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.

Saturday, April 23, 2016

Gluten Free Diets To Prevent or Cure Type-1 Diabetes

One of my policies in blogging has been that I don't "play favorites".  I don't blog on something because I think it is a good idea, nor do I refuse to blog on something because I think it is a bad idea. I try to blog on all clinical trials which are aimed at curing type-1 diabetes no matter if I personally think they will be successful or not.  That is why I'm writing this blog on various researchers trying to cure type-1 diabetes with a gluten free diet.

Introduction

There is general consensus that celiac disease and type-1 diabetes are related conditions, in that people having one are noticeably more likely to get the other.  Many researchers think that both are autoimmune diseases and that they share some genetic susceptibility, so that that someone genetically more likely to get one is also more likely to get the other.

The standard treatment for celiac disease is a gluten free diet.  Since many of the bad effects of celiac disease are triggered by gluten in the diet, reducing or eliminating gluten can dramatically reduce symptoms.

Therefore, some researchers have looked at the possibility that a gluten free diet might help type-1 diabetics as well.  The rest of this blog discusses this research, divided into two sections: Completed Studies (everything until about 2012) and Underway Studies (basically 2013 - on).

My discussion is at the end.

Completed Studies

From 1999: Gluten-free diet prevents diabetes in NOD mice.

NOD mice (the standard animal model of type-1 diabetes) were given either gluten-free or normal diets.  The diabetes rate in the normal diet was about four times higher than in the gluten-free mice, and the if they did get diabetes, the gluten-free mice got it later in life.  Both effects were statistically significant.

Abstract: http://www.ncbi.nlm.nih.gov/pubmed/10585617

From 2011: Gluten Free First Year Does Not Prevent Type-1 Diabetes

This study involved 150 babies.  Half started eating gluten normally (at 6 months).  The other half delayed gluten until 12 months.  All of the babies had a family history of type-1 diabetes and a genotype (called HLA) which raised their chances of getting type-1 diabetes.

These children had their autoantibodies measured at 3 years and their type-1 diabetes status measured at 10 years.  The results were the same in both groups, so a gluten free first year did not prevent or delay either autoantibodies or actual onset of type-1.

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/21515839
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT01115621

From 2012: Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus.

This is a single case study (not a clinical trial), but it generated the interest in gluten free diets reflected in the clinical trials currently underway.  These doctors reported on the case of one newly diagnosed type-1 diabetic who immediately went on a gluten free diet, and did not need to inject insulin after that.  This patient was followed for 20 months, and did not need to use insulin during that time.  The doctors in this case were of the opinion that the gluten free diet had extended the length and strength of his honeymoon remission.  The patient was a 5 year old boy, and tested positive for the GAD autoantibody.

Abstract: http://www.ncbi.nlm.nih.gov/pubmed/22729336

Underway Studies

Gluten Free Diet Starts a Phase-I Honeymoon Trial

This trial will enroll 20 people between 2 and 18 years old within 3 months of diagnosis.  All will eat a gluten free diet; there is no control group. C-peptides and insulin usage will be measured after 1 year to see if a gluten free diet results in slower or less loss of beta cells or less need for injected insulin.

This study is being run by Jannet Svensson, PhD at the Copenhagen University Hospital in Herlev, but is already fully enrolled.  She was one of the authors of the case study listed above.  This study started in March 2012 and has already finished.  It has been submitted for publication, but I have no news yet on when it will be published.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02284815

Gluten Free Diet Starts a Phase-II Prevention Trial

This trial will enroll 60 people between 2 and 50 years old who have one or more autoantibodies, but are not showing other symptoms of type-1 diabetes.  Half will eat a gluten free diet and half will eat a normal diet, while both groups will get Vitamin D, Omega 3 fatty acids, and probiotics. C-peptides will be measured throughout the trial to see if a gluten free diet results in slower or less loss of beta cells.

If you are interested in enrolling, you can contact  Dr. Helena Elding Larsson at Lund University, Department of Clinical Sciences Malmö, Sweden, 20502

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02605148

Gluten Free Diet Starts a Phase-II Honeymoon Trial

This trial will enroll 60 people between 1 and 17 years old within 4 months of diagnosis.  Half will eat a gluten free diet and half will eat a normal diet. C-peptides will be measured after 1 year to see if a gluten free diet results in slower or less loss of beta cells.

