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

This posting contains some bits and pieces of interesting news.

A Phase-II Abatacept Trial to Prevent T1D in At-Risk People Finishes Recruiting 

You can read my previous postings on Abatacept here:
https://cureresearch4type1diabetes.blogspot.com/search?q=Abatacept
Abatacept is a treatment that prevents T-cells from becoming activated.  Presumably, for type-1 diabetes, it works by blocking the "bad" killer T-cells from activating.  This drug is already approved for use in rheumatoid arthritis when other treatments have failed, and is marketed as Orencia.

This is a large (212 person) trial started in 2013, and recruited it's final person in February 2020.  Since they plan to collect data from each person for at least a year, this trial is likely to finish in February 2021.  The goal of this trial is to see if Abatacept can be given to people before they are diagnosed with T1D, and prevent or delay the onset of the disease.  The people enrolled in this study have tested positive for two or more autoantibodies, so they are almost certain to be diagnosed with type-1 diabetes sometime in the next 10 years.

History and Discussion

Abatacept has already been tested on people with T1D in their honeymoon period, and the results were that people treated with Abatacept continued to generate about 50% more of their own insulin, than those not treated.   The amount of insulin generated years after diagnosis is pretty small, so the actual difference is half of a tiny number.  One way to view these results was that Abatacept delayed the "end of honeymoon" by 9.5 months.  Someone who got the drug generated the same amount of insulin 36 months after diagnosis as someone who did not get the drug generated 27 months after diagnosis.

So this result is similar to the recently published Teplizumab results, although the Teplizumab results were a little stronger.

Clinical Trial Registry: https://www.clinicaltrials.gov/ct2/show/NCT01773707

Phase-I Clinical Trial of Substance P Is Over Two Years Overdue

Substance P is a peptide (a part of a protein) which is used by several different organs and for several different purposes.   Research done in the early 2000s found that a specific type of neuron (called "TRPV1(+) pancreatic sensory neurons") control islet inflammation and insulin resistance. Removing these neurons from NOD mice prevented diabetes from developing.  Injecting NOD mice with Substance P, which affects these neurons, has increased beta cells in mice, and also lowered inflammation.   This clinical trial tested this same treatment in people, rather than mice.

The trial started in 2016 and was expected to finish in 2017.  The clinical trial record has not been updated since 2016, and I cannot find any published data from this study or the company that sponsored it (Vanilloid Genetics Inc).  Twice I've sent email to the researchers running this study, and I have gotten an "on vacation" email back from one of them, so I know they are still at the University where this research was done, but I have not gotten any other reply.  I have not found any corporate email info for Vanilloid Genetics. 

So therefore, I'm going to remove this study from my list of active studies.  If I ever see positive results, then I'll put it back on.

Clinical Trial Registry:  https://www.clinicaltrials.gov/ct2/show/NCT02820558

PROCHYMAL® (Adult Stem Cells) for the Treatment of Recently Diagnosed T1D

Way back in 2012, I reported on an unsuccessful Phase-II- study of PROCHYMAL (adult stem cells) by a company called Osiris.  However, in March 2020, the clinical trial record for that trial (now completed for 8 years) was updated.  The changes made were all small, and I would describe them as "cosmetic".  I don't know what this means.  If it means anything at all.  But it is unusual for the clinical trial record for a trial completed so long ago to be changed.

Clinical Trial Record: https://www.clinicaltrials.gov/ct2/show/NCT00690066


Changing Terminology: At-Risk Instead of Presymptomatic

In the past, I have used the term "presymptomatic" to describe people who have two autoantibodies, but none of the classic signs of type-1 diabetes.  TrialNet has published data over the last few years that shows that just about all of these people will have symptoms of T1D within 10 years.  Therefore many researchers consider that people with two autoantibodies, but no other symptoms, really do have T1D, it is just that they don't have symptoms, yet.  So I used the term presymptomatic to describe the studies being done on these people.

But "presymptomatic" is a mouth full, and it is not a natural sounding word.  Also, people who don't inject insulin and don't count carbs don't think of themselves as having T1D at all.  So therefore, I'm going to start using the term "at-risk" to refer to these people, and the clinical trials that enroll them.  I think it is a more natural English phrase to describe people who are not showing symptoms yet.  

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.

Results From a Phase-I Clinical Trial of IMCY-0098

IMCY-0098 is an immune therapy designed to cure/prevent type-1 diabetes by teaching the immune system not to attack beta cells.  The treatment is being developed by the Imcyse company, but this clinical trial is run by academic researchers in Europe as part of a European Union research project which targets T1D.

