Sunday, December 22, 2019

Clinical Trials Using Probiotics For Type-1 Diabetes

Some people believe that the gut microbiome (bacteria in your digestive system) can impact type-1 diabetes.  If true, that would mean that type-1 diabetes might be cured, prevented or delayed by changing your gut microbiome, and one way to do this is to give people probiotics in the hope that it will improve their gut microbiome.

This blog posting is a general update on all the probiotic clinical trials aimed at curing, preventing, or delaying Type-1 Diabetes that I know of.  The research included here uses several different bacteria.  If you know of any more, please tell me, so I can update this posting.

An important part of all the trials that I discuss below, is that they have a control group so we can compare what happens to people who get probiotics to those who don't.   This is important because right now, a lot of people eat probiotics (foods which contain these bacteria), so it is hard to know what effects these have.  By comparing groups that got them to control groups that did not, these studies should provide better information than the anecdotes (personal stories) we have now.

Five Trials Currently Underway

Trial #1: Prevention of Autoimmunity With Lactobacilli

Patients will get a daily pill containing two "good" bacteria: Lactobacilli plantarum and Lactobacilli paracasei in the hope that it will delay or prevent the onset of type-1 diabetes.

This trial is open to anyone who tests positive to one autoantibody associated with type-1 diabetes, celiac disease, or thyroid disease.  They will recruit 200 people.  Half will get treatment and half will get a placebo and be a control group.  The trial is randomized and blinded.

Each person will be followed for one year.  The primary end point is the number of autoantibodies they are positive for at the end of the study.  Remember, everyone starts with at least one to enter the trial, so the question is, how many more do they accumulate in a year?  They started recruiting in Oct-2019 and hope to finish in Dec-2021. 

This trial is being done at one location in Sweden:
Clinical Research Center, Malmö, Sweden, 20502
Contact: Carin Andrén Aronsson, PhD    +46 40 391113    

Clinical Trial Registry:


This is a prevention/delay study (not a cure or a treatment study).  That is why it is measuring number of autoantibodies as an end point.  It is the quickest measurement which might give a signal that T1D has been avoided or delayed.  Furthermore, it is now well established that just about everyone who has two autoantibodies will eventually get T1D.  People in this study start out with one, so even those who gain only one more, end up at two, and are almost certain to eventually be diagnosed with T1D.

For me, the open question is, how many people in this study will have type-1 diabetes?  Because they are recruiting people with autoantibodies from any one of three different diseases, it is not clear to me how many people will be in the T1D part of the trial.  Given the short time period (just 1 year), and unknown number of people in the T1D part of this trial, I'm worried they will not have enough data to answer the question.

For comparison, the Teplizumab study which also tested to see if T1D could be delayed or prevented, included 76 people (all had T1D) and ran for 5 years, which means the whole study was about 380 person-years.  The maximum this study could possibly have is 200 person-years, and that is assuming everyone has T1D (no one has celiac disease or thyroid disease).  If the three diseases are recruited evenly, then there will only be about 66 person-years in the T1D arm, making it about 1/6 as big as the Teplizumab study.

Trial #2: The Effect of Probiotics on Type 1 Diabetes Mellitus in Children

This study is giving children with established type-1 diabetes three probiotics: Lactobacillus salivarius, Lactobacillus johnsonii, and Bifidobacterium lactis for six months.  This is a phase-II study from my point of view, enrolling 80 people with randomization and a control group.  Primary outcome measurements are A1c and fasting BG measurements.  Secondary outcomes include measures of inflammation and internal immune response.

They started in Aug-2018 and hope to finish in July-2021.

This study is being done in Taiwan:
    China Medical University Hospital, Taichung, Taiwan, 40447
    Contact: Chung-hsing Wang    886-4-22052121 ext 4640  
    Contact: Hung-chih Lin    886-4-22052121 ext 4640  
    Principal Investigator: Chung-hsing Wang   

Clinical Trial Registry: 


Because this study does not measure C-peptide as a primary or secondary outcome, I don't consider it cure focused, and so won't follow it long term, unless the immune results suggest that it might be a path to a cure.  However, it will tell us if probiotics can help people who have T1D better manage their blood sugars and A1c numbers, and I know many people are interested in that.

Trial #3: Probiotics in Newly Diagnosed T1D

This is the follow-on study to a previous phase-I/pilot study.  Unfortunately, that previous study was tested on people who did not have T1D.  So I would describe this study as a phase-II? study: it is the size of a phase-II trial, but does not have T1D results from a phase-I trial behind it.  The probiotic being studied is a commercial product called Visbiome made by ExeGi Pharma.  You can read more here:

This study will enroll 60 honeymooners and follow them for 3 years.  The study is blinded and 40 will get the treatment while 20 get a placebo and be a control group.  The primary end point is a measure of inflammation, while the secondary end points include C-peptides, gut bacteria measures, and more measures of inflammation.

They started in April-2019 and hope to finish in Jan-2025.

This study is recruiting now at one site:
    Medical College of Wisconsin, Milwaukee, Wisconsin, United States, 53226
    Contact: Susanne Cabrera, MD    414-955-4903    

Clinical Trial Registry:
Earlier Study Clinical Trial Registry:


This is the only study that has C-peptide as a end point, so it is the only one that can be said to focus on finding a cure to T1D.

Trials #4 and $5: Lactobacillus Johnsonii 

These two studies are identical, except that one enrolls adults who have had T1D for less than 3 years, while the other enrolls children and adolescents who have had T1D between 4 months and 2 years.  Both studies will enroll about 60 people in a randomized and blinded study lasting just under a year.

Unfortunately, the only primary outcome is a measure of side effects, and there are no secondary outcomes listed in the clinical trial registry. 

