TOL-3021 Starts A Phase-II Clinical Trial

TOL-3021 causes the body to generate proinsulin so that over time the immune system will get used to (or tolerate) it.  Proinsulin and insulin are similar molecules.  Since insulin is one of the targets of the broken immune system which leads to type-1 diabetes, teaching the immune system to stop this attack may cure (or prevent) T1D.  There is other ongoing research where people are given insulin prior to the onset of T1D to try to teach the immune system not to attack insulin.  TOL-3021 takes this one step farther, by getting muscle cells to generate proinsulin over time, so the person does not need to take it repeatedly.

TOL-3021 was originally developed at Stanford University, and was then productized by Bayhills Therapeutics (where it was know as BHT-3021).  After Bayhills went out of business, development was taken over by Tolerion, Inc.

Prior to this study, this drug had been tested in an 80 person clinical trial from about 2007 to 2011.  You can read my previous blogging on TOL-3021 here:
https://cureresearch4type1diabetes.blogspot.com/search/label/TOL-3021
https://cureresearch4type1diabetes.blogspot.com/search/label/Bayhill


TOL-3021 Has Started A Phase-II Clinical Trial

This trial will enroll 50 people who are within 5 years of diagnosis.  Of those, 2/3s will be treated with TOL-3021 and 1/3 will get a placebo and be a control group.  (The previous study used weekly injections, but this study does not say exactly how often people will get the treatment.)  They will be followed for a year to measure effectiveness and then two more years for safety.  The primary end point is C-peptide production (showing an increase in insulin production).  There are also about two dozen different secondary end points covering efficiency, immunology, safety, etc.  A unique feature of the design of this trial, is that they will keep track of honeymooners separately from people with established T1D.  When the data is published, we will be able to compare how it worked on each group.

They started recruiting in July 2019, and hope to finish collecting their primary data in Aug 2021, and complete the safety follow up in 2023.

The following sites are either recruiting now, or plan to in the future:

• Stanford University California, USA, 94305 Contact: Trudy Esrey    650-498-4450    tesrey@stanford.edu  
• Chase Medical Research, LLC Hamden, Connecticut, USA, 06517 Contact: Melissa Capasso mcapasso@chasemr.com        
• Baptist Health Research Institute Jacksonville, Florida, USA, 32258  Contact: Kristy Clemmer    904-271-6363    Kristina.Clemmer@bmcjax.com               
• University of Miami Diabetes Research Institute Miami, Florida, USA, 33101-6960 Contact: Jay S Skyler, MD, MACP              
• Iowa Diabetes and Endocrinology Research Center West Des Moines, Iowa, USA, 50256 Contact: Tara Herrold    515-329-6803    therrold@iowadiabetes.com        
• Naomi Berrie Diabetes Center, Columbia University New York, New York, USA, 10032 Contact: Sarah Pollack    212-851-5425    sjp2174@columbia.edu         
• SUNY Upstate Medical University Syracuse, New York, USA, 13210 Contact: Jane Bulger    315-464-9008    bulgerj@upstate.edu        
• Mountain Diabetes and Endocrine Center Asheville, North Carolina, USA, 28803 Contact: Will Cooley    828-684-9588 ext 315    wcooley@mdecresearch.com      
• University of North Carolina Diabetes Care Center Chapel Hill, North Carolina, USA, 27517 Contact: Julie Uehling    984-974-3010    julie_uehling@med.unc.edu  
• Diabetes and Glandular Disease Clinic San Antonio, Texas, USA, 78229 Contact: Terri Ryan    210-614-8612 ext 1630    terri.ryan@dgdclinic.com  
• University of Virginia Charlottesville, Virginia, USA, 22903 Contact: Mary Voelmle    434-924-2327    MKV9F@hscmail.mcc.virginia.edu    

Registry: https://clinicaltrials.gov/ct2/show/NCT03895437

And Two More Are Preparing To Start

In addition, Tolerion has two more studies in preparation, with plans to start by the end of the year.  Both are registered with the FDA's clinical trial registry, but have not yet started recruiting.

