Monday, August 30, 2021

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

This blog is a collection of short updates, mostly from the ADA conference.

Diet (Macronutrients) Does not Impact T1D Risk

Macronutrients are carbohydrates, protein, fat, sugar, and fiber (things that you eat large amounts of).  This study also looked at glycemic index and glycemic load.  It did not look at micronutrients, such as vitamins and minerals (things that you eat small amounts of).  This study enrolled people who already tested positive for autoantibodies to see how long it took them to show symptoms of type-1 diabetes.  

This study covered 881 people divided into four groups by age: 1-4 years old, 5-12 y/o, 13-22 y/o, and 23 and over.  Here is the summary of their findings:

Given multiple comparisons, there was no significant association between rate of progression from IA to T1D and daily dietary intake of any macronutrients analyzed, after adjusting for [confounders]. ... Baseline dietary macronutrient intake does not appear to influence rate of T1D diagnosis in children, adolescents, or adults with IA.  

This study is strong evidence that feeding low carb, low sugar, low fat, or any other type of macronutrient based diet cannot prevent (or even delay) the onset of type-1 diabetes, at least among people who have autoantibodies.

Abstract: https://diabetes.diabetesjournals.org/content/70/Supplement_1/1116-P

Maternal C-Peptide Generation

It has been known that women with T1D often have increased levels of C-peptide when pregnant, and especially later in pregnancy. In the past this has been considered a hopeful sign that pregnancy caused beta cells to regrow (generating the C-peptide) and that perhaps research into this phenomena could lead to a way to regrow beta cells in others with T1D.

Unfortunately, a study at ADA2021 implies that beta cells are not regrowing.  Rather, the fetuses C-peptides are moving across the placenta so they are found in the mother.  To quote the abstract:

... This suggests transfer of C-peptide from fetal to maternal serum and is inconsistent with pregnancy-related β-cell regeneration.

Tweet: https://twitter.com/ClaireMeek5/status/1409028250450509824
Full Paper: https://care.diabetesjournals.org/content/early/2021/06/05/dc21-0028 

Leptin

Leptin is a hormone generated by fat cells which helps the body regulate hunger and energy use, and may regulate other body processes as well.  Back in 2011 there was hope that it might become a cure for T1D, but clinical trials were unsuccessful.  However, there is still hope that Leptin (in addition to standard insulin use) might end up helping to treat T1D by lowering insulin spikes after meals, resulting in better control.

A poster at ADA reported on a phase-I study (7 treated people, 3 in a control group).  Basically, they gave a small dose of Leptin to people with T1D who were fasting, and then cut their pump basal insulin by 50%.  The control group's blood sugar and glucagon levels went up (as expected), but the treated group's levels went down, even though they were getting less insulin.  The effect lasted less than 3 hours.  This is a good result, if you are positioning Leptin as a "take with meals" drug to lower blood sugar spikes caused by eating.  However, this is not a cure, and I don't expect to cover it in the future.

ADA 2021 had results for a 10 person study: https://www.hcplive.com/view/oral-leptin-formulation-offers-short-term-benefit-type-1-diabetes-patients
Abstract of poster: https://diabetes.diabetesjournals.org/content/70/Supplement_1/121-LB

Viacyte Update

Viacyte was in the news this summer because they released some data at ADA (American Diabetes Association) 2021 Scientific Sessions.  Unfortunately, the data they released was from one person who was part of their "PEC-Direct" study.  The PEC-Direct study still requires people to take immune suppressive drugs for the rest of their lives.  Therefore, I don't consider this to be a cure, because it swaps one drug regimen (insulin replacement) for another drug (immune suppression).  Immune suppression has serious long term side effects, possibly worse than T1D itself.  Furthermore, I don't put much stock in single person results, so their press release had two reasons for me not to get excited.

The data showed that one person's transplanted beta cells were working well 9 months after the transplant.  Her A1c was 6.6% (compared to 7.4% before the operation) and her time within range was 84% (up from 54%).  She was still injecting insulin, however.

Viacyte is also running another study called PEC-Encap.  This study will use encapsulated stem cells and so these people will not need to take immune suppressive drugs for the rest of their lives.  I do consider that a cure.  Last I heard (from the JDCA) they were hoping to have interim results from this study in the second half of 2021 (soon!)  Those are the results I care about.