This trial is the first test in people.  It enrolled 41 honeymooners into four groups, a control group and three different dose groups.  No safety issues were found, but the people who were treated did not see any improvement to their T1D.  There was no improvement in C-Peptide generation (meaning no improvement in beta cells) and the people used about the same levels of insulin.

The results of this study have been reported as a poster at a conference and the company has issued a press release, but there has not been a journal article.

Discussion

The results from this study reminded me that companies that sponsor research are almost always very positive about the outcomes of that research, even when (objectively) those outcomes are disappointing.  If you read the press releases for clinical studies put out by the sponsoring companies, they often work very hard to find even a tiny silver lining in a study that has failed.  This is why I look at the data from the study and decide if it is a failure or not, and do not pay much attention to the researcher's opinions.

It is important to remember that even in a total disaster, you can always be positive about some small detail, or weaken the definition of success to the point were mediocre news suddenly becomes a success.  Take a look at this:

No statistically significant differences could be observed in the different dose cohorts, but trends towards better outcomes in higher dose cohorts were [observed]. 

"Statistically significant differences" is the standard for determining if a clinical trial is successful or not, so this trial was not successful.  "Trends towards better outcomes" is a lower standard, which the company is talking about specifically because it has failed in the normal definition of success.

In the press release, the company (via its Chief Medical Officer) is very positive about future clinical trials.  If there are future clinical trials, then I'll certainly cover them.  However, I'll wait for better results before getting excited about this research.  So far, it has one unsuccessful clinical trial, and no successful ones. 


Results Poster: http://www.arianapharma.com/wp-content/uploads/2019/10/Poster-T1D-EASD-Final-PDF.pdf
Interim Results: https://www.easd.org/virtualmeeting/home.html#!resources/phase-ib-clinical-trial-of-imcy-0098-in-young-adults-with-recent-onsent-type-1-diabetes-e381b2d6-766b-4c4d-acc7-27337bb80b32
Clinical Trial Registry: https://www.clinicaltrials.gov/ct2/show/NCT03272269 
Clinical Trial Registry for extension: https://clinicaltrials.gov/ct2/show/NCT04190693
Press Release: https://www.biospace.com/article/imcyse-reports-successful-first-in-human-phase-1b-study-in-type-1-diabetes-with-imcy-0098/ 
Project summary: https://cordis.europa.eu/project/rcn/110445/reporting/en?rcn=3862

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.

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    carin.andren_aronsson@med.lu.se    

Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT04014660

Discussion

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    d5894@mail.cmuh.org.tw  
    Contact: Hung-chih Lin    886-4-22052121 ext 4640    d0373@mail.cmuh.org.tw  
    Principal Investigator: Chung-hsing Wang   

Clinical Trial Registry: https://www.clinicaltrials.gov/ct2/show/NCT03880760 

Discussion

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:
https://www.visbiome.com/pages/about-us

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    t1dinfo@mcw.edu    

Clinical Trial Registry: https://www.clinicaltrials.gov/ct2/show/NCT04141761
Earlier Study Clinical Trial Registry: https://www.clinicaltrials.gov/ct2/show/NCT03423589

Discussion

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     hallemj@peds.ufl.edu    
    Contact: Miriam Cintron     352-273-5580     cintrm@peds.ufl.edu

Clinical Trial Registry: https://www.clinicaltrials.gov/ct2/show/NCT03961854
Clinical Trial Registry: https://www.clinicaltrials.gov/ct2/show/NCT03961347

Discussion

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: https://www.clinicaltrials.gov/ct2/show/NCT03556631

Probiotics in Newly Recognized Type 1 Diabetes
Clinical Trial Registry: https://www.clinicaltrials.gov/ct2/show/NCT03032354

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.

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 T1DTrials@joslin.harvard.edu

Trial Registration: https://www.clinicaltrials.gov/ct2/show/NCT03895996
Trial Site Web Page: https://t1dtrials.org/
Paper describing the basis for this trial: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947239/
Commentary on that paper: https://www.jci.org/articles/view/44395

Discussion

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

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.

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.

TOL-3021 Starts A Phase-II Clinical Trial

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

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

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


TOL-3021 Has Started A Phase-II Clinical Trial

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

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

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

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

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

And Two More Are Preparing To Start

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

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

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

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

Discussion

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

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

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

Joshua Levy 

http://cureresearch4type1diabetes.blogspot.com 

publicjoshualevy at gmail dot com 

All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.