Results From Phase-I Clinical Trial of Proinsulin Peptide Vaccine in Honeymooners (MonoPepT1De)

For over 10 years there has been a research group at Cardiff University (UK) working on creating vaccine-like treatments to cure or prevent type-1 diabetes, and this blog posting covers their recent results.

As background: one of the autoantibodies that is associated with type-1 diabetes targets insulin molecules [d1]. Therefore, there is a theory that giving people with T1D a protein fragment from insulin might prevent or delay the onset of type-1 diabetes.  It would train the body not to produce this autoantibody. The process is vaguely similar to giving small amounts of peanut proteins to people with peanut allergies [d2].  These researchers are using a peptide (a small part of a protein) from proinsulin, which is a precursor of insulin.

Results From Phase-I Clinical Trial of Proinsulin Peptide Vaccine in Honeymooners

This trial involved 27 people divided into three groups.  One group got a placebo and was a control group, the other two groups got the Proinsulin Peptide injections for 6 months.  One group got the peptide every 2 weeks, the other every 4 weeks.  The people were adult, honeymoon diabetics (within 100 days of first insulin injection).  They will be followed for 3 years, although this publication only covers the first year after treatment.

The untreated group went through a normal honeymoon period, where over time they gradually generated less and less of their own insulin, and had to inject more and more.  However, the treated people (on average) held steady in their ability to generate their own insulin, and did not lose their ability to generate insulin for the time covered. So this meant that the treated group did better than the untreated group over time, and the difference was statistically significant.  Also, there were no safety issues.

JDRF funded this trial specifically, and this whole line of research, in general.

News Coverage:
http://www.medicalnewstoday.com/articles/318899.php
http://www.latimes.com/science/sciencenow/la-sci-sn-diabetes-immunotherapy-20170809-story.html
Abstract: http://stm.sciencemag.org/content/9/402/eaaf7779
Full Paper: http://stm.sciencemag.org/content/9/402/eaaf7779.full
Clinical Trial Record:  https://clinicaltrials.gov/ct2/show/NCT01536431

Discussion

I think there are three important points for this research:

First, these results are good enough to spur a phase-II trial, and the Cardiff researchers have already made it clear they hope to run a phase-II trial starting in 2018.  Two of the authors of this paper are consultants to UCB Pharma to help design that trial.  So that is good.

These results join a growing number of treatments with what I call "medium good" results in honeymooners.  "Medium good" means that the treated group did not get worse, but did not improve either.  This is in comparison to the untreated group which did get worse.  (During the honeymoon phase, people with type-1 diabetes get worse: they gradually lose the ability to generate insulin.  They go from generating a little insulin, to generating none.)  I think there are about half a dozen treatments which have phase-I or phase-II? results of this type.  So it's better than nothing, but because none of these treatments have moved forward to even better results, I'm not not particularly excited about them.  I'm still hoping for better results in future trials.

These "medium good" results may become even more valuable in the future, if they can be applied to people in the earliest stages of type-1 diabetes, when they have two autoantibodies, yet are not showing any other symptoms.  I'm hopeful that preserving insulin generation at that level could delay or prevent needing injections completely.

Second, this same research group is working on another clinical trial closely related to this one, but it has not gotten as far along the development path: https://clinicaltrials.gov/ct2/show/NCT02837094  (This is an 8 person clinical trial without a control group.)

Finally, this same research group is working on a similar treatment, but based on many peptides, rather than just one.  That trial is called MultiPepT1De:
https://clinicaltrials.gov/ct2/show/NCT02620332
They completed recruiting on 3 July 2017, so should finish gathering data about the end of 2017.

Details

[d1] Autoantibodies are the malfunctioning antibodies which cause the immune system to attack beta cells. There are five autoantibodies associated with type-1 diabetes, and there may be more that we haven't discovered yet. The five we know about are:
* micro insulin autoantibodies (mIAA or just IAA)
* islet-cell antibodies (ICA)
* glutamic acid decarboxylase (GAD) antibodies
* islet antigen-2 (IA-2) antibodies
* zinc-transporter 8 (ZnT8) autoantibodies

[d2] It is important to realize that type-1 diabetes is NOT a conventional allergy to insulin. It is similar to allergies in that it is the body's immune system overreacting to something that it should not react to, but other than that, is quite different. Allergies involve the immune system overproducing histamines. These histamines attempt to get physical irritants, like pollen, out of your body. You can counter this histamine reaction by taking antihistamines. Type-1 diabetes involves the immune system overproducing malfunctioning killer T-cells (or perhaps under producing regulatory T-cells). These malfunctioning killer T-cells mistakenly kill beta cells, thinking they are foreign cells (ie. living creatures like viruses, that have invaded the body). So the mechanism is different (histamines vs. T-cells), and the mistaken target is different (physical things, like pollen or wheat vs. living organisms, like viruses).