JDCA update on Viacyte from early 2021: http://thejdca.org/viacyte-2021
Viacyte press release on PEC-Direct: https://viacyte.com/press-releases/viacyte-reports-compelling-preliminary-clinical-data-from-islet-cell-replacement-therapy-for-patients-with-type-1-diabetes/
Viacyte press release on PEC-Encap: https://viacyte.com/press-releases/viacyte-announces-initiation-of-phase-2-study-of-encapsulated-cell-ther-apy-for-type-1-diabetes-patients/
News coverage: https://endpts.com/after-years-of-failure-viacyte-shows-off-first-proof-of-concept-for-diabetes-stem-cell-transplants/

Viacyte is part of a long line of attempts to cure T1D by encapsulating beta cells.  This sounds easy: just wrap the implanted cells in a membrane that lets sugar and oxygen in, insulin and carbon dioxide out, and does not allow T-cells to enter).  Seems straightforward.   For all of the last 25+ years there have been companies working on this, and none has succeeded yet.  So it is clear to me that there is something more complex and difficult about this path than we currently know.  At the moment, I think there are 3 companies working on this approach that are in human trials, or close to it.

BCG News

Dr. Faustman's lab released their most recent BCG result as a poster at the ADA 2021 conference.  They reported on demethylation of signature Treg genes.  BCG (Bacillus Calmette–Guérin) is a biologic which has been given to over a billion people (in low dose) as a tuberculosis vaccine, and is also approved (in much higher doses) as a bladder cancer treatment. It is a generic drug with a very long record of safety. 

BCG was tested as a T1D cure or preventative several times in the early 2000s (including once by this same lab), and all those clinical trials were unsuccessful.  However, Dr. Faustman's continues to run clinical trials with BCG.

In my view, these results are another step in the collapse of BCG as a possible cure. When this research started 20 years ago, it was based on curing mice. Then, the first results in people (in a tiny phase-I trial) showed very small progress to a cure in people. Later, a follow on trial showed no progress to a cure in people, but maybe small progress to treatment. Now we have these results which don't show any progress to treatment, but instead are looking at demethylation, a type of gene expression change.  The particular change they report certainly does not cure T1D, and may have nothing to do with T1D at all. By itself, it does not show progress to either a cure or treatment.

Press coverage: https://www.fiercebiotech.com/research/ada-tb-vaccine-repurposed-type-1-diabetes-restores-gene-expression-key-immune-cells?fbclid=IwAR0Jhuk8gC-IjQG6qyoX7u8UYDuP00hRtjrF5TT33RVIqnG91FnR84jazmM

Poster: https://diabetes.diabetesjournals.org/content/70/Supplement_1/1142-P

 

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.
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Saturday, July 17, 2021

TrialNet In General

I have blogged dozens of times on clinical trials run by TrialNet, but I've never discussed TrialNet as an organization, so this blog contains some information on TrialNet, starting with their web site:
 
A Little History
 
The pre-history of TrialNet traces back to a large study called Diabetes Prevention Trial of Type 1 (DPT-1) which started 1994, which was testing oral insulin as a prevention of T1D.  TrialNet was formally founded in 2001, and (for me) is best known for their huge study now called "Pathway to Prevention" (previously called "Natural History Study").  This study is central to the mission of preventing T1D, by both (a) studying what is the normal progression of T1D and (b) creating a large pool of people in the process of developing T1D, which makes prevention focused clinical trials much easier to run. 

Kevan C. Herold of Yale University became chair of TrialNet on June 1st, 2021.  Prior to that, from 2015 to 2021, Carla J. Greenbaum of the Benaroya Research Institute was the chair, and before that, Jay Skyler.  Carla Greenbaum continues to direct the TrialNet Clinical Hub.
 
In writing this, I searched for a concise history of TrialNet, but was not able to find anything.  So if you have an interest in the history of science, this might make a great paper, or even a thesis.  Also, I was not able to find any public organizational or governance materials, so can't include any information on how TrialNet decisions are made.

Goals and Methods

TrialNet's goal is to prevent, delay and slow the progression of the T1D.  I would describe their basic method as a research funnel:
  1. They start out screening relatives of people with T1D, looking for those who have autoimmune antibodies.
  2. They then follow those people to see if the number of autoimmune antibodies increases, if they start having higher than normal blood glucose after eating carbohydrates, and if they are diagnosed with T1D.
  3. For those who develop T1D, they follow them to see how the disease evolves over time.