Both studies start in Oct-2019 and should end in July-2020.

Both of these trials are recruiting at one site:

UF Clinical Research Center, Gainesville, Florida, United States, 32610
    Contact: Michael Haller, MD     352-273-9264    
    Contact: Miriam Cintron     352-273-5580

Clinical Trial Registry:
Clinical Trial Registry:


Because these studies do not measure C-peptides, autoantibodies, A1c, or BG numbers, by themselves, they are not going to provide information on a cure, prevention, delay or even a treatment of T1D.  The best they can do is clear the way for a follow-on trial(s) with cure focused end points.

Trials In The Future:

There are two more studies which are listed in the Clinical Trials registry but have not yet started recruitment.  Both are getting old, and I'm worried that they might never start, or conversely that they have already started, but the researchers have not updated the Clinical Trials registry:

Effect of Live Combined Bifidobacterium and Lactobacillus on Glycemic Control and Other Outcomes in Type 1 Diabetes
Clinical Trial Registry:

Probiotics in Newly Recognized Type 1 Diabetes
Clinical Trial Registry:

Joshua Levy 
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, December 3, 2019

Avotres's AVT001 Starts A Phase-I Trial

AVT001 is an "autologous dendritic cell therapy" meaning that a person's own dendritic immune cells are taken out, processed in some way, and then put back.  Dendritic cells can be thought of as the immune systems "sensors".  They detect foreign invaders and then communicate that knowledge to other types of immune cells (especially T cells).

This trial flows out of some work done at Columbia University.  Basically, researchers there found a defect in a specific type of immune cell called a HLA-E–restricted CD8+ T cells.  They believe that this defect leads to the immune system attacking the beta cells in the pancreas and causing type-1 diabetes.  The researchers found this defect in many (but not quite all) people with type-1 diabetes, but not in people who did not have the disease.  They also found a way to fix the defect in the immune cells.

The basic technique being tested here is to take out dendritic cells from the patient and treat those cells so that when they are put back into the patient, they (in turn) fix the defect in the HLA-E–restricted CD8+ T cells, which leads to type-1 diabetes.

This Study

The trial will enroll 24 people in two groups, treatment and control.  Everyone will be in their honeymoon (diagnosis within the last year), and everyone will be tested to make sure they have the immune cell defect the researchers are targeting.  The treatment group will get three dendritic cell treatments.  Everyone will be followed for 5 months, and they hope to have primary results by Nov-2020, which is quick for a human trial.  However, they will continue to gather data until June-2022.

There are three primary end points for this trial, and all are safety related.  Two are measures of adverse effects and the third checks for changes in blood chemistry.  They also have three secondary endpoints.  These include C-peptide and A1c numbers, which will give an indication if the treatment is working, and an immune measurement, which will give some insight into the mechanism by which it works.   

They are recruiting at the Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.  Contact information is:
Jason Gaglia, MD 888-813-8669

Trial Registration:
Trial Site Web Page:
Paper describing the basis for this trial:
Commentary on that paper:


Although both treatments involve dendritic cells, this research is not related to Dr. Trucco's previous work, which I have blogged about in the past.

This trial is sponsored by Avotes Inc.  However, I can not find any useful information on the company or their technology.  So I'm vague on the details.  As far as I can tell, Avotes does not have a corporate web page, and there are no web pages which describe in any detail what the treatment involves, which is very unusual for a clinical trial.

Joshua Levy 
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.

Saturday, November 23, 2019

Combo of AG019 and Teplizumab Starts A Phase-I Trial In Honeymooners

This is another clinical trial using Teplizumab, but since this trial is more focused on AG019, I've put in a separate blog post from the other Teplizumab research.

AG019 is a pill containing an engineered micro-organism (Lactococcus lactis, often shortened to "L. lactis") which generates Proinsulin and Interleukin-10 (IL-10).  People in the study will take 2-6 pills once a day.  So there is a lot to consider:

First, there is Lactococcus lactis.  This is the microorganism that turns milk to cheese.  It is also involved in making beer, buttermilk, pickled veggies, kefir, etc.  The L. lactis used here has been modified to generate proinsulin and IL-10. The idea is that as the L. lactis passes through the intestine it will dose the patient with proinsulin and  IL-10.  The effect should be similar to injecting small amounts of Proinsulin and IL-10 many times per day, but much less hassle and no needles.  The L. lactis does not colonize the person's digestive system; it just passes through.

Second, what will the Proinsulin do?  Proinsulin is a molecule closely related to insulin.  It is naturally created by the body as part of the process of creating insulin.  To make insulin, first beta cells make Proinsulin, and then at the last step, they break up the Proinsulin in order to create insulin.  The goal behind giving Proinsulin is that it will help the immune system learn not to attack insulin, which is one of the things that lead to T1D.

Third, what will the IL-10 do? In mice, IL-10 can prevent or delay the onset of type-1, although this is dependent on when and where the IL-10 is given. The mechanism involves stimulating more regulatory T cells, and fewer "killer" T cells.  An on-going issue with directly dosing IL-10 is that it does not last for very long in the body, so it would require many small injections around the clock.  That is why these researchers (and others) are using a microorganism to continually secrete it.

Proinsulin and IL-10 generated by L. lactis has cured mice, which you can read about here:

This Trial

Everyone involved in this trial will be honeymooners (within 150 days of diagnosis).  The trial is complex and will have two separate parts.

The first part is open label (so everyone will get the treatment, and the researchers will know who got which doses).  This part will be AG019 only (no Teplizumab).  There will be 4 groups of six people each.  The first two groups will be adults.  The first will be tested at a low dose and the second group at a high dose.  The next two groups will be teenagers, and again, the first will get a low dose, the second a high dose.

