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.

Data From A Phase-II Clinical Trial of TOL-3021

Data From A Phase-II Clinical Trial of TOL-3021 by Tolerion
(Previously known as BHT-3021 by Bayhill)

Tolerion recently reported results from a Phase-I/II clinical trial of TOL-3021.  This treatment started life as BHT-3021 under development by Bayhill Theraputics, so you can read my previous blogging on it under that name:
http://cureresearch4type1diabetes.blogspot.com/search/label/Bayhill

Background

The best results (most positive results) were seen in people dosed 1 micro gram, which was a middle dose in this trial, which tested a range of different doses.  Those are the results I discuss below.  This study was a true phase-I/II study.  The researchers started out dosing a few people to check for safety and to get early efficacy data for a very small number of people (the phase-I part). They then expanded into a larger group, which got four different dose levels (plus a placebo group).  The goal of the phase-II part was to find the best dose for future trials.  The people in this trial had type-1 diabetes for years prior to the start of the treatment.

Results

The researchers reported three interesting results:

1. Treated type-1 diabetics generated more of their own insulin, but only a tiny amount more.
The "top line" results for this study is that 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%.)  On the one hand, this is a tiny amount.  So little that their insulin requirements did not change noticeably (ie. in a statistically significant amount).  On the other hand, any increase at all in well established type-1 diabetics is big news.  Even ten years ago, it was thought to be impossible.

2. Treated type-1 diabetics generated less autoimmune cells ("bad killer T cells"), targeting proinsulin.  The immune system generates cells ("killer T cells") that attack foreign cells.  In type-1 diabetes a small number of these killer T cells mistakenly attack the body's beta cells in the pancreas, which causes type-1 diabetes.  These are called "bad killer T cells".  These researchers specifically measured "bad killer T cells" (separately from other killer T cells) and found fewer of them in patients who got TOL-3021 as compared to those which got a placebo.  This is direct evidence that the treatment is working in the way the researchers expected.

3. Treated type-1 diabetics did not change their immune response to foreign cells.
One of dangers of immunology in general, is that you might damage the body's immune system. You might cure the type-1 diabetes, but hurt the body's ability to fight off disease in the future. These researchers specifically looked at the effect of TOL-3021 on the body's reaction to foreign bodies (the viruses, cancers, and foreign cells that the immune system is supposed to attack).  They found there was no change in the immune system's ability to do it's job of attacking these foreign cells.  This is interesting for at least two reasons: first, it's unusual.  Most immune treatments end up lowering the immune response across the board.   Second, it's important.  By showing this treatment did not effect the rest of the immune system at all, it puts TOL-3021 in a good position to move forward, because the safety worries will be lower and the potential doses can go higher.

Moving Forward

So what is the next step?  Well money, for one thing.  Or, better yet, a strategic partnership.  Since these are phase-II results, the obvious next step is either a phase-III study or another phase-II study.  Either path requires money.  Of the four phase-III studies I've followed in the past, three were funded via a strategic partnership with a "big pharma" company; only one was funded by a smaller company itself.

What are the problems to overcome?  The small results are a big problem.  They need to see a larger C-peptide production, if they are going to produce a treatment, much less a cure.  A second issue is duration.  The biggest results were seen 15 weeks into the treatment. since the treatment was given for 12 weeks, this is close to the point of longest duration of treatment.  That suggests to me that the treatment might need to be given for a longer duration, or given more often, or improved in some way, in order to be more effective in the long term.

What sort of clinical trial comes next? There are a lot of options here. Since TOL-3021 seems to lower the autoimmune attack, but does not create replacement beta cells.  An obvious trial would be to try it on honeymooners or even pre-diagnosis, high risk relatives of type-1 diabetics. Those people have more surviving beta cells, so the benefit should be more obvious. Another option would be to combine it with a treatment that stimulates beta cell regrowth. Simply repeating the treatment for a longer period of time would be interesting, as well.

