Thursday, May 19, 2016

Research In The News (May)

This blog posting covers a couple of different topics, but starting with a piece of bad news:

 Perle Biosciences Ends A Phase-II Trial of a Combination Cure

In November 2015 I blogged on a clinical trial by Perle Biosciences testing a combination of Cyclosporine and Omeprazole.  You can read the details here:
http://cureresearch4type1diabetes.blogspot.com/2015/11/perle-biosciences-starts-phase-ii-trial.html
Unfortunately,  that trial was listed as "Prematurely Ended", but I'm not sure exactly when.  There hasn't been an official press release on the trial, but JDCA quoted Perle Biosciences's president as saying the trial was stopped because "Enrollment was disappointing in Europe and we are planning to move all studies to the U.S."

Of course, I'm hopeful that they do start a trial in the US, and soon.  They are working with a combination of drugs: one of which stops the autoimmune attack and the other regrows beta cells. Both are already approved in the US (one is over the counter).  So you can see why this is an exciting treatment.

Unfortunately, this is not the first time Perle has had problems starting a study.  Prior to starting this European study, Perle filed paperwork to start two studies in the US.  This paperwork languished for over two years and the American studies never did start.   A parallel effort in Europe did led to this study, which has now been ended.

JDCA Coverage: http://thejdca.org/practical-cure-project-update-perle-bioscience-drug-combination-human-trial-ends-prematurely

Not In Human Trials: Stem Cells From Self

Researchers were able to create beta cells from stem cells, the stem cells having been created from skin cells of people with type-1 diabetes.  This might be important for a couple of reasons.  First, these cells could be used to test new drugs.  Many people have noticed (especially in the world of type-1 diabetes) that treatments which work on mice often don't work on people.  This is a way to test treatments on beta cells similar to a type-1 diabetic's actual beta cells.  Second, these cells could be used in transplants.  But remember, that only solves half the transplant problem.  Transplanted beta cells have two problems: the body's good immune system is trying to kill them because they are foreign and the body's bad immune system is trying to kill them because they are beta cells.  Since these cells are from the patient's own body, they will not have the first problem, but might still have the second problem.

To the best of my memory, previous reports of making beta cells from stem cells always involved the use of 3rd party stem cells (ie. the stem cells did not originate from the person who would eventually get the beta cells).  So this is a step forward in that regard.

This is animal research only right now, but could get into human trials in 3-5 years, which would then take an additional 10-15 years to become generally available.  That is, assuming it is successful.

Press Release: https://www.sciencedaily.com/releases/2016/05/160510132809.htm
Paper: http://www.nature.com/ncomms/2016/160510/ncomms11463/full/ncomms11463.html


Stepping Back from Artificial Pancreas Coverage

I've decided to scale back my coverage of artificial pancreas research.  This is for two reasons:
  1. Because limited functionality Artificial Pancreas devices are already available from Medtronic now in Europe (the 640G) and in the United States (the 530G), and because an all-but-meal Artificial Pancreas device (the 670G) is planned for release in both places in the next few years, there is a lot of "regular" news coverage on Artificial Pancreas developments.  I do not think I'm adding a lot of value to Artificial Pancreas research reporting.  To be blunt: DiabetesMine, diaTribe, ASweetLife, and similar web sites are doing such a good job publicising AP progress, I don't feel like I'm needed in that area.
  2. Because there is so much progress being made, on so many different Artificial Pancreas fronts, the avalanche of information is overwhelming me.  I just can't keep up.
Obviously, these are both good reasons to stop coverage.  I'm absolutely confident that a full Artificial Pancreas will be available in the United States in a few years, and I'd rather spend my time following research that is less certain, and harder to interpret.

If you are desperately in need of an AP update, read these:


My Internet World

I use Blogger, LinkedIn, Facebook, and Twitter, but I divide up my internet world like this: The blog is very specifically focused on clinical trials aimed at curing type-1 diabetes. If that is what you care about, then either follow the blog or sign up for mail notifications when a new entry is posted. (There is a field in the upper right hand corner of the blog for that.)  My twitter covers type-1 diabetes more broadly and also some non-diabetes issues which are important to me.  It is more than half type-1 and less than half other issues.   I try to keep LinkedIn very strictly for work related stuff, and Facebook for family and friends.  So if you are linked with me either on LinkedIn or Facebook, but only care about diabetes news, then you'd probably do better to either sign up for emails from my blog or link with me on Twitter.

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, May 1, 2016

General Update on IL-2 Research

This is a long blog posting, because I'm attempting to summarize all the current research which attempts to cure type-1 diabetes using Interleukin-2 (IL-2).

IL-2 is a protein that the body's immune system uses for communications.  It is part of the system that helps the immune system identify the body's own cells from foreign cells.  Since the root cause of type-1 diabetes is a failure in this process, IL-2 is a possible cure.  Several different groups are testing it (or have tested it).  More information is on Wikipedia:
http://en.wikipedia.org/wiki/Interleukin_2

Of course, IL-2 cures type-1 diabetes in NOD mice:
http://jem.rupress.org/content/207/9/1871.short

Overview Of IL-2 Research

Many of these clinical trials have similar names and some of them are being run by the same researchers in the same organization.  So in the list below, I've included their FDA registration number (starting with NCT), to help me keep track of which trial is which.