The trial started in March 2015 and should end in March 2017 (meaning they should be finished with enrollment right about now: March 2016).  If you are interested in this study you can contact  Dr. Eba Hathout at Loma Linda University, California.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02605564

Discussion


Somehow I think that if gluten free diets could prevent or cure type-1 diabetes, someone would have noticed before now.  There are human populations, such as Inuit (Eskimos) and Masai, who have naturally gluten free diets.  If this theory were correct, these populations would have low or nonexistent rates of type-1 diabetes, and that would have been noticed by now.  Also, in the early 1900s (prior to the discovery of insulin) one of the common type-1 life prolonging diets was essentially gluten free, but it did not cure type-1 diabetes, either.

My basic summary is that right now, if you look at clinical trials (and ignore case studies and animal research), there is one published study, and it was unsuccessful.  In the next few months we will get one more, and two additional results in the next two years or so.  That will be a total of four studies, and should be enough to answer the question (or at least show a strong trend).

Obviously, the optimism about gluten free diets is generated from the case study.  It does appear that the child had type-1 diabetes (and was not a misdiagnosis).  I say that because they detected GAD antibodies, a marker for type-1 diabetes, and also because the researchers involved were (and are) heavily involved in type-1 research.  I just don't see them making a misdiagnosis error.  Going insulin free for 20 months after diagnosis is certainly very unusual.  Going insulin free for a short period of time after diagnosis does happen.  And we do not know how long the longest honeymoon period is. However, even taken together, 20 months insulin free is highly unusual.  Of course, the gluten free diet could just be random chance.  (That is, not causation, not correlation, but just lucky chance.)  But it is exactly the kind of coincidence that should be followed up on, and these four studies are a strong follow up.

One final point I want to make: often times I hear proponents of alternate medicine complain that their theories are ignored by mainstream medicine. Specifically they say that drug based treatments are pushed in preference to diet based treatments, so that drug companies profit.  The research described here is a strong counter example.  Given a single case study showing a diet based therapy might work, mainstream researchers have launched three clinical trials in an attempt reproduce the result.  The results will speak for themselves.

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.

Tuesday, March 29, 2016

Research In The News (March)

Here are a few updates related to possible cures for type-1 diabetes being tested in people:

Grifols Therapeutics Completes Recruiting on a Phase-II Trial of AAT

In February 2016, Grifols completed recruiting people for their phase-II trial of AAT (Alpha-1 Antitrypsin).  This is a 76 person study with two different dose treatment groups and a placebo group. Assuming the study progresses normally, they will finish collecting data in February of 2018 and publish the year after that.

AAT is an anti-inflammatory / immunomodulatory drug, which the body makes naturally, and which is already FDA approved for people who have a rare condition where they don't make enough of it on their own. Using AAT to treat type-1 diabetes is based on the idea that one of AAT's effects (lowering inflammation, immune modulation, or wound healing) can cure/prevent/treat the disease.  My previous blogging on AAT is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/AAT

Discussion: My summary of AAT's status is this: after several phase-I studies which did not give a strong signal of success, we now have two phase-II studies (the other is Kamada's involving about 60 people) and these will finish collecting data in 2016 and 2018, respectively.   When those two trials are published, we should have a clear success/failure signal.

Previous blogging on AAT: http://cureresearch4type1diabetes.blogspot.com/search/label/AAT
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02093221

Combo of Diamyd and Vitamin D Starts a Phase-II Prevention Trial

This is a classic prevention trial.  The researchers will enroll 80 children (between 4 and 18) who are positive for two autoantibodies (GAD and any one other), but not yet showing any symptoms of type-1 diabetes.  These people will be followed for 5 years to see how many are diagnosed in that time. This study started in March 2015 and is expected to finish in March 2022.  Half the children will be given Diamyd and Vitamin D, the other half, just Vitamin D.

Diamyd is similar to GAD, which is the target of the most common autoantibody seen in type-1 diabetes.  The hope is that Diamyd will train the immune system not to autoattack.