The first is called DAWN.  It will enroll 210 people from 12 to 35 years old.  All of these people will be in the honeymoon phase of T1D.  Initially, only adults will be enrolled, but once there is enough history to show no bad side effects, they will open enrollment to younger people.  This trial will take a year to gather the data it is looking for.

The second is called DAY.  It is the same as DAWN, except that it will enroll people who have had T1D for between 1 and 5 years.  So it will exclude honeymooners, and gather data on people who have established T1D.

Tolerion's web site: https://tolerion.bio

Discussion

How Did It Work Last Time?
This trial is the follow on to a phase-I trial, so the obvious question is "how well did it work before?"  The answer is: people treated with TOL-3021 saw a 28% increase in C-peptide production, which means a 28% increase in the amount of insulin their bodies were naturally producing. (I'm reporting on "spread" here: the treated group went up about 20%, the placebo group went down about 8%, so the spread was about 28%.)

Phase-I Paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516024/

For comparison, this is similar to how well Teplizumab did in it's phase-III study, although Teplizumab did much better than that in subgroups and in earlier phase-II trials.  However, TOL-3021 had fewer side effects as compared to Teplizumab.  You can read my previous blogging on Teplizumab (and its effectiveness and safety) here:
https://cureresearch4type1diabetes.blogspot.com/search/label/Teplizumab

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.

JDRF Funding for a Cure 2019

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: 71% of the treatments currently in human trials have been funded by JDRF. (And the number is 83% 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 groups that JDRF has funded, and those JDRF has never funded.

The list below 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.  On the other hand, if it is in many clinical trials, all with established T1D, then it will be listed only once, no matter how many different trials are being run.
Established: One or more trials are open to people who have had type-1 diabetes for over a year.
Presymptomatics: 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. For example, JDRF is not funding the current trials for AAT, but they did fund earlier research into it, which helped it grow into human trials. I also include indirect funding of various kinds. The JDRF funds nPOD, ITN, and several other organizations, so I include research done by these other groups as well.

The Difference Between Phase-II and Phase-II? Trials
Phase-II trials are "classic" phase-II trials; they are done after a successful Phase-I trial in type-1 diabetes.  What I call Phase-II? trials are done on known safe treatments, so they don't need Phase-I trials, but have never been tested on type-1 diabetes before.  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.

Waiting For FDA Approval
Summary: currently there is 1 drug in process of getting FDA approval for sale, and it is funded by JDRF.

• Teplizumab by Provention Bio (Presymptomatics)

Note: Provention Bio is preparing to submit Teplizumab for FDA approval for presymptomatics (people who have tested positive for two autoantibodies related to T1D, but who are not yet taking insulin) in 2020.  In clinical trials in this population, Teplizumab delayed the onset of T1D and helped preserve some insulin production for two years.  However it is unclear how long these effects will last.

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

• AAT (Alpha-1 Antitrypsin) by Kamada 
• ATG and GCSF by Haller at University of Florida (Established) 
• Abatacept by Orban at Joslin Diabetes Center 
• Abatacept by Skyler at University of Miami (Prevention) 
• Aldesleukin (Proleukin) at Addenbrooke’s Hospital, Cambridge, UK 
• Diamyd, Ibuprofen ("Advil"), and Vitamin D by Ludvigsson at Linköping University
• Diamyd, Etanercep, and Vitamin D  by Ludvigsson at Linköping University
• Diamyd and Vitamin D by Larsson at Lund University (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 
• TOL-3021 by Bayhill Therapeutics (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 14 trials in phase-II, and 8 of them has 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
• GNbAC1 by GeNeuro (Established)
• Golimumab by Janssen
• Golimumab by Greenbaum (Established)
• Hydroxychloroquine by Greenbaum (Presymptomatic)
• Intranasal Insulin by Harrison at Melbourne Health (Prevention)
• Rituximab by Pescovitz at Indiana University

Not funded by JDRF:

• Azithromycin by Forsander
• Albiglutide by GlaxoSmithKline
• Ladarixin by  Emanuele Bosi of Dompé Farmaceutici
• Liraglutid (Presymptomatics)
• NNC0114-0006 and Liraglutide by Novo-Norsk
• Rapamycin Vildagliptin Combo by IRCCS (Established)

Phase-I Human Trials
Summary: there are 18 trials in phase-I, and 12 of them are funded by JDRF, while 6 are not. Here is the list funded by JDRF:

• Alefacept by TrialNet 
• CGSF by Haller at University of Florida 
• Exsulin and Ustekinumab by Rosenberg at Jewish General Hospital, Canada (Established) 
• Golimumab by (Presymptomatics)
• 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)
• Tauroursodeoxycholic Acid (TUDCA) by Goland at Columbia University
• Pro insulin peptide by Dayan at Cardiff University 
• VC-01 by Viacyte (Established)

Not funded by JDRF:

• Gluten Free Diet by Carlsson at Lund University
• IMCY-0098 by Imcyte
• Mesenchymal Stromal Cell by Carlsson at Uppsala University
• Microvesicles (MVs) and Exosomes by Nassar at Sahel Teaching Hospital 
• ProTrans by NextCell (Established)
• Substance P by Vanilloid Genetics at Hospital for Sick Children Toronto (Established)

Summary of all Trials
56 in total
40 funded by JDRF
So 71% 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 (21%) are being tested on established type-1 diabetics.
Of these, 8 are funded by JDRF.
So 75% of the trials recruiting established type-1 diabetics are funded by JDRF.

Compared to Last Year
In 2018 there were 59 treatments in clinical trials, in 2019 there are 56 (a drop of 5%).
In 2018 (and every previous year) there were no treatments waiting for approval to sell, in 2019 there is 1.
In 2018 there was 1 treatment in Phase-III trials, in 2019 there are 2 (growth of 100%).
In 2018 there were 22 treatments in Phase-II trials, in 2019 there are 21 (a drop of 5%).
In 2018 there were 12 treatments in Phase-II? trials, in 2019 there are 14 (growth of 17%).
In 2018 there were 24 treatments in Phase-I trials, in 2019 there are 18 (a drop of 25%).

A Little Discussion
The big break through this year is that Teplizumab has completed the clinical trials that Provention Bio thinks are required to get FDA approval. This is the first time any drug aimed at changing the course of T1D has ever gotten so far in the regulatory process.
 

The money that we all donate is the thing that is going to move more Phase-II studies into Phase-III studies, the Phase-I studies to Phase-II, create more Phase-I studies, and so on.  If you don't like where we are on research, donating money is the way to make it better.  And if you do like where we are, then money is the way to push these things forward into the market.  If you're worried about your money going to non-research, then you can do what I do: fill out the attached form or go to the following website and send it in with your donation: http://thejdca.org/good-giving-landing-page/  (Unfortunately I don't know how to do this for on-line donations.)

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. Also, I list experiments separately if they use at least one different drug. 
• The ITN (Immune Tolerance Network) has JDRF as a major funder, so I count ITN as indirect JDRF funding. 
• 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 this year was a population based study, so also not included.
• I've removed Dr. Faustman's BCG research from my list of potential cures, because it is no longer aimed at a cure.  For more information read this blog:
  https://cureresearch4type1diabetes.blogspot.com/2018/09/every-year-in-september-or-october-i.html and for even more details
  https://cureresearch4type1diabetes.blogspot.com/2018/07/dr-faustman-publishes-follow-on-bcg.html
• 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.
• Serova's Cell Pouch and DRI's BioHub: These two clinical trials are both testing one piece of infrastructure which might be used later in a cure. They are testing a part of a potential cure. However, in both cases, the clinical trials being run now require immunosuppression for the rest of the patient's life, so I'm not counting them as testing a cure.

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

• 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 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.  I'll be at the San Francisco (California) JDRF One Walk as part of "The Narwhals" team.  Come by and say "hi", or strike up a conversation about research.  I love to talk about research!

Joshua Levy 

https://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 adult 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.