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:
https://cureresearch4type1diabetes.blogspot.com/2011/05/orbans-phase-i-results.html

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    mara.kinney@ucdenver.edu 
    Contact: Hali Broncucia    303-724-7526    hali.broncucia@ucdenver.edu 
    Principal Investigator: Peter Gottlieb, MD 

Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT03624062

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:
https://cureresearch4type1diabetes.blogspot.com/2011/05/orbans-phase-i-results.html

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
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, 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.