This study is enrolling "by invitation only", so if you are interested in enrolling, you can contact Dr. Helena Elding Larsson at Lund University, Clinical Research Center, Pediatric Endocrinology, Jan Waldenströms gata 35, 60:11 Malmö, Sweden, 20502

Discussion: Diamyd was unsuccessful at curing honeymoon type-1 diabetes in a large phase-III clinical trial and also unsuccessful in curing adult onset type-1 diabetes, but their earlier, smaller phase-II trial showed better results, so this study is testing it as a preventative. According to TrialNet research, essentially all of the people in this trial will eventually be diagnosed with type-1, but not within 5 years.  It will be interesting to try to match up the numbers from this study and TrialNet.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02387164

Combo of Diamyd, Vitamin D, and Etanercept Starts a Phase-II Trial

This trial will test a combination of Diamyd, Vitamin D, and Etanercept as a cure for type-1 diabetes.
The trial will enroll 20 honeymooning children (ages 8 to 18), all of whom will get the treatment. There will be no control group.  People will be followed for 2 1/2 years, checking for C-peptide (natural insulin generation), A1c, and insulin, plus a bunch of safety measures and immunological measures.  This trial is expected to finish in November-2018, but that will only happen if they are fully enrolled by May-2016, which is coming up quickly!

The hope for this trial is that Diamyd will stop or lower the autoimmune attack, Etanercept will lower inflammation and stop the immediate loss of beta cells, and Vitamin D will do some unspecified good (based on the fact that countries closer to the equator have more sunlight so more Vitamin D and less type-1 diabetes).

They are recruiting people all over Sweden:
Eskilstuna Hospital -- Eskilstuna, Sweden -- Contact: Ulf Söderström, MD      
Helsingborg Hospital -- Helsingborg, Sweden -- Contact: Anna-Karin Albin, MD      
Linköping University Hospital -- Linköping, Sweden -- Contact: Johnny Ludvigsson, MD      
Lund University Hospital -- Lund, Sweden -- Contact: Annelie Carlsson, MD      
Skåne University Hospital, UMAS -- Malmö, Sweden -- Contact: Tore Vigård, MD      
Sachsska, Södersjukhuset -- Stockholm, Sweden -- Contact: Björn Rathsman, MD      
Uddevalla Hospital -- Uddevalla, Sweden -- Contact: Ragnar Hanås, MD      
Västerås Hospital -- Västerås, Sweden -- Contact: Carl-Göran Arvidsson, MD      
Örebro University Hospital -- Örebro, Sweden -- Contact: Stefan Särblad, MD

Discussion: Diamyd has been tested in much larger trials, and has not been found effective.  Vitamin D has not yet been tested in an intervention trial (and the news is mixed from population studies), but Etanercept did have one successful phase-I trial, but it did not (by itself) rise to the level of a cure. I've blogged about all these separate treatments, but this is the first study I know of which combines them:
http://cureresearch4type1diabetes.blogspot.com/search/label/Diamyd
http://cureresearch4type1diabetes.blogspot.com/search/label/Vitamin%20D
http://cureresearch4type1diabetes.blogspot.com/search/label/Etanercept

Don't mix this research up with the DIABGAD trial (also done by Dr. Johnny Ludvigsson), which combined Diamyd, Vitamin D, and Ibuprofen.  Although the two projects are similar in that they are both Diamyd plus Vitamin D and an anti-inflammatory.  Ibuprofen and Etanercept are both anti-inflammatories, although they use different mechanisms: Ibuprofen is a COX inhibitor, while Etanercept is an TNF inhibitor.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02464033

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, March 20, 2016

LCT Update


LCT gave a presentation in late 2015 with an update on their "Diabecell" encapsulated cell technology. They have been testing this in people for more than 10 years, and you can see my previous blogging on them here:
http://cureresearch4type1diabetes.blogspot.com/search/label/LCT
The following blog posting covers LCT's history up until about 2008:
http://cureresearch4type1diabetes.blogspot.com/2008/12/lcts-research.html

LCT uses pig beta cells encapsulated in a proprietary coating, so patients do not need a lifetime of anti rejection drugs.

The new information is from eight patients in a phase-II trial who were followed for about 2.5 years. The trial was done in Argentina.  All the patients got two transplants.  The first group got a medium dose, and the second group got twice as much.  The results are still being analyzed, but the basic results seem to be:
  • A1c before the transplant was between 8.5 and 9.5, and afterwards was around 7.5 (for the lower dose group) and 6.5 (for the high dose group).
  • At the same time, insulin dose dropped about 10% in the lower dose group, and 25% in the higher dose group.
  • They presented data on fewer "unaware lows" and estimates of how much insulin the transplanted beta cells were generating.  
Discussion

I think that these are some of the best results I've seen for encapsulated beta cells, but it is still hard for me to get excited about them.  Earlier on, I was hopeful that they could just transplant more cells and get better results, but that does not appear to be happening.  Specifically:
  • A phase-I trial reported in 2008 that overall insulin usage dropped 24%, and reported two patients went insulin free, one for weeks and the other for months.
  • A phase-II trial reported in 2010 that overall insulin usage dropped 30%, but no reports of people going insulin free.
  • A phase-II trial reported in 2013 that overall insulin usage dropped 20%, and no reports of going insulin free.
  • A phase-II trial reported in 2015 that overall insulin usage dropped 10% and 25% (in different groups), and no reports of going insulin free.
I find this lack of progress to be disheartening.  It does not feel like they have "cracked the code" to an encapsulated beta cell cure.  At least not so far.