The second part has two groups, adults and teenagers.  Each group will be 12 people, but the first 2 people will be "open label" (meaning the researchers will know they got the treatment).  The next 10 people will be blinded and randomly assigned to get the treatment or get a placebo at a ratio of 4:1.  This means that for the blinded/randomized group, 10 people will get the treatment and 2 will not.

This study is mostly measuring safety and pharmacodynamics of the treatment.  C-peptides are being measured as a secondary endpoint (although not listed in the clinical trial record).  Pharmacodynamics refers to how much of the treatment is actually getting into the patient.  Since this trial is testing a two step process (give the person a microorganism, and then the microorganism makes the treatment, there is a real question of how much treatment the patient will end up with, and how consistent it will be.  So measuring pharmacodynamics is important. C-peptide measures how much insulin a person is producing, so increases in C-peptide shows progress towards a cure.

This study started in Oct-2018 (sorry I'm so late in reporting it) and is expected to finish in June-2020.  However, since they are still recruiting new participants, and will gather data for a year for each participant, I don't see how they can finish in less than a year from now (Oct-2020).

This clinical trial is funded by ActoBio Therapeutics which is a subsidiary of Intrexon.  The animal research that led to this trial was funded by JDRF and a large collection of European charity and research funds.

Press Release:
US Clinical Trial Registry:
EU Clinical Trial Registry:

Joshua Levy
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, November 15, 2019

Is there any association between gut microbiota and type 1 diabetes?

Recently "gut microbiota" has become a trendy area of research for many different diseases, including type-1 diabetes.  Gut microbiota refers to the microorganisms which grow inside a person's digestive tract.  Over the last few years there have been some papers published showing changes in the gut microbiota at the time of T1D diagnosis, or differences between the gut microbiota between people who get T1D and those that don't.  However, because gut microbiota has only recently been studied, it is hard to tell if these differences mean anything or if they are normal variations.  Even if they do mean something, it is also not clear if they are a cause of T1D or a symptom of T1D.

Recently a group in Tehran systematically searched for all English language scientific papers that dealt with gut microbiota and T1D and reviewed the 26 papers that they found.  You can read their paper here:

The papers they reviewed covered about 2600 people in 17 different countries.  The top line results were that 24 out of 26 papers found some changes or differences in the gut microbiota between people with T1D and those without.

However, I wanted to see if these 24 studies found the same differences between people with T1D or different differences.  For example, if one study found that people with T1D had more of bacteria A, while another study found they had more of bacteria B, and a third found they had less of bacteria C, well those all found "differences" but it is not at all clear that these matter.  On the other hand if the three studies all found more of bacteria A, then (in my opinion) that is a much stronger finding.

My Data Analysis

I started out with the list of results that the researchers provided in their "table 3".  This was a list of each study, and each microbe that the study found to be either increased or decreased between the people who had T1D and who did not.  (Since we are looking for differences, either an increase or a decrease might be important.)

With that list, I then scored each microbe family, giving it +1 for every study which found an increase and a -1 for each study that found a decrease in levels when comparing people with T1D to those without.  I then looked for microbe families which had a score of +4 or greater, or those that had a -4 or smaller.  These would be microbe families which showed a difference in several different studies.

There are two limitations with my data analysis technique:
  1. I did my analysis on a study by study basis, which means that a larger study carries the same weight as a smaller study.  Obviously, that is not ideal, but it does make the analysis easier.
  2. Some of the studies tested for specific species (such as "Bifidobacterium adolescentis") while other studies only tested for families (such as "Bifidobacterium spp." with "spp." standing for "any species").  Unfortunately, if one study found Bifidobacterium adolescentis but another found Bifidobacterium spp. there is no way to know if they both found the same species or not.  Therefore, I did my analysis at the family level.  So I would say that both studies found a Bifidobacterium spp.

My Results

The only family of microbes which had a strong signal was Bacteroides spp.  Ten different studies found increase levels of these microbes in people with T1D, and only one study found decreased levels.  That is a net score of +9.

The Blautia spp. had a net score of +4, with 4 studies showing an increase and none showing a decrease.

I was surprised by the number of bacteria families were different in only 1 or 2 out of 24 studies.   For me, this implies that either there is a lot of natural variation in gut microbiota, or that we are not good at measuring it, or that we are not measuring the right parts of it.  In any case, it suggests that we should not depend too much on these studies.  If something really was different, we would expect to see it in more than 1 or 2 studies.

I was even more surprised by the number of bacteria families that were found increased in some studies, but decreased in other studies.  There were over 10 of these.  That is even more worrisome, because it suggests the results might just be random variation.  And with a little bad luck, maybe the Bacteroides spp. and Blautia spp. might be random variation as well. (Normally, p values are used to estimate the chance of random variations being mistaken for real results.  However, because this is a summary of many different sized studies, I don't think p value analysis is a reasonable thing to do here.)

My Opinion

Overall, having gone through this exercise, I'm less likely to think the gut microbiota is important to type-1 diabetes.  The more I look at these studies, the more I think we don't have enough history and background studying the gut microbiota to understand the differences that we are seeing, and even be sure they are "real" differences.  However, if there are differences, then we should look for them in the Bacteroides and Blautia families first.  Those are the most likely places to see differences.

Joshua Levy
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.

