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    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.

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 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.

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:
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.

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: 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.

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:
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.

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: http://thejdca.org/good-giving-landing-page/  (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:
    https://cureresearch4type1diabetes.blogspot.com/2018/09/every-year-in-september-or-october-i.html and for even more details
    https://cureresearch4type1diabetes.blogspot.com/2018/07/dr-faustman-publishes-follow-on-bcg.html
  • 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 
https://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 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:
https://cureresearch4type1diabetes.blogspot.com/2014/11/beta-o2-starts-phase-i-trial-and-update.html

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.

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/29288549
Full Paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055594/
Clinical Trial Record: https://www.clinicaltrials.gov/ct2/show/NCT02064309

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:
https://cureresearch4type1diabetes.blogspot.com/2016/08/ladarixin-starts-phase-ii-clinical-trial.html

This study finished recruiting in June-2018, and they now expect to complete in Oct-2019.
Clinical Trial Record: https://www.clinicaltrials.gov/ct2/show/NCT02814838

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: https://clinicaltrials.gov/ct2/show/NCT03878277


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.