It will be interesting to see how LCT's Diabecell results compare to Viacyte's VC-01 results.  Both companies are working on encapsulated beta cell cures, so a head-to-head comparison makes sense when Viacyte's phase-I (40 person) results come out in 2017.  Hopefully LCT will have results from a similar number of people by then as well.  

Press release and presentation: http://www.asx.com.au/asxpdf/20151116/pdf/433073gv8cc3wx.pdf
This presentation contains a lot of data from several different clinical trials and case studies.
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT01739829

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.

Monday, February 29, 2016

Results from a Phase-II Dual Stem Cell Trial

Back in 2011, when this clinical trial was registered, I was not careful about blogging on all the new research.  Somehow I completely missed this study. So this is my first blog posting on this research.

The Clinical Trial

This trial was testing the impact of giving two different stem cell treatments at the same time.   The people in this trial had long established type-1 diabetes.   No long term immunosuppression was used. The study was randomized and controlled, but was not blinded. The researchers and the patients both knew who was getting the treatment and who was not.  A total of 21 people were treated and they were compared to 21 people not treated.  This paper reports on data gathered for a year after treatment.

The people were all adults, and had been diagnosed (on average) for 7 to 10 years.  Everyone had type-1 diabetes for at least 2 years when the trial started.  The clinical trial record describes it as phase-I / II, but the paper calls it a "pilot trial".  Based on size I'm calling it a phase-I trial.  But it's large for a phase-I trial.

The treated people were given two types of stem cells:
  • Stem cells harvested from the umbilical cord.  Everyone got stem cells from the same umbilical cord.  These are called "umbilical cord mesenchymal stromal cells" (UC-MSCs).
  • Stem cells "self donated" from the patient's own bone marrow.  These are called "autologous bone marrow mononuclear cells" (aBM-MNC).
The Results

The following two graphs include the most important results, from my point of view.  The F graph shows fasting c-peptide levels. The A graph shows c-peptide levels 3 hours after a meal.  In both cases, higher numbers are better.  C-peptide is generated when the body produces it's own insulin, so these graphs show the body generating about twice as much insulin in two different situations.

In addition, they measured A1c and insulin usage, plus some psychological measurements of happiness and number of low BG instances.

Discussion

The results here are much stronger than the positive results that I've seen in other trials, and the fact that these results are seen in long established type-1 diabetics makes them all the stronger.  The treated patients generated about twice as much C-peptide at the end of the trial as at the beginning. For an oversimplified comparison to other clinical trials done on long established type-1 diabetics:
  • This study:  100% more C-peptide
  • Stem Cell Educator: very roughly 100% more C-peptide
  • TOL-3021: 28% more C-peptide
  • BCG: 22% more C-peptide
It's important to remember that since all of these people were established type-1 diabetics, they were generating very little C-peptide of their own to start with, so twice a small amount is still a small amount.

The treated group's insulin usage dropped about 30% (while their A1c levels dropped also!).   You could argue that these researchers are 30% of the way to a cure, although that does oversimplify things.  Again, an oversimplified comparison to other clinical trials done on long established type-1 diabetics:
  • This study: 30% less insulin
  • Stem Cell Educator: 25% or 38% less insulin
  • TOL-3021: not measured.
  • BCG: not measured.
All of this is good news, and similar to Stem Cell Educator results, which (up until now) have been the absolute best results seen in long established type-1 diabetics.

Conference Abstract:
http://conference.idf.org/IDF2015/CM.NET.WebUI/CM.NET.WEBUI.SCPR2/SCPRfunctiondetail.aspx?confID=05000000-0000-0000-0000-000000000003&sesID=05000000-0000-0000-0000-000000001276&absID=07000000-0000-0000-0000-000000008843
Paper Abstract: http://care.diabetesjournals.org/content/early/2015/11/29/dc15-0171.abstract
Full Paper: http://care.diabetesjournals.org/content/early/2015/11/29/dc15-0171.full.pdf
Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT01374854


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.