Three studies have been completed:
  • DF-IL2 (NCT01353833)
  • DILT1D (NCT01827735)
  • Combo (NCT00525889)
And three more are recruiting now:
  • DFIL2-Child (NCT01862120)
  • DILfrequency (NCT02265809)
  • DIABIL-2 (NCT02411253)
Completed Clinical Trials

DF-IL2 (NCT01353833)

This was a "mechanistic" trial, meaning that it's goal was to show that IL-2 would increase the number and activity of good immune cells (T-reg cells).  T-reg cells regulate the immune system so that it does not self attack, and many researchers believe that getting the body to generate more T-reg cells, and making them more active, is a key to stopping the autoimmune attack.  This trial involved 25 people within two years of diagnosis.  They were divided into four groups: three getting different IL-2 doses, and a placebo group.

This first trial was successful because the researchers saw changes in the T-reg cells.  However, they did not measure C-peptide, A1c, insulin usage or any other "patient impacting" parameters, so we don't know if the T-reg changes that they saw actually resulted more natural insulin, better A1c number, etc.

This same group of researchers has started a follow on trial, called DFIL2-Child (NCT01862120) and described later.


DILT1D (NCT01827735)

This trial completed in May 2014, but results have not been published.  However, the researchers involved have started a follow on trial, called DILfrequency (NCT02265809) which is described later.  This trial included 40 people, within 2 years of diagnosis.  It was not blinded, and had no control group.


Combo (NCT00525889)

This trial combined two treatments: Rapamycin and IL-2.  Rapamycin suppresses the immune system.  It enrolled 9 patients with no control group.  These people had been diagnosed less than 4 years ago, but more than 3 months ago.

This trial was not successful (in terms of moving us towards a cure).  Although it did result in more regulatory T cells, yet C-peptide numbers (a measure of the body's ability to create it's own insulin) dropped at the same time.  

(Thanks to the ADA for making this paper freely available.)

Clinical Trials Currently Underway

DFIL2-Child (NCT01862120) 

This is a 24 person phase-II study, where different groups will get three different doses of IL-2, and a fourth group will get placebo.  The primary end point is a CD4 measurement 22 days after dosing. The secondary measures are more clinically useful: C-peptide numbers (which show insulin production) and A1c number.  They are also measuring changes in T-regs, to give insight into the mechanism of how IL-2 works.  The study will gather data for each participant for about 15 months.  This trial started in June 2013.  Since they completed enrollment in April-2016, they should finish collecting data by mid-2017

This trial in France and is open to children aged 7 to 14, who are in the honeymoon phase (treated with insulin for less than 3 months). Here is the contact information for this trial:
David Klatzmann, MD, PhD   Phone: +33(0) 1 42 17 74 61   Email: David.klatzmann@upmc.fr

This study is recruiting at many different hospitals:
Service d'Endocrinologie Pédiatrique -- Le Kremlin Bicetre, France, 94275
Service de Pédiatrie - CHU de Nîmes -- Nimes, France, 30029 cedex 9
CIC pédiatrique - CHU de Necker -- Paris, France, 75015
Service d'endocrinologie pédiatrique - CHU de Necker  -- Paris, France, 75015
CIC 9202 CHU Rober Débré -- Paris, France, 75019
Service d'endocrinologie Diabétologie pédiatrique CHU Robert Débré -- Paris, France, 75019

Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT01862120


The DILfrequency Trial (NCT02265809)

This study is testing Aldesleukin (also called Proleukin or IL-2), and uses "adaptive design". Basically, they give the early participants many small doses of the drug they are testing, and based on how and when they react to those doses, the later people in the trial get "better" doses.  (The engineering term for this is "fast feedback loop" and the software term is "agile development".)

This trial is for adults (18-70) who are within 5 years of diagnosis, so not just honeymooners.

If you really want to keep up with these researchers, they are all over twitter and facebook:
https://twitter.com/t1diabetestrial
https://www.facebook.com/ClinicalTrialsType1Diabetes

Update

Since January, this study is enrolling the last group of patients needed for completion.  There is no control group so everyone is getting the drug.  One patient has completed all follow up visits.  But the big news from my point of view, is that they are well past their "learning" phase, and are now testing doses based on the data from the earlier phases.

Once they have recruited all their patients, it will take them less than 4 months to collect their data. They hope to finish by October 2016.

I'm wondering if this clinical trial represents the future of clinical trials in an internet world.  Take a look at their list of URLs:

Web Page: http://www.clinical-trials-type1-diabetes.com/
Facebook: https://www.facebook.com/ClinicalTrialsType1Diabetes
Twitter: https://twitter.com/t1diabetestrial
Pinterest: https://www.pinterest.com/t1diabetestrial/
Clinical Trial Registery: https://clinicaltrials.gov/ct2/show/NCT02265809

Pretty soon, they will need a web page to keep track of their web pages.   From my point of view, all this information gives me a great view into the process of running the clinical trial.  Especially, it tells me when various internal milestones were reached.   Usually, I don't have any knowledge of those milestones, so it is great to see them.