Saturday, October 19, 2019

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:

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  
  • Chase Medical Research, LLC Hamden, Connecticut, USA, 06517 Contact: Melissa Capasso        
  • Baptist Health Research Institute Jacksonville, Florida, USA, 32258  Contact: Kristy Clemmer    904-271-6363               
  • 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        
  • Naomi Berrie Diabetes Center, Columbia University New York, New York, USA, 10032 Contact: Sarah Pollack    212-851-5425         
  • SUNY Upstate Medical University Syracuse, New York, USA, 13210 Contact: Jane Bulger    315-464-9008        
  • Mountain Diabetes and Endocrine Center Asheville, North Carolina, USA, 28803 Contact: Will Cooley    828-684-9588 ext 315      
  • University of North Carolina Diabetes Care Center Chapel Hill, North Carolina, USA, 27517 Contact: Julie Uehling    984-974-3010  
  • Diabetes and Glandular Disease Clinic San Antonio, Texas, USA, 78229 Contact: Terri Ryan    210-614-8612 ext 1630  
  • University of Virginia Charlottesville, Virginia, USA, 22903 Contact: Mary Voelmle    434-924-2327    

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:


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:

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:

Joshua Levy 
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, October 11, 2019

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:  (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: and for even more details
  • 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:
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 
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.

Saturday, September 28, 2019

Possible Cures for Type-1 in the News (September)

Unsuccessful Phase-I Clinical Trial of Beta-O2's Encapsulated Beta Cells 

Encapsulated beta cells are implanted devices.  The encapsulation coating allows blood sugar in, and insulin out, but does not allow the body's immune system to attack the beta cells. It also allows nutrients in and waste products out. This allows the beta cells to naturally grow and to react to the body's sugar by generating insulin which goes into the body's blood system. Meanwhile, the body's autoimmune attack cannot target these beta cells, and you don't need to take any immunosuppressive drugs (as you would for a normal beta cell transplantation).  I previously blogged about this trial here:

Unfortunately, they published unsuccessful results last year.  To quote their abstract:
Implantation of the βAir device was safe and successfully prevented immunization and rejection of the transplanted tissue. However, although beta cells survived in the device, only minute levels of circulating C-peptide were observed with no impact on metabolic control. 
Encapsulated beta cells have been an active area of research for over 20 years.  Currently ViaCyte and Sernova are both active in clinical trials in this area, and there are other contenders testing in animals.

Full Paper:
Clinical Trial Record:

The Phase-II? Clinical Trial of Ladarixin Is Fully Enrolled

Ladarixin targets two specific immune system chemicals: IL-8a and IL-8b. The idea behind this trial is that suppressing this part of the immune system will stop the autoimmune attack which causes type-1 diabetes.  I previously blogged about this study here:

This study finished recruiting in June-2018, and they now expect to complete in Oct-2019.
Clinical Trial Record:

Fully enrolled is an important milestone for two reasons.  First, because it is now possible to predict when they will finish collecting data.  Second, because much of the uncertainty that surrounds clinical trials, is involved with recruiting participants.  It is often unclear how hard it will be to recruit people, and how long it will take.  But that this point, all that uncertainty is behind the researchers.  From now on, it is just gather data, then analyze data, and then publish data.  Researchers have a lot more control over those later stages, then over recruiting people in the first place.

Coffee In Pilot Clinical Trial To Improve Renal Function

I will not be following this trial, because it is aimed at long term complications of T1D, not a cure.  But it sounded like so much fun, I'm mentioning it here.  Apparently caffeine changes renal (kidney) function in some unique ways which are not duplicated by other drugs.  The researchers think that a coffee in the morning might improve kidney function in a way that helps people with T1D.

They are testing this in teenagers (12-21 years old).  It is a 10 person, open label, no control group trial, which is enrolling by invitation only.  You need to already be participating in a different trial (called "CASPER") to get invited.  They drink Starbucks® cold brew every morning for 6 days.  Kidney function will be tested on the 7th day.  No word on the Peet's® version.

Clinical Trial Registry:

Joshua Levy 
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.

Thursday, September 19, 2019

Teplizumab Phase-II Results For Prevention And Starts A Phase-III On Honeymooners

As with previous years, the American Diabetes Association's annual scientific meeting is mostly about type-2 diabetes, and even the type-1 part is mostly about treating it, not curing it.  However, this year was better than most, in that there were a couple of interesting results which were cure related. For me, the Teplizumab result, which I discuss below, was the high point of the scientific sessions.

I'm not sure why, but I wrote this blog while listening to The Amorettes "Everything I Learned, I Learned from Rock and Roll:

This is a treatment with a long history, and this is a very long posting.  You will see some marks like [d1] showing that there is more discussion at the bottom.  This blog posting benefited from a lot of external review, so I want to thank all of the reviewers.  Of course, any remaining mistakes are my own.

Strong Results From a Phase-II Teplizumab Prevention Trial

Teplizumab is a humanized monoclonal antibody [d1] which targets CD3 cells in the immune system in order to lower (or stop) the body's autoimmune response. This treatment tries to prevent type-1, or lessen it's severity, by "turning down" [d2] the immune system's attack on the body's own pancreas cells. This basic approach has resulted in treatments (but not cures) for other autoimmune diseases.

The Clinical Trial

This clinical trial was aimed at a prevention.  It enrolled people who had a family history of type-1 diabetes, already had two (out of five) autoantibodies, and were showing abnormal blood glucose measurements after a meal.  These are people who have a high chance of showing the classic symptoms of type-1 diabetes within a few years.

The treatment was a 14 day regimen of Teplizumab, given intravenously at a clinic (this is not something you can do yourself at home), and the people were followed for a long time (2-9 years) to see how many were diagnosed with type-1 diabetes.

The results (in terms of preventing/delaying the diagnosis of type-1 diabetes) were very strong, in my opinion:
  • 19 (43%) of participants treated with Teplizumab were diagnosed with T1D, versus 23 (73%) of participants on placebo. 
  • On average, people who got the treatment were diagnosed with type-1 after 4 years.  People who got the placebo were diagnosed with type-1 after 2 years. 
The graph below is the key finding of the study.  The blue lines represent people in the study who got Teplizumab, the red line represents people who did not.  In this chart, the higher the line, the better; as the line drops more people are getting type-1 diabetes.  Notice that the red lines drops more quickly than the blue line, especially in the first few years.