Throughout this whole process, they are recruiting people for more specific studies to test preventions or cures appropriate to their stage in the disease. 

Without TrialNet, if a researcher wanted to recruit 50 people at-risk for type-1 diabetes from the general population, they would need to test thousands of people to find the 50 they were looking for.  That process alone would likely take years and cost hundreds of thousands, if not millions, of dollars.  Even if they could focus on the relatives of people with T1D, they would still need to test 100s of people, and it would still cost a lot and take a long time.  But TrialNet has already found many people who can participate in those studies.

Research Achievements

I consider the following items to be TrialNet's three biggest achievements in chronological order: 
 
First: showing the normal progression of T1D.  In particular documenting the length of the honeymoon period, and what should be expected during that time.  To understand why this is important, consider the saga of BCG.  In the 1990s there was a small clinical trial which gave BCG to six people with newly diagnosed type-1 diabetes (no control group).  One of them went a few weeks without injecting insulin.  At the time (before the TrialNet results), this triggered a lot of optimism, including at least three follow-on studies.  The follow-on studies all had control groups and all failed, because (in fact) that result is pretty normal for the honeymoon period without any treatment at all.  With the TrialNet information, researchers do not waste their time following up these "normal, but we didn't know it was normal" results.  Also, there is now much more and much better information on what should be expected during the honeymoon period, which is a very stressful time for everyone involved.
 
Second, showing that a person who tests positive for two autoantibodies would later develop T1D in nearly all cases.   This process might take up to 10 years, but it would eventually happen.  Without TrialNet we would not know how number of autoantibodies related to chance of being diagnosed with T1D, or how long it would take on average.  The whole idea of using number of autoantibodies to predict chances of being diagnosed with T1D is based on TrialNet data.

I know that many people are unhappy with this knowledge, especially when their kids test positive for those first two autoantibodies.  However, this knowledge has opened up a wide range of research to try and prevent this diagnoses which would never have been possible without it.

Third,  Teplizumab, which I've blogged on before:
TrialNet did the earliest research into Teplizumab, and they continued researching Teplizumab even when clinical trials run by commercial companies were unsuccessful.  This dogged determination led directly to Teplizumab's current status. In November 2020, Teplizumab was submitted for marketing approval by the FDA for preventing or delaying the onset of T1D when given to people at-risk of the disease.  (Obviously, I'll blog if it is approved.)  If approved it will be a huge breakthrough: the first treatment to delay the onset of T1D.  More than that, the first treatment to change the immune reaction which causes T1D.  First treatments are rarely perfect, but even if not perfect, they often point the way to better treatments, and TrialNet was key to Teplizumab's research success.

Current Research

List of TrialNet's honeymoon research:
    http://www.trialnet.org/our-research/newly-diagnosed-t1d
List of TrialNet's at-risk research:  

In addition to TOPPLE T1D, which is for adults within 4 years of clinical diagnosis, TrialNet is
also running trials on Abatacept and Hydroxychloroquine (HCQ) for at-risk individuals.  In the past, TrialNet and has run multiple trials in honeymooners, most recently on ATG/GCSF, and also run two and oral insulin trials in people at risk of T1D.

By far the largest research project is TrialNet’s Pathway to Prevention which is focused on Risk Screening and Monitoring.  These are cooperative large scale monitoring trials, involving tens of thousands of people.  Relatives of people with T1D are tested for autoantibodies, and then monitored or enrolled in prevention trials if autoantibodies are found.  If they develop T1D, its progression is followed through the LIFT study. TrialNet's prevention studies are open to anyone who has  autoantibodies, no matter if they have relatives with T1D or not.

In the past, I know that some people did not want to participate in risk screening style research, because they "didn't want to know if there was nothing they could do".  However, that thinking is now out of date.  Because of several clinical studies underway to prevent or delay T1D, there now is something you can do, if you know ahead of time.  Furthermore, if Teplizumab is approved, then there will be a treatment available to delay the onset of T1D.

Also, these risk screening projects have been critical to learning how T1D naturally progresses, and also to finding people to participate in the more specific prevention and delay studies mentioned above.  So participants are helping to move forward important parts of T1D research, no matter how much they personally benefit during the study.

