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.

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.

 

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.

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.

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.

Sunday, December 27, 2020

Results from a Faecal Microbiota Transplantation Phase-I Clinical Trial

Faecal Microbiota Transplantation (FMT) is a surgical procedure where stool is transferred from a healthy donor into the gastrointestinal tract (usually the colon) of the patient.  The standard use is to treat people whose gut microbiota has been decimated by antibiotic treatment or who have a runaway Clostridioides difficile infection (commonly called "C. diff").  The goal is to seed the regrowth of a healthy microbiota.  This is sometimes called "bacteriotherapy" or "fecal transplant".

Recently some researchers have thought that type 1 diabetes might be triggered or encouraged by something in the gut microbiota.  I reviewed this theory (in the context of probiotics) a year ago:
https://cureresearch4type1diabetes.blogspot.com/2019/11/is-there-any-association-between-gut.html

The DIMID1 Study

This study enrolled 20 adults with T1D during their honeymoon phase (within 6 weeks of diagnosis).  Half got transplants from healthy people, and half got transplants from themselves.  Both groups went through the same procedures, but the second group got no new microbiota.  Both groups got three procedures in the first four months, and were followed for a year.  The exact times are marked with an arrow in the charts below. The primary results were C-peptide production (which measures the body's ability to generate insulin), and the secondary results were a wide variety of immunological, microbiota, and blood sugar control measurements.

This study was funded by the AMC Hospital several Dutch organizations.  It ran from 2013 to 2017 in the Netherlands. The researchers did not report on the ethnic composition of the participants.

Results

The primary results are summarized below.  The blue lines represent the people who got the a transplant from a healthy (non-T1D) donor and the red represents people who got a transplant from themselves.  These are all people in their honeymoon phase, and you can see the "transplant from healthy" group C-peptide numbers drop (as expected from an untreated group) but the "transplant from self" group stays steady, which is better than expected.  After a year the "transplant from self" group has not gotten worse, but the "transplant from healthy" group has, and the difference is statistically significant.  The "C" results are for fasting (sometimes called "baseline") C-peptide generation, while the  "D" results are for C-peptide generated in response to eating a meal.

Copyrighted material provided for educational purposes only.

Journal article: https://gut.bmj.com/content/gutjnl/early/2020/10/25/gutjnl-2020-322630.full.pdf
Personal note: this article is very well written, and easy to read.  The authors often describe why they chose to do one thing rather than another, so it is very informative.  People who want to understand why the gut microbiota might effect T1D can read the introduction for a quick, easy to understand justification.  

Clinical trial registry: https://www.trialregister.nl/trial/3542 

Discussion

Remembering that C-peptide is a measure of the body's ability to generate insulin, people who got the "transplant from self" treatment in their honeymoon phase did not deteriorate (in terms of generated C-peptide) over the next year.  Those who got the "transplant from healthy" treatment lost their ability to generate insulin (as would be expected over the course of the honeymoon).

But, what does this mean?  Is it important?  Will it lead to a cure?  These are the open questions. When I started this blog, results like this made me optimistic.  I thought that if a treatment could preserve beta cells in early testing, then as we learned more about it, later tests might show it increased beta cells and lead to a cure.  However, that has not happened in any of the treatments which showed this result early on.  Therefore, I'm no longer so positive about them. 

My current thinking is that these results are more likely to grow into a delay or prevention rather than a cure.  In particular, if this treatment had the same effect on people who were at-risk of T1D, as this study showed for people in the honeymoon phase, then it would naturally cause a delay.  If prevention turns out to be the natural result of a long delay, then this treatment could become that as well.  All that would be required is to see the same results seen here, but in at-risk people rather than honeymooners.  Of course, we can still hope for it turning in a cure, but that is less likely.

One interesting point about this result, is that the good effect was seen in the "transplant from self" group, rather than the "transplant from healthy" group.  It seems more likely that a transplantation from someone who did not have T1D would be beneficial while moving Microbiota around within the same person would not change anything.  However, in fact, the reverse is seen.  That is an odd result (at least to me) so I'm interested in seeing where it goes, if it goes anywhere.

The researchers wanted to include 34 people in their study (17 in each group).  Unfortunately, they were not funded enough to do that, so they ended up with 20 people (10 in each group).  Luckily, their results were strong enough to show up with the smaller numbers, but that is not often true.  So this study shows the practical impact of less money for research: fewer subjects in each study, and more uncertainty in the outcomes because of that. 

Other Research

Only one other clinical trial is testing FMT right now.  It is a pilot study, enrolling 10 people:
https://www.clinicaltrials.gov/ct2/show/NCT04124211

There are several clinical trials using probiotics to try to improve a patient's T1D.  This can be viewed as an alternate treatment to FMT, both of which are based on the same "gut based T1D" theory.

