-for-the-Delay-or-Prevention-of-Clinical-Type-1-Diabetes-in-At-risk-Individuals

April 2021 
The FDA reports on a serious problem in the Teplizumab application, which will require Provention Bio to address it before their application can move forward.

So what happened?  Teplizumab has been tested by several different companies over 15+ years.  The Teplizumab from the earlier, longer studies was made by Eli Lilly, while the Teplizumab for the later, smaller study (and for future sales) is being made by AGC Biologics.   Provention submitted data to show that these two Teplizumabs were the same as absorbed by the patients [d2].  However, the FDA did not accept that the data showed this.  This problem could (in the worst case) cause a long delay because it might imply that studies done with Eli Lily made Teplizumab may not be used to approve a treatment based on the AGC Teplizumab.  Or, it might mean that more "bridging study" data is needed.  This is data to show that the two Teplizumabs are not as different as first thought.  There are other solutions to this problem as well.

Press Releases:

http://investors.proventionbio.com/2021-04-08-Provention-Bio-Provides-Regulatory-Update-on-Biologics-License-Application-for-Teplizumab-for-the-Delay-or-Prevention-of-Clinical-Type-1-Diabetes-in-At-Risk-Individuals

http://investors.proventionbio.com/2021-04-27-Provention-Bio-Provides-Additional-Regulatory-Update-on-Biologics-License-Application-for-Teplizumab-for-the-Delay-or-Prevention-of-Clinical-Type-1-Diabetes-in-At-Risk-Individuals

May - Sept 2021
Provention Bio and the FDA exchange various communications and have meetings to discuss this issue.  Also the FDA's committee of experts recommends approval of Teplizumab, even with the issue found in April.

These proceedings are described from Provention's point of view by various press releases here:
http://investors.proventionbio.com/news?l=100&year=2021

I'm not going to describe the back-and-forth, except to point out that it lasted 9 months.

January 2022
At this point, the FDA decided (and Provention Bio agreed) that the company can resubmit their application to specify dosing based on the earlier clinical trials, rather than on the last clinical trial.  This means that no new clinical trials will need to be done.  Provention will change the dosing given to patients so that it matches the dosing used in the previous clinical trials, taking into account the differences between the Teplizumab used in older vs. newer studies.
 
Discussion and Opinions
This is, in my opinion, the best possible outcome for the T1D community and for Provention Bio.  Faced with two different absorption profiles from different manufacturers, The FDA could have required Provention Bio to run more clinical trials in order to generate enough data for approval for Teplizumab based solely on the current absorption profile.  That would have cost a lot and caused a many years delay (if Provention did it at all).  The solution proposed by the FDA, to tailor the dosing schedule to the absorption curve used by the previous clinical testing, only requires a change in application paperwork.  This is vastly cheaper and should only take months rather than years. 

I view this as a good call by the FDA, but remember, they are trading off a little safety in order to get this treatment to market sooner.   The most conservative (i.e. safest) path forward is to require all testing on new medicines to use the exact same product as will be sold.   However, the FDA already has a lot of experience in allowing slightly different formulations (especially in the context of "generic" drugs and "biosimilar" biologics), and so I think this safety trade off is a reasonable one to make.   More discussion here: [d3].

Press Release: http://investors.proventionbio.com/2022-01-27-Provention-Bio-Resubmitting-Biologics-License-Application-for-Delay-of-Clinical-Type-1-Diabetes-in-At-Risk-Individuals-Following-Type-B-Meeting-with-the-FDA

Why Is This Important?

I'm going to discuss why the approval of Teplizumab is important from two different points of view.  First the "tactical", how it would change the life of families with T1D right now, and second the "strategic", how it would change the research landscape of trying to cure T1D.