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.

News From EASD (European Association to Study Diabetes)

Back in October 2016 was the European Association to Study Diabetes (EASD) conference, which is the largest scientific meeting on diabetes in Europe.  Much like ADA, it covers both type-1 and type-2 diabetes. The Europeans are way ahead of the American in terms of on-line access.  The EASD 2016 web site has recordings of many of the talks, and much more content than the ADA web site. You can see it here:
http://www.easdvirtualmeeting.org/

Clinical Trials Aimed at Curing Type-1 Diabetes
The only research which I saw which was directly aimed at curing type-1 diabetes was a talk and a poster given by Dr. Ali from the Cardiff Diabetes Vaccine Development Center (which is part of Cardiff University, Wales, UK).  This is part of the ongoing work by Dr. Peakman and others.

Results of the Monopept1de Phase-I Trial of An Insulin Peptide

This research has been on-going for at least 10 years.  Here is my previous blogging:
http://cureresearch4type1diabetes.blogspot.com/search/label/Proinsulin
The basic idea is to give people with type-1 diabetes an injection containing part of the insulin molecule, which will teach the body's immune system not to attack itself.  The idea is vaguely similar to giving people tiny amounts of peanut protein to desensitize them from peanut allergies.  It is important to remember that type-1 diabetes is NOT a classic allergy.  The analogy is not perfect, but that's the general idea.

The study showed that the treatment was safe and did not trigger any serious adverse effects, or unexpected adverse effects of any kind.  The success/outcome data was weaker.  C-peptide production did NOT increase, but insulin usage went down, and H1c numbers showed a downward trend in treated people.  None of this is strong data for effectiveness, but this trial was aimed at gathering safety data.  The researchers think the safety data is plenty strong enough to support a phase-II study.

Poster: http://www.easdvirtualmeeting.org/resources/proinsulin-peptide-immunotherapy-in-new-onset-type-1-diabetes-is-well-tolerated-and-associated-with-reduced-daily-insulin-usage
11 Minute Talk: http://www.easdvirtualmeeting.org/resources/proinsulin-peptide-immunotherapy-in-new-onset-type-1-diabetes-is-well-tolerated-and-associated-with-reduced-daily-insulin-usage-203021b2-7c50-4239-81b8-84fe0d8a0291
Older Poster On The Same Research: http://www.easdvirtualmeeting.org/resources/proinsulin-peptide-immunotherapy-in-type-1-diabetes-safety-data-of-a-first-in-new-onset-type-1-diabetes-phase-1b-trial--2

This same research group is working on another clinical trial called "MultiPepT1De", which is testing using several different proteins at once.  The trial reported on here only used one. The MultiPepT1De trial was scheduled to finish in Feb-2017, but is running late:
https://www.ukctg.nihr.ac.uk/trials/trial-details/trial-details?trialId=5462
https://clinicaltrials.gov/show/NCT02620332

Other Interesting Talks

Faustman
This was a 15 minute talk by Dr. Denise Faustman, where she discusses a particular chemical pathway (TNFR2):
http://www.easdvirtualmeeting.org/resources/in-vitro-tnfr2-agonism-for-correction-of-treg-activation-defect-in-type-1-diabetes-c96e016f-57c0-4432-9805-9918efcd364e

Viral Infections as Triggers
The talk in the next link discussed looking for viruses in the pancreases of 6 newly diagnosed adults. It is 30 minutes long and has 114 slides: 
http://www.easdvirtualmeeting.org/resources/the-pathogenesis-of-type-1-diabetes-virus-involved-lessons-from-the-divid-study
These researchers are trying to answer the question "does a viral infection trigger type-1 diabetes", by looking at pancreases close to the time of diagnosis.  They did find more viruses in people with type-1 diabetes, but it was low grade persistent infection, not an acute infection.  They were all enteroviruses, no two of the same strain, and the exact virus could not be identified (due to low levels).

Also, they found that 36% of the islets were still producing insulin approximately 5 weeks after diagnosis, which is higher than previous estimates that I'm familiar with.  This definitely comes down on the "viruses are involved in triggering type-1", but the study was a small pilot study, in need of follow up.

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.