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

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

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

Results

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

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

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

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

Discussion

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

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

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

Joshua Levy

http://cureresearch4type1diabetes.blogspot.com

publicjoshualevy at gmail dot com

All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

 

JDRF Funding for a Cure 2023

In the US, we are in the "Walking Season" when JDRF (Juvenile Diabetes Research Foundation) asks us to walk to raise money for a cure for type-1 diabetes. So I'd like to do my part, by reminding you all of how important JDRF is to the human trials of potential cures for T1D, which I track.

Let me give you the punch line up front: 65% of the treatments currently in human trials have been funded by JDRF.  This is a strong impact; one that any non-profit should be proud of.  Below is a list of all the treatments, grouped by phase, and separated into trials that JDRF has funded, and those JDRF has never funded.  

 

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

 

The List, Divided by Phases

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

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

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

Approved!

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

• Teplizumab by Provention Bio (At Risk)

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

In Process of FDA Approval

Nothing is in process of approval right now.

Phase-III Human Trials

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

• Oral Insulin (Preventative)
  

Not funded by JDRF:

• Ladarixin by Dompé
  

Phase-II Human Trials

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

• ATG and GCSF by Haller at University of Florida (Established) 
• Abatacept in honeymooners and as a prevention by Orban at Joslin Diabetes Center and Skyler at University of Miami (Prevention)
• Aldesleukin (Proleukin) at Addenbrooke’s Hospital, Cambridge, UK 
• Diamyd in several combinations by Ludvigsson at Linköping University and Larsson at Lund University (Honeymoon and Prevention) 
• Difluoromethylornithine (DFMO) by Panbela
  
• Gleevec by Gitelman at UCSF 
• Gluten Free Diet: Three Studies  (Preventative)
• Stem Cell Educator by Zhao (Established) 
• Tocilizumab by Greenbaum/Buckner at Benaroya Research Institute 
• TOL-3021 by Bayhill Therapeutics (Honeymoon and Established)   
• Umbilical Cord Blood Infusion by Haller at University of Florida 
• Ustekinumab by University of British Columbia
• Verapamil by Shalev/Ovalle at University of Alabama at Birmingham

Not funded by JDRF:

• ATG and autotransplant by several research groups: Burt, Snarski, and Li 
• Dual Stem Cell by Tan at Fuzhou General Hospital 
• Stem Cells of Arabia (Established)
• Vitamin D by Stephens at Nationwide Children's Hospital (Prevention)

Phase-IIΔ Human Trials
Summary: there are 14 trials in phase-IIΔ, and 8 of them have been funded by JDRF, while 6 have not. Here are the treatments that have been funded by JDRF:

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

Not funded by JDRF:

• Azithromycin by Forsander
• Ixekizumab/Taltz by Vastra Gotaland Region
  
• Liraglutid (At Risk)
• NNC0114-0006 and Liraglutide by Novo-Norsk (Established)
  
• Rapamycin Vildagliptin Combo by IRCCS (Established)
• Visbiome by Medical College of Wisconsin

Phase-I Human Trials
Summary: there are 25 trials in phase-I, and 16 of them are funded by JDRF, while 9 are not. Here is the list funded by JDRF:

• AG019 and Teplizumab by ActoGeniX
• DIMID1 (Faecal Microbiota Transplantation) at AMC Hospital 
  
• CGSF by Haller at University of Florida 
• Golimumab (At Risk)
• MER3101 by Mercia (previously IBC-VS01 by Orban)
• MonoPepT1De by Cardiff University
• Mozobil by University of Alberta (Established)
• MultiPepT1De (Multi Peptide Vaccine) by Powrie at King’s College London
• Nasal insulin by Harrison at Melbourne Health (Prevention)
• PRV-101 (Coxsackie B Vaccine) by Provention Bio (Prevention)
• Semaglutide by Dandona at University of Buffalo
  
• Tauroursodeoxycholic Acid (TUDCA) by Goland at Columbia University
• TOPPLE T1D by Novo Nordisk (Established)
  
• Pro insulin peptide by Dayan at Cardiff University 
• VC-01 by Viacyte (Established)
• VCTX210A by Viacyte/CRISPR (Established)
  

Not funded by JDRF:

• AVT001 by Avotres
  
• Baby Teeth Stem Cells by CAR-T Biotechnology
• Extracorporeal Photopheresis by ADSCC
  
• Gluten Free Diet by Carlsson at Lund University
• Mesenchymal Stromal Cell by Carlsson at Uppsala University
• NN1845 (Glucose Sensitive Insulin) by Novo Nordisk
• OPT101 by Op-T (Established)
• PIpepTolDC at City of Hope Medical Center
• ProTrans by NextCell (Established)

Summary of all Trials
59 in total
39 funded by JDRF
So 66% of the human trials currently underway are funded (either directly or indirectly) by JDRF. Everyone who donates to JDRF should be proud of this huge impact; and everyone who works for JDRF or volunteers for it, should be doubly proud.

