Results from MultiPepT1De (Multi Peptide Vaccine) by Powrie at King’s College London

This is the most recent result from a long line of research led by Colin Dayan and Mark Peakman, at Cardiff University and King's College London. The goal here is to train the body's immune system not to attack itself, by using either one peptide (in the first trial) or several peptides (in the more recent trial).  A peptide is a small part of a protein, and these peptides are part of the insulin molecule.  The idea is vaguely similar to giving people tiny amounts of peanut protein to desensitize them from peanut allergies.  However, it is important to remember that type-1 diabetes is NOT a classic allergy; the analogy is not perfect, but gives the general idea. 

You can read my summary of the results of the first clinical trial, using one peptide, here:
https://cureresearch4type1diabetes.blogspot.com/2017/11/results-from-phase-i-clinical-trial-of.html

This study was done on adults, within 4 years of diagnosis.  This is a little unusual, as most studies either pull from "honeymooners" (within 1 year of diagnosis) or "established" (longer than that).  The average time after diagnosis for everyone in this study was about 20 months.  So while this study does contain a mix of honeymooners and established T1Ds, there are more people with established T1D.

Here is an image overview of the results. The line with the square is insulin production in the group that got the placebo, while the triangle covers everyone who got the treatment (in three different doses).  My summary is two fold: (1) the treated group did better than the untreated group (2) neither group actually got better, it is just that the treated group dropped less than the untreated group.  

Another way to view the results is this graph:

And notice that in the placebo group, everyone gradually lost C-peptide production during the 6 months of the study.  That is what we expect, since people gradually loose insulin production throughout their honeymoon.  However, the people who got the smallest dose, two of them actually went up.  They were generating more C-peptide after 6 months.  The official summery is "Taken together, these findings provide some encouragement for the evaluation of efficacy signals in future, well-powered studies."

Discussion

For myself, I consider C-peptide results to be successful when they go up, and unsuccessful when they go down.  Here, the C-peptide results for the treated people went down, so that is disappointing.   It is important to see that the study was successful because the treated group generated more C-peptide than the untreated group, and this difference was big enough to be statistically significant.  However, both groups (treated and untreated) actually went down in C-peptide production.  It is just that the treated group dropped less than the untreated group.  So even though this study was scientifically successful, I don't think of the results as successful.

But there is another issue here, which the researchers touched on: "responder vs. non-responder".  The overall results in the first chart, the average of everyone who got the treatment and compare this to the average of everyone who did not, and those were the disappointing results.  However, the second chart shows all people individually.  Certain people got noticeably better, while others did not, or even went down.  If you happen to be one of the people who's C-peptide numbers went up, you would be very happy with the results. 

So, when evaluating these results should we look at an average of everyone, or focus on specific responders?

It's a complex discussion, too complex to go into here.  However, one of the key questions is, do you know ahead of time who will be a responder?  Do they share some characteristic or test result, so you know they will be a responder?  If so, you can give the treatment only to the responders, and see some big results.  If that is the case, the responder result is the important one, and focusing on it is a reasonable thing to do.

However, if you do not know who will respond, or why they respond, then hyping the responder success is just an excuse to exclude data that makes your treatment look bad.  In this research, there is no indication of why some people respond and some don't, but the research is still in its early stages.  If they do discover why some people respond, while others do not, then suddenly this research could become very valuable to people who are "responders".

Abstract: https://pubmed.ncbi.nlm.nih.gov/35073398/
Full Paper: https://diabetesjournals.org/diabetes/article/71/4/722/140961/Immune-and-Metabolic-Effects-of-Antigen-Specific
Clinical Trial Record: https://beta.clinicaltrials.gov/study/NCT02620332

Thanks to ADA's "Diabetes" journal for making this article free, and thanks to all the people who pressured (and continue to pressure) all scientific journals to make these results freely available.

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.