A final word about terminology: TrialNet uses a four stage timeline of T1D progression described here:
The basic summary is that stages 1 and 2 are people who have two or more autoantibodies [definition], but no symptoms that a patient would notice.  Stage 3 is honeymoon, and stage 4 is established type-1 diabetes.  However, this is not the terminology used (or understood) by most people effected by T1D, which is why I use more informal terminology: "at-risk" meaning people with 2 or more antibodies, but no symptoms (stage 1 and 2 in TrialNet terminology), and then "honeymoon" for stage 3 and "established" for stage 4.

More Reading


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.
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Sunday, April 4, 2021

Novo Nordisk and TrialNet Start TOPPLE T1D: Phase-I Trial of Four Protein Plasmid

This clinical trial is testing NNC0361-0041 which is a four protein plasmid. The drug was developed by Novo Nordisk, and the trial is being run by TrialNet. A plasmid is a bit of DNA which is not attached to the cell's main DNA.  You can think of it as a delivery service to get other molecules into a cell.  The other molecules, in this case, are four proteins: pre-proinsulin, TGF-β1, IL-10 and IL-2.  Pre-proinsulin is a chemical that is made by cells as part of the process to create insulin.  Pre-proinsulin is converted to proinsulin, which is converted to insulin.  The other three are proteins used by the immune system to communicate.  All of them have been subjects of clinical trials in the hopes they would cure/treat T1D.  So there is some appeal in the idea of using them all at once, and the plasmid is a convenient way to get all of them into cells together. 

I'm working on a blog posting which describes TrialNet, and which should come out in a month or so.

This Study

This study has a lot crammed into it.  It is the first test in people, so a phase-I trial.  However, it will enroll a total of 48 people, so closer in size to most phase-II trials.  The people will be grouped into four cohorts.  Each cohort will get a larger dose than the previous cohort, and each will have its own control group (9 treated and 3 controls per cohort).  Each cohort will be followed for a year.  The study started in Nov 2020 and they plan to finish in July 2022.

This study is open to adults (18 to 45 years old) within 4 years of T1D diagnosis; it is not limited to people in the honeymoon phase.

The primary outcome of this study is adverse events, so it is focused on safety.  However, the secondary outcome measures C-peptide, which measures how much insulin is being generated and measures progress to a cure.  The treatment will be weekly subcutaneous injections for 12 weeks.  (Subcutaneous injections are the same type as used for insulin.)

Recruiting
 
This study is recruiting all over the United States.  The entire list of recruiting sites is listed at the end of the blog.  For recruitment and enrollment related questions contact: info@trialnet.org
 
If you are a relative of someone with T1D, and want to learn about TrialNet's "Pathways to Prevention" trial, there is information here: https://trialnet.org/participate

Discussion

What really jumped out at me, was how much information they are going to get from one fairly quick study.  Normally, a phase-I trial is small.  It tests on a small number of people with a small dose.  But this study combines many of the goals of a phase-I and phase-II trial into one (especially in terms of testing multiple doses and on a total of almost 50 people).  I also like the speed of this study: less than 2 years from start of recruitment to expected results.  I just hope they are successful in recruiting enough people quickly enough to make that timeline.

While TrialNet has in the past partnered with industry to assure access to drugs, to the best of my knowledge, this is the first time TrialNet and a commercial drug company have worked together on a clinical study like this.  I think that this is an important step forward for T1D research in general. TrialNet is in a unique position to recruit people who are at-risk of T1D, but have not yet shown symptoms.  Commercial companies are well suited to develop treatments which might prevent or delay the onset of T1D.  So having these two working together plays to each of their strengths.   


Wikipedia pages:  

Trial Web Page:  https://www.trialnet.org/our-research/newly-diagnosed-t1d/TOPPLE
Clinical Trial Record:  Clinical Trial Record for NCT04279613

A personal note on the small size of the world:  In the 1970s, when I was a kid, I was called "little Josh".  That was because my family was friends with another family whose father was Joshua Lederburg, who we called "big Josh".  At the time, as a 10 year old, I knew that Big Josh was a smart guy who worked at Stanford University.  As it turns out, Joshua Lederburg was the scientist who named the plasmid in a paper he wrote in 1952. Six years later, he would be awarded the Nobel prize for related research.  In a sense, the clinical trial I'm reporting here is the 70 year follow on to the breakthrough he made back then.
 