 

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, December 12, 2020

Glucose-Sensitive Insulin (NN1845) Starts A Phase-I Clinical Trial

Glucose sensitive insulin refers to any insulin formulation which becomes more available as blood glucose levels rise, and less available as those levels drop.  You can think of these insulins as self regulating or self dosing.  A person would inject enough to last for a day or more, but the insulin would only be used by the body when glucose levels were high.  A highly sensitive insulin could eliminate the need for measuring blood glucose levels and for determining insulin doses based on food, exercise, or anything else.  That would transform T1D management to the same injection each day.  In the same way people take high blood pressure medicine each day, a T1D could take glucose sensitive insulin each day, and otherwise ignore their T1D.  If successful, this could lead to a "practical cure" even if the person still "had" T1D. 

NN1845 is a glucose sensitive insulin under development by Novo Nordisk.

The Phase-I Clinical Trial

Officially, this is one clinical trial, but it is better to think of it as two separate clinical trials under one authorization. Both parts are focused on how NN1845 will act within the body (called pharmacology) and how safe it is.  Each part is expected to gather data for 10 days, so this study can be done quickly.  A total of 78 people will be enrolled.

The first part will give healthy people (people who do not have T1D) one dose of NN1845, to measure adverse effects (bad side effects), how their blood glucose changes over time, and what happens to the NN1845.  Half the people in this group will get NN1845 and half will get a placebo.

The second part will give people with established T1D either one dose of NN1845 or one dose of  insulin degludec (Tresiba®).  Again the researchers will look for adverse effects (bad side effects), how their blood glucose changes over time, and what happens to the NN1845.

This study is recruiting at the Novo Nordisk Investigational Site in Mainz, Germany, 55116.  The only contact information provided is an American phone number:     
(+1) 866-867-7178     clinicaltrials@novonordisk.com

 
Discussion
 
One thing that I really like about this study is that it should be quick.  Each part only requires about 10 days of data collection.  This is in stark contrast to most trials I follow, which are often 1 or 2 years.  This is because NN1845 is being tested like a new insulin rather than a possible cure.  Insulins start out by being tested with one dose, and then for a few weeks, and then for longer.  But those first tests are very quick.  While people given a potential cure are generally followed for a year or two, and this is true even in the early clinical trials.  Therefore, they take a lot longer to move through the development pipeline.
 
But there are big issues here.  The first is that glucose sensitive insulin is not "fixing" someone's type-1 diabetes.  In many ways, it is closer to a pin holding together a bone.  The bone is still broken, but the pin allows the person to ignore the fact that the bone is broken.  Is that a cure?  Is it a practical cure?  I'm going to track this as a potential cure, because I think some people will consider it one.  However, not everyone will.  If you don't consider this a cure, then just ignore my coverage of it.
 
The second issue is that this insulin may not be glucose sensitive enough to be a practical cure.  If NN1845 is so sensitive that you can take it in the morning, and it will act as a background insulin all day, and react so quickly that you don't need to take extra insulin for meals, for me, that would be a practical cure.  But NN1845 may not be that sensitive or that fast acting.  Maybe it will act as a background insulin, and make it extra hard to go low, but is not sensitive enough to react to meals.  That has some advantages in terms of extra safety as a background insulin, but it is not a practical cure in my mind.  For this issue, only clinical trials will answer the question of how sensitive and how fast NN1845 is.  Therefore, I'll follow the research and see what we learn.
 
Other Glucose Sensitive Insulin Research
 
An earlier glucose sensitive insulin was known as "Smart Insulin".  That insulin was developed by Smart Cells, Inc. which was bought by Merck.  The insulin made it to Phase-I trials, but the results were not good enough to continue in clinical trials.
 
About two years ago, Novo Nordisk bought Ziylo, a company developing a glucose sensitive insulin.  However, NN1845 is not the Zilyo product.  Novo Nordisk development of the Ziylo product was in the news as recently as mid-2020, so the company is positive enough on the general idea of glucose sensitive insulins to develop two different candidates in parallel.  That is a strong commitment.

There are several other glucose sensitive insulins currently in animal testing.  Maybe a dozen over all.  I'll cover those when they move into human testing.

Thanks
 
I want to specifically thank the JDCA (Juvenile Diabetes Cure Alliance) who tracked down some important background information about NN1845, Novo Nordisk, and Ziylo, and then kindly shared what they learned with me.  You can see their other research here: http://thejdca.org/2020-reports
JDCA does not fund T1D research.  They do publish the best public information on how money flows through the T1D research process, and great overviews of the research landscape in general.

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.