The Next Trial: A Phase-III Honeymoon Trial

A little history: in 2018 a company called Provention Bio acquired Teplizumab from MacroGenics, which had previously owned the rights to develop the treatment.  As I discuss more in the timeline section, MacroGenics's phase-III trial was unsuccessful, but Provention Bio reanalyzed data from several clinical trials and felt it was worth developing.  In March 2019 they started [d3] a phase-III clinical trial.  This was all before publication of the data from the "Phase-II Teplizumab Prevention Trial" that I described above.

Provention Bio's trial is a phase-III trial in people with honeymoon type-1 diabetes.  This is a large (300 person) trial recruiting people aged 8-17 who have been diagnosed within the last 6 weeks.  They will get two treatments, six months apart.  Each treatment is 12 daily infusions of  Teplizumab.  People will be followed for 20 months although the primary end point is at 18 months.  They plan to have results in May 2022.

The primary end point is C-peptide production which measures the body's ability to generate insulin.  There are several secondary end points for safety, immunology, and indirect measures of insulin production.

It is recruiting now at 15 sites across the US.  Too many to list here, but if you live in the US, check out the list in the clinical trial record, give them a call, or send them email.  Contact info is 908-356-0514 or, and they have plans to start recruiting in 16 more places in the future. 

Provention Bio's web site:
The clinical trial record for this is here:


Provention Bio's Plan Moving Forward
Provention plans to commercialize Teplizumab as quickly as possible, in a two step process.

First, the data for the completed phase II prevention trial will be submitted for approval for use in pre-symptomatics (people who test positive for two or more autoantibodies, but who don't yet have the symptoms of T1D).  The company calls this "the at-risk population".  They plan to do the submission to the FDA by the end of 2020.

Second, if the phase III Honeymoon trial is successful, its data will also be submitted for an additional approval for honeymooners (which the company calls "the newly diagnosed population").


Both steps assume that the FDA will approve a treatment that raises insulin production, even if it does not remove the need for injected insulin.  It is generally understood that people with T1D who produce more of their own insulin have all kinds of good benefits.  Their BG is "in range" more often, they have fewer DKA episodes, and they have fewer of the serious long term complications of T1D which we all fear later in life.  But will the FDA approve a new treatment on that basis?  And if they will, how much improvement in insulin production would be required for approval?  No one knows, because it has never (to my knowledge) come up before.

C-peptide is an accepted biomarker for insulin production, so the FDA accepts it as a way to measure progress towards a cure.  But will they approve a treatment just because it improves C-peptide numbers without going as far as a cure, or without showing specific improvement in long term complications?  That is unknown.

Also, the second step assumes that the FDA will approve Teplizumab even though Provention Bio will only conduct one phase-III trial.  Usually, two such studies are done.  Provention is assuming that the data from previous studies means that the FDA will not require them to do another phase-III trial.

Provention has already started a dialog with the FDA to determine if the data they have is enough for eventual approval.  The next major step in that process is a meeting later this year, where they expect that the FDA will agree "in principal" that the amount of data they have is enough.   After that, Provention makes the formal submission, and the FDA reviews it, and makes the final decision based on the data actually submitted. 

If the first part of the plan works, then Teplizumab would be available in 2021 (that's my best guess).  It would be approved for people who have 2 autoantibodies (but doctors might proscribe it in other situations).

Normally, when a person says they hope their treatment will be on the market in 20xx, what they really are saying is if various clinical trials are successful, then they hope it will be on the market in 20xx.  However, in this case, the clinical trials are already done.  Here, the question is one of FDA approval.  In the last 15 years, I've never blogged on a cure focused treatment that had completed all the trials and was waiting for approval in the US.  It is a big difference between "scientific risk" (the risk that it just doesn't work), and "approval risk" (the risk that it will not get approved).

Now, this treatment does have a higher than average "approval risk".  Those are the risks I discussed above, but it is still a big milestone: to get to a point where a company thinks it already has enough data to get FDA approval for a treatment which preserves beta cells.  Now we all just need to wait and see if the FDA agrees.

Delay Or Prevention?
A big, obvious question is this: Is this treatment delaying the onset of type-1 diabetes, or preventing it?  That's a big difference, and there is no way to know which it is.  The people in the trial will continue to be followed, so we will have more data which might resolve the issue.  In the mean time, my opinion (and remember, I'm not a researcher) is that the graph shows delay rather than prevention [d4].

Is More Better?
If you look at the "survival curve" (ie. the number of people who do not have type-1 diabetes) in the study as time progresses you can see that the treatment is most effective in the first year.  After one year only about 5% of the treated group had been diagnosed with type-1, while about 45% of the untreated group had been.  The next two years were pretty good as well, but in the last 2 years, the effect seemed much smaller, both groups dropping at about the same rate.

So one obvious follow on study, is to repeat the treatment once a year and see what effect that has on the results.  If this creates the same effect seen in that first year, but repeatedly over many years, that would be a clear improvement.

The phase-III study is clearly trying to learn from earlier results.  Not only do they repeat the treatment once, but their primary end point is 18 months after the first treatment and 12 months after the second.  This is when the largest differences between treated and placebo groups were seen in earlier trials, so it is the best time to compare the two.

Combination Treatments
For many years, it has been generally understood that one possible path to a cure in people with established T1D is to combine a treatment which stopped/lowered the autoimmune attack with a second treatment which encouraged beta cell growth or regrowth.  But researching these "combo cures" is harder than you might expect, because there are two unknowns [d5].