List of Recruiting Sites

Stanford University
Stanford, California, United States, 94305
Contact: Trudy Esrey    650-498-4450    tesrey@stanford.edu        

Barbara Davis Center at University of Colorado Anschutz Medical Campus 
Aurora, Colorado, United States, 80045
Contact: Morgan Sooy    303-724-5686    MORGAN.QUIST@CUANSCHUTZ.EDU         

Yale University School of Medicine 
New Haven, Connecticut, United States, 06519
Contact: Laurie Feldman    203-737-2760    laurie.feldman@yale.edu        

University of Florida 
Gainesville, Florida, United States, 32610
Contact: Jennifer Hosford    352-294-5759    jennifer.hosford@peds.ufl.edu        

Indiana University - Riley Hospital for Children
Indianapolis, Indiana, United States, 46202
Contact: Maria Spall    317-278-8879    malnicho@iu.edu         

Joslin Diabetes Center
Boston, Massachusetts, United States, 02215
Contact: Nora Bryant    617-309-4141    nora.bryant@joslin.harvard.edu        

University of Minnesota
Minneapolis, Minnesota, United States, 55466
Contact: Janice Leschyshyn    612-626-8467    lesch004@umn.edu       

The Children's Mercy Hospital 
Kansas City, Missouri, United States, 64108
Contact: Jennifer James    913-696-5059    jljames@cmh.edu        

The Naomi Berrie Diabetes Center at Columbia University Medical Center
New York, New York, United States, 10032
Contact: Sarah Pollak    212-851-5425    sjp2174@columbia.edu     

University of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15224
Contact: Kelli DeLallo    412-692-5210    kelli.delallo@chp.edu  
    
Benaroya Research Institute
Seattle, Washington, United States, 98101
Contact: Corinna Tordillos    206-341-8937    ctordillos@benaroyaresearch.org
 
UCSF
San Francisco, California
Contact: Karen Ko  415-514-3730  karen.ko@ucsf.edu

University of Texas Southwestern
Dallas, Texas
Contact: Lindsay Harter 214-648-4725 Lindsay.Harter@UTSouthwestern.edu

Emory University
Atlanta, Georgia
Contact: Xiaomiao Lan-Pidhainy  404-712-0051 xlanpid@emory.edu

Vanderbilt University
Nashville, Tennessee
Contact: Brenna Hammel (615) 337-9597 brenna.hammel@vumc.org

Children’s Hospital of Orange County
Orange, California
Contact: Heather Speer (714) 509-8613 hspeer@choc.org
 



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.
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Saturday, March 27, 2021

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

This posting is a collection of shorter news items. 

Fenofibrate Extends Cure Of T1D In Single Case Study

I originally reported on Fenofibrate in June 2019:
https://cureresearch4type1diabetes.blogspot.com/2020/06/strong-results-from-single-case-use-of.html
This was a single person case study (so not a clinical study), but the results were very strong.  The person was treated during her honeymoon phase, and has not needed to inject insulin since.

The update is that she has now gone about 31 months without needing injected insulin.  This is up from 21 months at the time of my previous report.  She continues to take one pill a day.  I know of nothing unique about this person or her type 1 diabetes, so there is every hope that this success can be tested and the used on others in the future.

Oral Insulin is Unsuccessful For At-Risk Patients (Pre-POINT-Early Study)

Rational: One of the autoantibodies that is associated with type-1 diabetes targets insulin.  Therefore, there is a theory that giving insulin to people with T1D might prevent or delay the onset of type-1 diabetes by training the body not to produce this autoantibody.  The process is vaguely similar to giving small amounts of peanut proteins to people with peanut allergies.  But I want to stress that T1D is not a classic allergy.  The mechanism for T1D is very different than the mechanism of classic allergies. 

Results: There were no statically significant results in the primary outcome.   "Immune responses to insulin were observed in children who received both insulin and placebo, and the trial did not demonstrate an effect on its primary outcome." (Quote from the abstract, but I've removed the numbers to make the English flow better.)  So from an effectiveness point of view, the study was unsuccessful.

Trial Registry: https://clinicaltrials.gov/ct2/show/NCT02547519

Discussion: Oral Insulin has been tested as a possible cure or prevention for T1D for longer than this blog has existed.  In that time, several different clinical trials have been run.  All have been unsuccessful, like this one.   A few have been unsuccessful, but the researchers did extra analysis after the study was over, and found that maybe if they had tested oral insulin in a different subgroup of patients, then it might have worked.  That, in turn, has kept hope of oral insulin alive, and the cycle repeats.

