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:
https://diabetes.diabetesjournals.org/content/early/2014/03/25/db13-1236.abstract?papetoc
https://diabetes.diabetesjournals.org/content/66/2/448

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: https://investors.dna.com/2018-10-29-ActoBio-Therapeutics-TM-Doses-First-Patient-in-Phase-Ib-IIa-Clinical-Study-of-AG019-for-the-Treatment-of-Type-1-Diabetes
US Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT03751007
EU Clinical Trial Registry: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-002871-24/BE

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.

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: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791003

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

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.