However, this result, coupled with previous Teplizumab results, provides strong evidence that Teplizumab is lowering the autoimmune attack in pre-symtomatics enough to have a major impact on the progression of T1D.  When combined with Teplizumab's good safety results, this could open the doors to a bunch of "combo trials" in people with established T1D where Teplizumab is paired with various drugs believed to help grow or regrow beta cells.  There are several such drugs out there: Harmine, Verapamil, the whole class of DPP-4 inhibitors, and possibly a whole class of non-prescription drugs called PPIs (proton-pump inhibitors) [d6].

On the other hand, in pre-symptomatics, a different type of combo treatment may be effective.  Pre-symptomatics have enough beta-cells, so for them Teplizumab could be combined with a second  immune modulator so that the combination would be more effective than these results.  Treatments like Rituximab, Abatacept, and Alefacept have all shown some beta cell preservation during the honeymoon phase, but not enough to delay/prevent/cure by themselves.  However combining them with Teplizumab might result in a stronger effect.

If Provention Bio succeeds in getting Teplizumab approved by the FDA, all of these combo trials will become much easier to run.  Instead of two unapproved medicines being tested at once, it will be a standard treatment plus an experimental one, and that is a much more common situation.  It is less risky for all involved, and leads to faster approvals.

Discussion Of Prevention (vs. Cure)
I know many people touched by type-1 diabetes don't care about prevention.  And I understand that; after all, in a sense prevention is too late for them.  But I will continue to care about prevention, even though it will not help my daughter.  First, because I think we might learn something from a prevention that might lead to a cure in the future.  That is not always true, of course, but it certainly is possible.  Second, because someday my daughter may have kids of her own, and a prevention for my grandchildren would be worth a lot to me.  Third, just in general, I want the world to be a better place even if my family doesn't personally benefit.  And prevention will surely help many people in the future.  (Of course, there is a counter argument: that prevention will cause research money aimed at a cure to "dry up", because there will be less and less need of it in the future.)

Why were previous trials unsuccessful (or weakly successful [d7]) but this one strongly successful: Definitions Of Success and Honeymooners vs. Pre-symptomatics
This is a complicated subject, which I cannot do justice in a few paragraphs, but I will try.

The MacroGenics phase-III trial was unsuccessful in that it did not meet its primary end point.
However, this phase-II prevention trial was successful because it did meet its primary end point.
So a central question is: will the next trial (the Provention Bio phase-III trial) be successful?  And, central to answering that question is: why was one unsuccessful and the other successful?

One theory is that MacroGenics failed because they chose a bad primary end point.  Modern cure focused studies use C-peptide as their primary end point but the MacroGenics study was designed at least 13 year ago, and they used a different primary outcome.  If this is the cause of the previous failure, then the Provention Bio study is in good shape because they are using C-peptide.  The MacroGenics study did measure C-peptide (it was a secondary end point) and Provention Bio did look at that data, and they do think that it shows success, and bodes well for their study.

An alternate theory is that  MacroGenics was unsuccessful because they targeted honeymooners, while the phase-II prevention trial was successful because they targeted pre-symptomatics.  If this is the cause of the previous failure, then the Prevention Bio study has a problem, because they are also are targeting honeymooners.  The researchers involved believe that there is no fundamental difference between honeymooners and pre-symptomatics, except fewer beta cells.  (And I think it is fair to say that this is the mainstream, consensus view of researchers in general, not just the people working on this project.)  Fewer beta cells cause the symptoms seen in honeymooners, but the disease process is fundamentally the same in both.  So these researchers believe that because the basic mechanism is the same in both, the success of the phase-II prevention study supports the future success of Provention Bio's phase-III study.

History Of Research

Teplizumab has a long, complex history and I cannot give more than a short overview in the space that I have, but here goes.  (Note that the dates are based on trial registration and publication dates [d3].)
  • Teplizumab is developed in the early 1990s.
  • An early clinical trial ran from 1999-2005.  It showed that Teplizumab could preserve beta cells.  I would describe these results as good, but weak.  There is a longer discussion about why I think that here: [d7].
  • From 2005-2013 there was a follow up which had similar results. [d8]
  • In 2008 Tolerx (in partnership with GlaxoSmithKline) starts two phase-III clinical trials on Otelixizumab in honeymooners which was a similar anti-CD3 monoclonal autoantibody.
  • In 2009, MacroGenics (in partnership with Eli Lilly) starts two phase-III clinical trials on Teplizumab. 
  • In 2009 TrialNet registers the phase-II prevention trial which I'm reporting on here, but it doesn't start recruiting until 2011.
  • In 2010, Tolerx publishes long term results from their phase-II trial.  They are successful (but not strong).
  • Obviously, there was a lot of excitement at this point.  Phase-III studies are usually the last step before marketing approval, and there are now four such studies in progress.
  • In 2010, disaster strikes: The MacroGenics phase-III finishes and the result is failure of the primary end point.  The company cancels the other ongoing studies they are running.
  • Also in 2010, Eli Lilly drops Teplizumab.
  • In 2011, the other shoe drops: Tolerx's phase-III finishes and it also fails primary end point, and they stop their second phase-III trial.
  • Later in 2011 Tolerx goes out of business after spending $150 million trying to bring Otelixizumab to market.
  • In 2018, Provention buys rights for Teplizumab from MacroGenics.
  • In 2019, Provention starts a phase-III trial in honeymooners.
  • Later in 2019, TrialNet reports results from their phase-II prevention trial.
There are two take home points from all this:
  1. The research proponents of Teplizumab did not give up even in the face of unsuccessful trials. 
  2. Research takes a long time.