There are three clinical trials of oral insulin which are currently running.  One is a 26 person study by a private company (Oramed).  Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT04150107

The other two are being done at Technische Universität München, and are called Fr1da and GPPAD-POInT.  Both are phase-II studies, of 220 and 1040 people, respectively.  The study reported above is a "proof of concept" version of the GPPAD-POInT. 

 
I'm often asked "If the proof concept Pre-POInT-Early study was unsuccessful, why then continue with the much larger, much more expensive GPPAD-POInT study?"  A detailed answer to that question would not fit here, but two things to remember are:
  1. There is no requirement of a successful small study in order to run a larger study.  Running a clinical trial requires a safety document (called an IND), money, and interest.  You do not need good results from previous studies, if you already have money.  There is never any regulatory review that previous studies were "successful enough" to start another study.  If the researcher is committed, and has the money, and the safety document, bad results from previous studies don't matter.
  2. Researchers are naturally optimistic, and we want them to be.  Most research fails, but we cannot let that stop research in general, or there would be no new breakthroughs.  So we need optimistic (even overly optimistic) researchers to push forward even in the presence of some bad news.  Of course, we don't want to waste money on research which has a history of failures, either, and so it is a tough judgement call.

More Bad News from a BCG Meta Analysis

Years ago, there was a lot of hope that BCG might cure type-1 diabetes, and this lead to several clinical trials.  All of those were unsuccessful.  The only BCG trial still ongoing is aimed  aimed at lowering A1c numbers (so treatment rather than a cure).  Recently a group of researchers, who were not previously involved in BCG research, published a meta analysis which combined data from four different clinical trials of BCG.  Each trial involved giving BCG to people with established T1D and measuring A1c and C-peptides.  The results did not show statistically significant improvement for people treated with BCG:
So even as a treatment, it appears that BCG is unsuccessful.


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.

 

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Sunday, February 21, 2021

Ruxolitinib Case Study

Note: this blog reports on a Ruxolitinib case study, it is different than my report last year on a case study of Fenofibrate.  These are different case studies on different drugs; don't mix them up.
 
This blog is different from most of my blogs because I'm reporting on a case study rather than a clinical trial.  A case study is the experience of one person who got a treatment, as reported in a medical journal.  Even the smallest (phase-I) trials usually have 10 or more people enrolled.  But this journal article reports on a single person's experiences with a new treatment.

I'll discuss exactly what happened in more detail below, but the summary is that: In a teenager who has many different health issues including type-1 diabetes, genetic testing found an unusual STAT1 gene which led to a diagnosis of STAT1 Gain-Of-Function Disease (SGOF).  Ruxolitinib is a known treatment for SGOF.  Using it improved the symptoms of many of the issues he faced.  His need for injected insulin gradually decreased until he stopped using it and has been insulin free for over a year as of Oct-2020.

More Details

The person involved had chronic immune triggered yeast infections, chronic diarrhea, oral and rectal ulcers, recurrent infections (otitis, tonsillitis, sinusitis, and bronchitis), and an immune problem causing underproduction of immunoglobulins (called hypogammaglobulinemia). Two years later he was diagnosed with T1D.  Nine months later genetic testing found the unusual STAT1 gene, and he started Ruxolitinib.  This led to some of his previous symptoms resolving, while others improved, including his T1D.  He used less injected insulin and his A1c improved.  After 12 months of Ruxolitinib (21 months after diagnosis of T1D) he stopped using injected insulin completely.

Ruxolitinib is a JAK1/JAK2 inhibitor.  It has been approved for use in the US since 2011, but its use for SGOF is "off label" because its approvals are for cancer and graft vs host disease.  

The STAT1 gene mutation was "c.1154C→T, pT385 M".

The letter was written by these researchers in Houston and San Francisco:
Baylor College of Medicine, Houston, TX: Lisa R. Forbes (lisa.forbes@bcm.edu), Natalia S. Chaimowitz, Sophia J. Ebenezer, I. Celine Hanson
University of California, San Francisco, Medical Center, San Francisco, CA: Mark Anderson

Discussion

The obvious question is: Did Ruxolitinib cure his T1D specifically or did it cure SGOF in general and cured the T1D as a side effect of curing the SGOF?  Or, put more simply: will it work on people who have T1D but not SGOF?