Just Looking at Trials on Established Type-1 Diabetics

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

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

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

A Little Discussion

 
The money that we donate does many things:

1. It finances more clinical trials (especially early clinical trials).
2. It finances making clinical trials (especially early clinical trials) larger and better designed.
   
3. It helps push possible cures to the next level of trial.  It finances moving phase-I trials to phase-II, and phase-II to phase III.

I like to say that there are two reasons for donating money for research into T1D.  People who like the research being done should donate money to move it forward, faster.  People who don't like the research being done should donate money to start up different research which (presumably) they will like more.  So no matter which group you are in, you should donate.  😀

  

Trial Populations

 

The list above uses the following marks to show the nature of the treatments, and if one treatment is being tested in different populations, then it will be listed more than once.
Honeymoon: Most trials are done on people within the first year of diagnosis.  All the studies listed above which are not Established, At Risk, or Prevention are in this Honeymoon category.

Established: One or more trials are open to people who have had type-1 diabetes for over a year. 
At Risk: One or more trials are open to people who have 2 or more autoantibodies, but have not yet started showing symptoms of type-1 diabetes.
Prevention: This treatment is aimed at preventing type-1 diabetes, not curing it.
If a trial is not marked, then it is for people in the honeymoon (first year) of T1D.

I give an organization credit for funding a treatment if they funded it at any point in development; I don't limit it to the current trial.  

 

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

 

How I Count Trials for This Comparison

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

Some Specific Notes:

• Oral Insulin: This trial was a phase-III trial, meaning that it was large and designed to provide enough information so that, if successful, the treatment could be widely used. However, as it turned out, only part was successful, and that part was phase-II sized, so I don't think we will see widespread use based on this trial alone. You can think of this as a phase-III trial with phase-II results.
  

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

• https://cureresearch4type1diabetes.blogspot.com/2022/10/jdrf-funding-for-cure-2022.html
  
• https://cureresearch4type1diabetes.blogspot.com/2020/10/jdrf-funding-for-cure-2020.html
  
• https://cureresearch4type1diabetes.blogspot.com/2019/10/jdrf-funding-for-cure-2019.html
  
• https://cureresearch4type1diabetes.blogspot.com/2018/10/jdrf-funding-for-cure-2018.html
• https://cureresearch4type1diabetes.blogspot.com/2017/10/jdrf-funding-for-cure-2017.html
• https://cureresearch4type1diabetes.blogspot.com/2016/10/jdrf-funding-for-cure-2016.html
• https://cureresearch4type1diabetes.blogspot.com/2015/10/jdrf-funding-for-cure-2015.html
• https://cureresearch4type1diabetes.blogspot.com/2014/09/jdrf-funding-for-cure-2014.html
• https://cureresearch4type1diabetes.blogspot.com/2013/10/jdrf-funding-for-cure-2013.html
• https://cureresearch4type1diabetes.blogspot.com/2012/09/jdrf-funding-for-cure-2012.html
• https://cureresearch4type1diabetes.blogspot.com/2011/10/jdrf-funding-research-for-cure-2011.html
• https://cureresearch4type1diabetes.blogspot.com/2010/09/jdrf-funding-research-for-cure-2010.html
• https://cureresearch4type1diabetes.blogspot.com/2009/09/jdrf-funding-research-for-cure.html
• https://cureresearch4type1diabetes.blogspot.com/2008/10/jdrf-funding-of-cure-research-phases-ii.html

Please remember that my blog (and therefore this posting) covers research aimed at curing, delaying, or preventing type-1 diabetes that is currently being tested in humans. There is a lot more research going on than is counted here.

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

Thank You!

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

Joshua Levy

http://cureresearch4type1diabetes.blogspot.com

publicjoshualevy at gmail dot com

All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My kid has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.