Teplizumab is a new treatment, which has not been FDA approved for use in any other disease, so we do not have any real-world safety data for it (good or bad).  On the other hand, it has been tested in 9 different clinical trials, and no serious safety issues have surfaced to date.  Teplizumab is an anti-CD3 monoclonal antibody.  I know of two other anti-CD3 monoclonal antibodies, Otelixizumab and NI-0401.  Both are experimental treatments which never progressed out of development (so no real world experience).  Otelixizumab has been tested in multiple clinical trials [d9]. 

It is important to remember that treatments with names that end in -mab are all monoclonal antibodies.  But "monoclonal antibody" refers more to the method used to create them than their effect in the body.  They all target different cells within the body.  So if you hear of a safety issue for one -mab drug that does not mean that a different one is likely to have a similar problem.  It is far more important which type of cell the -mab is targeting.  If a -mab targets cell type X and is found to have a bad side effect, that does suggest that other -mabs that also target cell type X might also have the same bad side effect, but it does not tell us anything about -mabs in general.

Extra Discussion

[d1] Monoclonal antibodies is a method of creating therapies by cloning a single cell that attacks the cell you don't want.  You end up with a vast number of identical cells, all of which attack the cell you don't want.  By carefully choosing the starting cell, you can "target" the monoclonal antibody to attack a very specific type of immune cell.  Because of how they are produced, early monoclonal antibodies were targeted at mouse cells, rather than human cells, and this sometimes caused problems.  Later techniques were developed to make the cells more human like, but still not completely human.  These were called "humanized" or "chimeric" monoclonal antibodies.  Finally, techniques were developed to create fully human monoclonal antibodies, and these are called "human" or "fully humanized".  Teplizumab is a fully humanized monoclonal antibody.

There are scores of monoclonal antibodies (of all three types) approved for use in the United States, for a wide variety of illnesses.  Different monoclonal antibodies have different safety profiles.  Most have names ending in "mab".

[d2] The medical term for this is "modulate".  Teplizumab is said to modulate the immune system.  But it is important to realize that this modulation is narrowly targeted at one type of immune cell.  It is not modulating the whole immune system, but just the broken part.  An important part of these clinical trials is to make sure the treatment is stopping the bad parts without hurting the good parts.

[d3] This is the date the clinical trial was registered with the FDA's Clinical Trial registry (   The the dates in the timeline are the same: first registered dates.  Note that researchers have usually been working on the trial for months, even years, before this date to set up the study, but also that patients typically start treatment weeks or months after this date.

[d4] My opinion is based on this: if you look at the first 18 months of data, the placebo group had about 45% diagnosed with T1D, but the treated group only had about 5%.  So that means about 40% of the people were helped by the treatment.  If those people had been prevented from getting T1D, then the treated curve (the blue one) would never drop below 40%, even years later.  However, it does go lower (although just bearly).  Therefore, my guess is delay rather than prevention.  I would love for future data to prove me wrong.

[d5] These studies are hard to start, because researchers must do work to justificaty each drug and also must consider the safety of the combination of the two drugs.  That is more than twice the work of testing a single drug.  Also, the results are harder to interpret if the study is not successful.  You don't know if it failed because the first drug did not do its job, or the second drug failed, or something about the combination did not work.

[d6] More details of Harmine are here:
and here:

[d7] "Weak" Results
This is another long discussion, which I'm trying to make short:

There are three definitions of "success" when it comes to clinical trials.  A clinical trial is said to be successful if there are good results from the primary outcome.  However, researchers often refer to a study as successful if they learned something new or if they could measure some change.  On the other hand, people effected by T1D often consider research successful only if it leads to something useful to them: a cure, prevention, delay of onset, an improved treatment, lower rates of complications, easier management, something tangible.  So there is a grey area if a clinical trial shows some change that researchers think might be important, but doesn't really impact people with the disease.

In this blog I try hard to use the term "success" if there is "good data from the primary end point" and "unsuccessful" if there is not.  However, if the primary end point is something more of interest to researchers than to patients, I might say it is a "weak success" to show my opinion that the result is important more to researchers than to patients.  Similarly, if the size of the change is small, so that a patient might not notice the difference, again I might refer to those results as "weak".  Researchers might refer to the second type of results as "not clinically significant" meaning "we can measure a difference, but it doesn't really matter to the person with the disease".

Looking at this study specifically, it found that insulin production stayed constant during the honeymoon phase, or dropped more slowly than in untreated people.  But the people all started out with T1D and they all ended up with T1D.  Is that a success or a week success?  They used less insulin and had slightly better A1c numbers. So is that a success or a weak success?  We now believe that this saved insulin production leads to fewer long term complications, although how many fewer is still unknown.  Is it a success or a weak success?  Different people will have different opinions, but mine, at least right now, is "weak success".

The earlier study is reported here:

[d8] The AbATE study:

[d9]  Teplizumab and NI-0401 have not had significant safety issues.  Otelixizumab is a little more complex.  One of the trials showed increased Epstein-Barr viral loads.  However, that study did not have a control group, so there was no way to compare people who got Otelixizumabto people who did not.  I eye-balled the data, and there was no obvious relationship between Otelixizumab dose and increased Epstein-Barr loads.  The data looked pretty random to me.  It appeared that the change in viral loads did not impact the people in the study long term, but most did have flu-like symptoms for a week or two.  In any case, that was a phase-II study, and when the larger phase-III study was run (which did have a control group), there was not a safety issue.

Joshua Levy
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.

Thursday, August 8, 2019

Personal Note

I've been very busy this summer, and so I only published one blog posting in May, one in June, and none in July or August.  I do plan to restart my normal publishing schedule in September, which means 2 or 3 postings per month.

Also, when I do post in September, I'll be removing the "In my day job, I work in software for Bigfoot Biomedical." since that is no longer true.  I wish them all the best success.