My gut feeling is that this patient has a very different version of T1D than the vast majority of people with T1D.  Something much closer to "MODY", an unusual form of diabetes described here:
https://www.diabetesgenes.org/

However, I'm still interested in testing Ruxolitinib in a clinical trial.  Actually two: one for people who have T1D but not the STAT1 gene mutation, and another for people who have T1D and an unusual STAT1 gene.  A relatively small (10 person/one year) trial would immediately tell us if more research is worthwhile or not.  (And some researchers in Australia have already filed the paperwork to start one of these trials.  See below.)

I do think that people who have T1D and other symptoms related to STAT1 gain-of-function disease should either discuss this treatment with their doctor(s) or get in touch with these researchers.

This patient has already gone over a year without using insulin, so I'm totally comfortable saying that his T1D is in remission.  If others want to call him cured (or maybe temporarily cured), that is reasonable to me as well.  I do hope we get updates to see if this continues.

Sources and Extra Reading

The Letter: https://www.nejm.org/doi/full/10.1056/NEJMc2022226
News: https://medicalxpress.com/news/2020-10-treatment-reverses-young-diabetes.html
Here is some research from mice:  https://pubmed.ncbi.nlm.nih.gov/28292965/
Wikipedia on Ruxolitinib: https://en.wikipedia.org/wiki/Ruxolitinib

Related Research
 
There is an Australian, 83 person, phase-II clinical trial which was registered in February 2020, but has not yet started recruiting.  This study will use Baricitinib which is a different JAK1/JAK2 inhibitor.  This trial will recruit people in the honeymoon phase of T1D.  No STAT1 gene testing will be done, so this it the "T1D with normal STAT1" clinical trial described above.  As is my policy, I'll blog more fully on this once it starts recruiting.

 
A case study of Baricitinib on a person with T1D (and other autoimmune diseases) is described here:

The results included "Regarding the influence on slowly progressive type 1 diabetes, the required daily dose of insulin decreased rapidly after the start of treatment (17⟶11 units), and the HbA1c level also decreased (7.4%⟶6.4%)".  No data on C-peptide changes were reported.  

 

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.

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Sunday, January 17, 2021

PIpepTolDC Starts A Phase-I Clinical Trial

The idea behind this research is to remove dendritic cells from a person with T1D, grow them out with vitamin D3 and a fragment of proinsulin (C19-A3), and then put them back into the same person they came from.  The goal of this therapy is to teach the immune system to stop attacking the beta cells.

Proinsulin is a molecule that the body makes as part of the process of making insulin.  The body makes proinsulin first, and then (near the end of the process), coverts the proinsulin to insulin.  Proinsulin is  a target of the immune system's mistaken attack on beta cells, so teaching the immune system that proinsulin is a normal part of the body might cure (or help to cure) T1D.

Dendritic cells are part of the immune system which find foreign cells and "present" them to T-cells (another part of the immune system) so that the T-cells know what to attack.  You can read more about them here: http://en.wikipedia.org/wiki/Dendritic_cells.

Although this research is unique, it combines two parts which have each been used before.  Modifying dendritic cells has been done in the past by Trucco (late 2000s)  and DiaVacs (early 2010s).  Both groups were removing dendritic cells, treating/growing them, and then putting them back, just as done here.  The difference between all these lines of research was how the cells were treated while they were being grown outside the body.

Similarly, proinsulin (C19-A3) has been a focus of research by a group at Cardiff for over 10 years.  However,  they are testing a direct injection of proinsulin, not using it to train dendritic cells outside the body, as done here.

The Study

This is a phase-I study, enrolling 7 people, all of whom will get treated.  There is no control group.  The seven patients will be adults who were diagnosed between 1 and 4 years previously, so these are not honeymooners, they have established type-1 diabetes.  Each patient will receive two doses of the expanded dentritic cells, a month apart, and then be followed for two years.

The study has a total of five primary end points.  Some of these are safety related, and others measure the effects of the treatment (ie. how it effects the immune system).  There are also nine secondary end points, which measure effectiveness and more effects in the immune system.

This study is recruiting now and they hope to finish by October 10, 2022.  They are recruiting here:

City of Hope Medical Center, Duarte, California, United States, 91010
Contact: Ryotaro Nakamura    866-444-7538    DL-TolDC@coh.org   

This study is being funded by The Wanek Family Project.