Business News

The reason there was no news on TOL-3021, prior to these phase-II results, is that until recently this drug was known as BHT-3021 and was being developed by Bayhill Therapeutics.  Bayhill had all the trappings of a successful little pharmaceutical start up (several drugs in development, a deal with Genentech, about $50 million invested, etc.)  But it collapsed while BHT-3021 was in the middle of it's phase-II trial.  Luckily, the researchers focusing on BHT-3021 were able to rise, phoenix-like, from the ashes, and create Tolerion.

Some Discussion

One question I've heard is "why do they call this a vaccine" or "what is a reverse vaccine", and there is a simple answer to that.  Classic vaccines work by stimulating the immune system.  This product works by regulating (lowering) the immune system, so it acts like the reverse of a vaccine. It is similar to the way food allergies are treated.  For food allergies doctors sometimes give small amounts of what you are allergic to, so your body learns not to attack it.  The difference here, is that they are giving the body a specially crafted molecule, which is designed specifically to teach the body not to self-attack proinsulin.  Other researchers are giving small amounts of insulin to teach the body not to attack insulin, which is a related idea, but the hope here is that TOL-3021 will work better and more specifically than insulin.

Comparing TOL-3021 to BCG (ie. Tolerion's results to Faustman's results)

These two potential cures are similar in many ways.    Medically, they are both immunology based approaches.  They are both being tested on established type-1 diabetics (not honeymooners), and they both started clinical trials in the 2006-2007 time frame.   From a "marketing" point of view, their respective proponents each claimed that they targeted the exact cells that cause the destruction of beta cells in the pancreas.  They are not suppressing a whole class of immune cells, just the ones that are incorrectly attacking beta cells.

So with all those similarities, it makes sense to compare them in three different ways:
1: Effectiveness. The most important comparison would be C-peptide numbers. The BCG treated patients gained 22% of their C-peptide production, while the TOL-3021 group gained 28%. So TOL did slightly better.
2: Targeting.  One of the key advantages claimed by Dr. Faustman for BCG and by the Tolerion group for TOL-3021, is that they selectively target the bad T cells. Here the Tolerion group has published data supporting both sides of their claim: data showing bad T cells are lower when treated, and data showing other T cells don't change.  Dr. Faustman's trial found no difference in the number of active bad T cells, and did not measure the other T cells at all.
3: Research size/analysis. The TOL group was more than three times as large as the BCG group, which is always a good thing.   Finally, Tolerion's results were statistically significant as designed, which is different than Dr. Faustman's group.  They had to move a person out of the placebo group in order to get statistically significant results, and use different comparison groups for different measurements.

In a head to head comparison, TOL-3021 has better results across the board, and both treatments were tested in long established type-1 diabetics.

Note that Dr. Faustman's group reported C-peptide production in absolute numbers, while the Tolerion group reported as a percentage change. I did ask the Tolerion group for the absolute numbers, since that would make the comparison simpler, but that data is not publicly available. Therefore, I have converted Dr. Faustman's numbers into percentages in order to do the comparison. So the comparison is approximate. In my opinion, reporting absolute numbers (as done by Dr. Faustman) is the better way to go.

News: http://www.biospace.com/news_story.aspx?NewsEntityId=301263&source=news-email
http://news.yahoo.com/type-1-diabetes-vaccine-shows-promise-early-study-180404550.html
Press Release: http://www.tolerioninc.com/TOL-3021_press_release.html
Interview: http://www.bizjournals.com/sanfrancisco/blog/biotech/2013/06/type-1-diabetes-vaccine-stanford.html?page=all
Abstract: http://stm.sciencemag.org/content/5/191/191ra82
US Trial Registration: http://www.clinicaltrials.gov/ct2/show/NCT00453375
Company Web Site: http://www.tolerioninc.com/

Summary of ADA's Annual Conference

ADA just finished their annual conference. I enjoyed the summaries below. Remember that ADA covers both type-1 and type-2, so some of the news will be about type-2 diabetes:

http://www.integrateddiabetes.com/Articles/ADA%202013%20meeting%20notes.pdf
http://www.diabetesmine.com/2013/06/its-a-wrap-on-the-ada-scientific-sessions-for-2013.html
http://www.diabetesmine.com/2013/06/ada-scientific-sessions-part-2.html

Joshua Levy
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. 
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com