Joshua Levy 
publicjoshualevy at gmail dot com 
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF, JDCA, or Bigfoot Biomedical news, views, policies or opinions. In my day job, I work in software for Bigfoot Biomedical. 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, June 18, 2019

MER3101 Starts a Phase-I Clinical Trial

MER3101 is vaccine-like formulation of Insulin Beta Chain (IBC) and MAS-1, an adjuvant.   That makes more sense when you read it back to front, and go through it word by word:
  • An adjuvant is something that stimulates the immune system, so that the immune system reacts more strongly to a vaccine.  Think of it as a turbocharger for vaccines.
  • MAS-1 is a specific adjuvant which was developed by Nova Immunotherapeutics Ltd, and which they have already tested in another formulation (MER4101) targeting the flu.
  • Insulin B-Chain (IBC) is part of an insulin molecule.  Insulin is normally composed of an A-chain and a B-chain connected in two places.  
The idea behind this trial is to expose the immune system to part of the insulin molecule in order to train the immune system not to attack beta cells which generate that insulin.  This is vaguely similar to giving people with a peanut allergy peanut proteins in the hopes their body will learn to accept peanuts.  But remember that is a crude analogy, and type-1 diabetes is not a classic allergy!

We know that type-1 diabetes involves at least five different autoantibodies: islet cells (ICA), insulin (IAA), GADA, IA2 (also called ICA512), and ZnT8A.  Of these, the insulin autoantibody (IAA) often shows up first, so several researchers have tried to cure or prevent type-1 diabetes by teaching the immune system not to generate these autoantibodies.  This clinical trial is another in this line of research.

This study can be thought of as a follow on to this previous work:

This Study

The study design is more complex than usual.  It's clear they are trying to get as much out of this study as they can:
  • The study is divided into 4 groups.  Each group has 5 people getting the treatment, and 2 people serving as controls for that group.  
  • The first three groups will each test different doses of IBC, but the same dose of MAS-1.
  • The fourth group will test whichever IBC dose was most successful, but with a higher dose of MAS-1 that was previously used.
The primary results are safety and immune effect, which are important to running more studies in the future, and learning about the vaccine.  The secondary results are measuring success for both a cure and a treatment: C-peptide, A1c, and insulin use.

People in this study must be between 18 and 45 years old, and within 2 years of diagnosis.

The study started recruiting in August 2018, they hope to finish in April 2022, and was funded by the Helmsley Charitable Trust.

They are recruiting in one place:
    University of Colorado, Denver:  Aurora, Colorado, United States, 80045
    Contact: Mara Kinney    303-724-8272 
    Contact: Hali Broncucia    303-724-7526 
    Principal Investigator: Peter Gottlieb, MD 

Clinical Trial Registry:

The History

I usually don't discuss the corporate history of the treatments I cover, because all I really care about is the results of clinical trials, and it doesn't really matter what companies sold what technology to what other companies.  However, I'm describing the history here, because I think it shows the convoluted path that a lot of these smaller companies take in order to get their treatments to market.  And it helps explain why things take so long for less established companies.

Dr. Tihamer Orban has been working on curing / preventing type-1 diabetes using vaccines based on the Insulin B-Chain for at least 10 years.

The earliest human trials that I know of were done at the Joslin center and reported in 2010, on an IBC based formulation called IBC-VS01.  This is how I summarized the results back then:

In terms of safety, the results were fine: nothing bad happened, and this is a new treatment, so safety was an important question.  But in terms of effectiveness, the results are mixed.  The vaccine did result in a specific immune system change that looks promising. ... But no effectiveness was seen during the trial.  Their was no improvement in C-peptide generation of the treated group compared to the non-treated group.
You can read more in my previous post:

After this trial, Dr. Orban created his own company Orban Biotech to pursue this research which was issued patents in the 2012 to 2014 time frame, but is not operating now.

On the adjuvant side, a company called Mercia licenced an adjuvant technology from another company called Aphton and developed it into MAS-1.  They then started a group of research projects, collectively called MERIT, to combine MAS-1 with different vaccine parts (called "antigens") to create vaccine-like treatments for four different diseases (Type-1 Diabetes, Influenza, Alzheimer's, and Asthma).

The type-1 diabetes branch of this research was to work with Dr. Orban to combine his IBC-VS01 antigen with their MAS-1 adjuvant to create MER3101 which Mercia is now testing.  In order to show the history of MER3101, the Mercia web page shows some of Dr. Orban's previous IBC-VS01 results, renaming it MER3001.  In the world of fictional fandoms, this would be called retroactive continuity ("retconning" for short) to make it look like Mercia has been involved since before 2010.

Some Discussion
  • While I think 28 people in a phase-I trial is a solid number, in this case, they are divided into four groups.  Each group is 7 people, 5 people are actually getting the treatment and 2 are controls for that group.  Each group is pretty small, even for a phase-I trial.  My gut feeling is that if they see a small effect in only one group, that likely is a mistake.  However, if they see a reasonable effect in more than one group, that signals they are on the right track.
  • I don't think it is a good idea to recruit people within 2 years of diagnosis, because I view those people as two very different subgroups.  Some will be in their honeymoon phase, and therefore generating some of their own insulin from their own beta cells, while others will be passed that, and have almost no natural insulin generation.   I think mixing them in one study is dangerous, especially where each group only has 2 in the control group, and 5 in the treatment group.  I'm specifically worried that if both control members come from one subgroup, while the treatment group is split between both subgroups, that could cause differences that are not real.

Joshua Levy 
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF, JDCA, or Bigfoot Biomedical news, views, policies or opinions. In my day job, I work in software for Bigfoot Biomedical. 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.