Discussion

The researchers describe this as a "vaccine" or a "reverse vaccine", but most people would not consider it a vaccine at all.  Calling it a "reverse vaccine" is closer to how most people would think of this treatment.  A classic vaccine preps the body to fight off a disease.  It teaches the body about the disease ahead of time, so the body can stage a strong battle at the first sign of infection.  This treatment does the opposite.  It teaches the body not to attack something.  In some ways, it is similar to shots people sometimes get to lessen allergies.  (Although I want to emphasize that T1D is not a classic allergy.)  But in any case, I think it is a mistake to think of this as being like a classic vaccine.

Although this is a phase-I trial, it is not the first time this treatment has been tested.  It was previously tested in Europe.  This study gave three different doses to three people each (no control group).  Safety and feasibility data was good, but no effectiveness results were seen.  You can read the journal article here:
https://www.thelancet.com/journals/landia/article/PIIS2213-8587(20)30104-2/fulltext

News: https://www.businesswire.com/news/home/20201210005914/en/City-of-Hope-Now-Enrolling-Patients-for-Phase-1-Type-1-Diabetes-Investigational-Vaccine-Trial

Clinical Trial Registry: https://www.clinicaltrials.gov/ct2/show/NCT04590872

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.
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Saturday, January 9, 2021

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

Beta Cells Which Hide From The Immune System

This has not progressed to clinical trials, but it is a new approach.  There is a lot of ongoing research into creating beta cells which will generate insulin in response to blood glucose, and many people talk about these as though they were a cure.  But they aren't, at least not by themselves, and for two reasons.  First, as a foreign cell they are properly attacked by the immune system.  Second, type-1 diabetes is caused by the immune system improperly attacking beta cells.  So there are two reasons why the T1D immune system is going to attack and destroy these cells.

However, the Salk Institute has found a recipe which takes stem cells and creates functional beta cells which are invisible to the immune system.  They call them "Immune-evasive".  In theory, this could protect the cells from both kinds of immune system attack, and these cells could, by themselves, cure type-1 diabetes.

Obviously, I'm going to be very interested in the research when/if it moves to human trials.  The press release from Salk makes it clear that these cells are not even ready for human trials, yet.  They need to undergo another round of animal testing, and then they can start the 10-15 years of human trials required for approval.
 
This is exactly the kind of research where human trials are important.  They are trying to create human cells which are hidden from the human immune system, but they must work in mice to start with.  So they are working with a specific kind of mouse called a NOD/SCID mouse.  The NOD refers to mice which have autoimmune diabetes.  NOD mice are the standard mice used to research cures to T1D.  The additional "SCID" refers to mice in which it is possible to experiment with human cells, because their immune systems have been modified to allow it.  So NOD/SCID mice are quite different than NOD mice.  That is a two edged sword.  The researchers must do it, because they can't start out experimenting on people, and yet they need to create human cells.  But SCID is a big change to the mouse immune system, changing three basic types of immune cells.  So this research is not going from mice to humans, it is going from highly modified mice to humans.  For me, this is an even larger jump, so the first human results are even more important. 

 

No Results from A Phase-I Trial of Ustekinumab

In 2014 a Phase-I clinical trial started to test Ustekinumab on people with honeymoon type-1 diabetes.  They completed enrollment  on May 24, 2016, which means they should have finished gathering data by May 24, 2017 and published results by May 2018.  Successful results are usually published in less than a year after completion.  But now it is well past May 2020, and I can not find any results from the study.
  
From my point of view, this means the study was unsuccessful.

You can read my previous blogging on this treatment here:
I think there have been a total of  three studies done on Ustekinumab, but only one is still active.  That one is in the UK and expected to finish in Oct-2022.  You can read more about it here:

 

Reminder: Once Weekly Basal Insulin Under Development

This is not a cure, but I'm sure some people will find it interesting.  Novo Nordisk has finished phase-II trials on an insulin that you use once a week to cover your basal needs.  You still need to take insulin for meals, but it replaces daily (or twice a day) basal insulin injections with just one injection a week.  It is called Insulin Icodec, and still needs to go through phase-III clinical trials before it is approved for use.

Fun Web Article on the History of Clinical Trials

 
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.
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