DIABIL-2 (NCT02411253)

This trial is being run by the same researcher (Dr. David Klatzmann) who is running the DFIL2-Child study discussed above.  This trial is much larger (185 person), and is open to honeymooners (ie. within 2 months of diagnosis) between 12 and 35 years old.  It started in March 2015 and plans to finish in June 2018.

This trial is already recruiting in Germany, and many places in France.  It is planning to add Belgium, The Netherlands, Sweden, and Switzerland, too.

Service d'endocrinologie, diabétologie, maladies métaboliques, et nutrition, CHU de Bordeaux, Hôpital Haut Levêque Recruiting
Pessac, Aquitaine, France, 33604
Contact: Vincent RIGALLEAU, Pr.    06 63 24 45 51    vincent.rigalleau@chu-bordeaux.fr
Service d' Endocrinologie HOPITAL CAVALE BLANCHE Recruiting
Brest, Brittany, France, 29609
Contact: Emmanuel SONNET, Pr    02 98 34 71 19    emmanuel.sonnet@chu-brest.fr
Service de Pédiatrie, HOPITAL MORVAN Recruiting
Brest, Brittany, France, 29609
Contact: Chantal METZ, MD    00 33 2 29 02 00 04    chantal.metz@chu-brest.fr
Médecine pédiatrique, CHU Jean Minjoz Recruiting
Besançon, Franche-Compté, France, 59037
Contact: Anne-Marie Bertrand, Dr.    03 81 21 81 34    bertrand.anne-marie@wanadoo.fr
Service Diabétologie -Endocrinologie, CHU Jean Minjoz Recruiting
Besançon, Franche-Comté, France, 59037
Contact: Sophie Borot, Dr.    06 89 16 22 46    sophie.borot@gmail.com
Endocrinologie gynécologie diabétologie pédiatriques, Hôpital Universitaire Necker Enfants Malades. Recruiting
Paris, Ile De France, France, 75015
Contact: Michel Polak, Pr    +33 (0)1 44 49 48 02    michel.polak@nck.aphp.fr
Institut E3M, Hôpital Pitié-Salpêtrière Recruiting
Paris, Ile-de France, France, 75013
Contact: Agnés Hartemann, Pr.    01 42 17 81 18 ext 80 70    agnes.hartemann@psl.aphp.fr
Service d'Endocrinologie Pédiatrique, Hôpital d'enfants Robert Debré Recruiting
Paris, Ile-de France, France, 75019
Contact: Jean-Claude CAREL, Pr    01 40 03 53 03    jean-claude.carel@inserm.fr
Service Pédiatrie - Pôle femmes enfants, CHU de Nîmes, Hôpital Universitaire Carémeau Recruiting
Nïmes, Languedoc-Roussillon, France, 30029 Cédex 9
Contact: Tu Anh TRAN, Pr.    04 66 68 32 84 ext 32 85    tu.anh.tran@chu-nimes.fr
CHRU de Lille, Hôpital Claude Huriez Service d'endocrinologie Recruiting
Lille, Nord-Pas-de-Calais, France, 59037
Contact: Pierre FONTAINE    03 20 44 45 13    pierre.fontaine@chru-lille.fr
Service d'endocrinologie-diabétologie gynécologie pédiatriques, CHRU de Lille, Hôpital Jeanne de Flandre, Recruiting
Lille, Nord-Pas-de-Calais, France, 59037
Contact: Jacques WEILL, Pr.    03 20 44 46 95    Jacques.WEILL@CHRU-LILLE.FR
Institute of Diabetes Research, Helmholtz Zentrum München Recruiting
München, Bayern, Germany, D 80804
Contact: Annette G ZIEGLER, Pr    00 49 089 3187 2896    anette-g.ziegler@helmholtz-muenchen.de

General Discussion of IL-2 As A Cure For Type-1 Diabetes

Unfortunately, IL-2 does not have a strong history of success in previous trials aimed at type-1 diabetes.  If you look at the three completed trials: two saw some changes to T-regs, but not to "patient visible" results like C-peptides, A1C numbers, or insulin use; the other has not been published.

Of the trials currently underway, two are aimed at honeymooners, and one at long term type-1 diabetics, and all will have results in the next two years.  The trials currently underway are all gathering C-peptide data, which I consider the most important measure of progress in curing type-1 diabetes.  And they are also gathering information on A1c and insulin usage, plus various data which should show what is happening "inside" the immune system.  So I'm optimistic that with that data, it will be clear if IL-2 is worth further research or not.  Of course, when the results are reported, I'll be focusing on the results which directly impact people with type-1 diabetes: C-peptide, A1c, and insulin usage.

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, JDCA, or Tidepool 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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