For the tactical part of the discussion, I'm going to assume that Teplizumab does exactly what the existing research says it does: delay the onset of T1D by about 3 years on average.  I think that will have two important good effects.  First, I think, in some cases, delaying the onset, even for just 3 years, is a good thing all by itself.  In practical terms, that means that someone who would normally be diagnosed in college, might actually be diagnosed after college.  Or someone in high school might be diagnosed in college.  Everything I've heard from families diagnosed in the teenage years, is that later diagnoses would be better.   I don't think this would be true for everyone.  My daughter was diagnosed at 18 months, and I actually think it would have been worse to be diagnosed at 4 years, but for many families, a delay would be a good thing.  If approved, Teplizumab would give families and patients that choice.

Second, I think that a 3 year delay may cushion the psychological impact of diagnosis.  Right now, a person goes from healthy to having a chronic, incurable disease in a week or two.  As a parent, I experienced this shock, and it was very jarring, but I'm sure it is much worse for the patients themselves.  Teplizumab would give people a few years to transition from not-T1D to T1D.  We have no experience with this, but I'm hopeful that it will lead to better psychological outcomes, because people will have more time to adjust.

The approval of Teplizumab will also have a huge impact on future research aimed at curing T1D.  For example:

Right now, there is a lot of uncertainty, in terms of getting drugs approved to cure T1D.  Since no drug has been approved, no one knows (for sure) how much evidence the FDA will require in order to do the approval.  We can read generic FDA policy documents, but it is not the same thing.  But if Teplizumab is approved, then from now on, everyone will know how much data is required and what results are good enough.  This makes the whole approval process less risky.  And less risky means more companies will try.

Second, the first drug approved to treat a disease, is almost never the best drug.  Once one is approved, improvements follow.  So I think it is fair to view Teplizumab as being the first in a series of improving drugs.  Having one drug, makes the development of other drugs easier in several different ways.  It shows researchers where to focus their efforts, it encourages more researchers to enter this field, and it shows companies how much money is available.

Third, I think it will encourage people to participate in trials like TrialNet.  One of the things I hear over and over is parents who say "Why should I participate in TrialNet, even if they tell me my son/daughter will get T1D, there is nothing we can do."  Right now, that is not true because they can participate in research, but if Teplizumab were approved, then it would be even less true, because they would have the option of delaying their T1D.

What Next?
Provention Bio has announced that they will resubmit their application using the new dosing data as soon as possible (no exact date has been publicized).  At that point the FDA has 30 days to review the application, and we will all see what they find at that point.
 
Of course, everyone wants an estimate for when this will happen.   You won't get one from me.  Why not?  Because the availability of Teplizumab is based on two things, and I don't know either one of them:  First, when will Provention Bio put together its updated application, and second, when/if the FDA will approve it.  Considering all the back and forth between the FDA and Prevention Bio over the last year, I have to believe that it will get approved, eventually.  However, I have no insight on the exact time.  And, since this is the first treatment which changes the progression of T1D, and no one has ever been through the approval process before, there could always be a last minute issue. 

Definitions

[d1] The technical term for this is "disease-modifying" treatment.  This is very different from a treatment like insulin which treats the symptoms, but does not change the underlying cause of the disease.  Teplizumab has the potential to change T1D itself in ways that insulin does not.

[d2] This is called "pharmacokinetics/pharmacodynamics" (or PKs/PDs) which refers to how quickly a medicine is absorbed into the body, how quickly it is distributed to different parts of the body, and how quickly it is used up.

[d3] To over simplify a little, the FDA regulates three things: drugs, biologicals, and devices.  Drugs are chemicals, biologicals are cells and parts of cells, devices are electromechanical objects.  Since Teplizumab is a cloned cell, it is a biological.  The rules for approval for drugs and biologicals are similar.  The rules for devices are different and generally "looser".  The concept of a "generic" applies only to drugs, since the 1960s.  The same idea for biologicals is called "biosimilar" and has been in use only since 2015.  Devices do not have anything similar to generics or biosimilars for other companies, but do have a simplified approval system for newer versions of a previously approved device.

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.