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.

Research In The News (November)

MK-2640 ("Smart Insulin") Completes Enrollment Collection of a Phase-I Clinical Trial And Then Adds a New Part

MK-2640 is the Merck identifier for what we all know as Smart Insulin.  It is the only "self dosing" insulin currently in human trials.  The idea behind this drug is that you could inject it (maybe twice a day, maybe once a day, maybe once a week), and then it would release insulin if your BG numbers were high, and not if they were low.  It is sort of a chemical artificial pancreas.

Because there is no data from human testing (nor have I seen any animal data), there is no way for me to know if MK-2640 is going to turn into a "lantus killer" (i.e. a great basal insulin), or if it is going to turn into something much closer to an artificial pancreas.   For example, something you take once a week and not count carbs or otherwise worry about type-1 diabetes.

The First News 

On 29-June-2015 Merck updated the clinical trial record to show that they were no longer recruiting people for this trial.   Since this trial collects data for 37 days, that tells me that they finished in August. However, a different part of the record suggests they might have finished collecting data even earlier.  Yet another part of the record was updated to show an "Estimated Study Completion Date" of October 2015.  So that was all good news, and I was looking forward to them publishing results.

The Second News

Then (in September) they added a third part to what had previously been a two part clinical trial. Part three seems to be a continuation of part two (meaning they are testing in type-1 diabetics and are comparing MK-2640 to regular insulin.  They are now recruiting again (presumably for part three), and have pushed out the completion date to early 2016.  Part three will add 16 people to the test (from 58 to 74), but the testing looks pretty similar to part two.

A (Very Little) Discussion

Most of this clinical trial involves giving people MK-2640 (different groups of people getting three different doses), and then dripping sugar into them for 9 hours (7 hours in part three) and seeing what happens.  The sugar is an IV drip ("intravenous infusion"), not eaten in a meal.  In this case "what happens" means things like: side effects, BG levels, how quickly the body "clears" the drug out of the system, etc.

For me, the most important data will be how quickly MK-2640 lowers BG levels when sugar first starts hitting the bloodstream. If it lowers BG levels quickly, that means that it will work for meals (and is more of an AP replacement). However if it is slow to lower BG levels, that implies that it is more of a Basal insulin, and might replace Lantus/Levemir in the market, but not replace pumps/APs.

However, as I am an optimist, I will not forget that IV sugar is much faster acting than carbs eaten in a meal, so even if the results are so-so for IV sugar, I would expect better results from a real meal.  Of course, it could turn out exactly the opposite: the slower sugar absorption might result in slower MK-2640 reaction times.  I guess we'll have to wait for the first "real world food" tests.  I only hope it gets that far.

I interpret adding the new part three section to be all good news.  They added that after they had run the first two parts, and I don't think they would do more testing if the first parts did not look good.  (A pessimist might say that if part two was not good, they were hoping to save the trial with data from the new part.  However, I am an optimist so I think if part two was not good they would have just stopped, and since they pushed ahead, that is good news.)

Similarly, part two followed people for 9 hours, but part three only followed them for 7 hours.  Is that good news, because it means that Smart Insulin reacted quickly?  Or is it bad news because, Smart Insulin lost effectiveness after that?  There is no way to tell, until they publish.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02269735

MultiPepT1De (Multi Peptide Vaccine) Starts A Phase I Study

This is a follow on study to one of the very first clinical trials I ever followed:
http://cureresearch4type1diabetes.blogspot.com/search/label/Peakman
That older trial injected a peptide (part of an insulin molecule) in the hopes that the immune system would learn not to auto-attack.  This new study injects a mix of peptides to provide a broader education to the immune system.  The basic idea is like injecting peanut proteins to teach the immune system not to be allergic to peanuts.

The study will enroll 24 adults, within four years of diagnosis.  There is no information available on number of injections, duration of the study, primary or secondary end points.  They are recruiting in London, England.  Contact information is:  Ms Rhanya Chaabane, Tel: 02071888472 Ext: 81932,
rhanya.chaabane@gstt.nhs.uk.

Note: This trial is registered with the United Kingdom's clinical trial registry which contains a lot less information than the United States clinical trial registry.  It is also registered with the European Union clinical trial registry, but they don't publish records for phase-I trials at all.  Therefore, I have a lot less information about this trial than other trials, which is why they are not getting a blog posting of their own.

Trial web site: http://www.multipeptide.co.uk/
Magazine article: http://www.multipeptide.co.uk/pdf/jdrf_article_on_multipeptide.pdf
Clinicial Trial Record: http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=19114


Stop Following Gevokizumab (Xoma 052)

I've decided to stop following the drug Gevokizumab (which started it's research life as Xoma 052). You can see my previous coverage here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Xoma%20052

The last news I had related to this drug in type-1 diabetes was that it started a Phase-II clinical trial in 2009.  The clinical trial record was updated to "Completed" in 2014, but there is no listing for published results.  I have searched for any results, but can find none, so I'm going to assume that the phase-II trial was a failure.  (It was run by a commercial company, so there is no reason for them to publish the results, if the trial failed.)

Since that time, Xoma, the company developing Gevokizumab, has published clinical trial results for both type-2 diabetes and Behçet's disease uveitis (both failed their primary end point).

Based on all this, I'm going to remove Gevokizumab (Xoma 052) from the list of possible cures of type-1 diabetes that I follow.

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.

Peakman's Phase-I Results

Peakman's Phase-I Results

Years ago, when I first started tracking research to cure type-1 diabetes, Peakman's clinical trial was one of the first ones that I added to my list and started following. And it was very frustrating, because nothing happened. Years went by and nothing happened. But now something has happened. The phase-I clinical trial ended, and the results have been published.

This research is based on the idea of using a modified protein to teach the body's immune system to not attack it's own beta cells. The clinical trial gave some people no protein, some a little protein, and some a lot. The patients were all people with established type-1 diabetes.

You can see the abstract here. The full study is pay-for-view:
http://www3.interscience.wiley.com/journal/121536033/abstract
And JDRF (which helped to fund the work) has a good description of it here:
http://www.jdrf.org/index.cfm?fuseaction=home.viewPage&page_id=DD5ADF6D-110A-9BB5-F8684C43208F87D2
Here is a great quote from JDRF's description:

Peptide immunotherapy is a type of treatment that uses small proteins to "reset" the immune system to a healthy state, much like the common allergy shot. In the case of proinsulin peptide therapy, the goal is to train the immune system to tolerate the insulin-producing beta cells that are the target of the immune response that causes type 1 diabetes.

From a safety point of view, this study was completely successful: no safety issues were found. So they can move on to phase-II trials. They hope to start those in less than 6 months. (That will be interesting in itself. My experience is that the time between ending a phase-I and starting a phase-II is always more than 9 months, so it will be interesting to see if these guys can do it quicker.)

Safety is the official goal of every phase-I clinical trial. However, most of them also try to generate some data on effectiveness of the treatment. Since they are testing minimal doses (for safety), expectations are set low, but it is still common to see some improvement. But I don't see that for this trial. I don't see any record that they looked for or found lower BG rates, lower A1Cs or less insulin usage. They did see some small changes for a 6 month period in the patient's immune system, but it is not clear what impact those changes would have.

So my overall summary for the research right now, is that their results from phase-I definitely get them to phase-II testing, but there is no data to evaluate if it is working or not. We'll need to wait for the phase-II trial to finish for that.

Joshua Levy