Wednesday, February 17, 2016

Alefacept Reports on Phase-II Results


Alefacept is a drug that has been used to treat the skin condition, psoriasis. Psoriasis is generally considered to be an autoimmune disease, similar to type-1 diabetes, but with the body attacking it's own skin cells, rather than it's own beta cells. So trying a drug already approved for Psoriasis on type-1 diabetes seemed like a reasonable thing to do, and these researchers did it. You can read my previous blogging here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Alefacept

This was a honeymoon trial. 33 people got the drug and were compared to 16 who did not. The treated group got a dose a week for 12 weeks, then a 12 week break, and then weekly doses for 12 more weeks.  This publication is the two year follow up; they have already published a one year follow up.  The graphs below summarize the main findings.



For me the "A" and "C" graphs are the important ones.  The "A" graph (upper left) shows that untreated people's C-peptide levels did not drop in the first year, and even in the second year,they dropped less than the placebo group.  Remember that generation of C-peptide measures how much insulin the body is naturally producing, so more is better.  The "C" graph (lower left) shows that untreated people used about 30% more insulin after two years, which is also a good result, especially when graph B shows that both groups had the same A1c numbers.


Discussion

Cure Results
My reaction to this is the same "boilerplate" reaction that I've had recently to other honeymoon research where the untreated group got worse, and and the treated group held steady, so at the end of the study, there was a statistically significant difference between the two:

I think I was much more excited about them in the past.  Part of my lack of excitement now is that the treatments with these results that I saw a few years ago have not progressed. They don't give better results in more recent studies.  That might be because the research is taking longer than expected, or it might be that getting a small result is much easier than getting a useful (to patients) result.  But in any case: I haven't seen forward progress in other treatments with similar initial results, so I've become less excited about these kinds of results, in general.

So in general, these results go in my "good start, but more is needed" category of results.
I like them; I think they represent potential, but I'm not excited by them.

Treatment Results
If you look at chart D above you can see that the people who took Alefacept had half as many low blood glucose events, as those who were not treated, and this was statistically significant.  From a treatment point of view, this is an interesting finding.

Not Moving Forward
Unfortunately, in a certain sense, none of this matters.  The company that made Alefacept stopped production in 2011, so it has not been available for years.  I don't know of any planned clinical trials with Alefacept, nor any similar fusion proteins.

COMPare:  +16/16 (100%)
Primary outcome given less prominence than secondary.           

COMPare is an experimental methodology for reporting switched or misreported results.  As my own experiment, I'm going to report on COMPare metrics for all results that I blog about in 2016.  I will explain this methodology in a blog posting in a week or two.  So the text in green should make sense then.  For now: this study has a very good COMPare score.

Discontinuation: https://www.psoriasis.org/media/press-releases/amevive-alefacept-voluntarily-discontinued-us
Press Release: http://www.eurekalert.org/pub_releases/2015-07/bri-apb071615.php
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/26193635
Full Paper: http://www.jci.org/articles/view/81722


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 31, 2016

Research In The News (January)

These are a couple of old news items that I'm catching up with.

Kamada Changes Phase-II Alpha-1 Antitrypsin (AAT) Study
Kamada has announced a major change to their Phase-II trial of AAT.  Although there are several AAT trials underway, this is the farthest along, and the largest.  You can read my previous blogging here:
http://cureresearch4type1diabetes.blogspot.com/search/label/AAT

AAT is an anti-inflammatory / immunomodulatory drug, which the body makes naturally, and which is already FDA approved for people who have a rare condition where they don't make enough of it on their own. Using AAT to treat type-1 diabetes is based on the idea that one of AAT's effects (lowering inflammation, immune modulation, or wound healing) can cure/prevent/treat the disease.

Prior to the change: The trial would collect data on 180+ people for two years.  The first half would be double blind, but at the half way point (90 people and 1 year) the data would be analysed unblinded, to check for safety and do futility analysis.  Results from the completed trial probably would not be published until 2019, maybe longer, depending on how long recruiting took.

After the change: The 60 patients enrolled by the end of 2015 will be followed for one year, and then results will be published, probably in 2017.

What does this mean?  It means we will see results from this trial quicker than originally planned, but it also means there will be less data.  Is this good or bad?  I thought about this question quite a bit, and there are two ways to answer that question.  From my point of view, this is good, because it will mean that we have results faster.  It is true they will not be as definitive, but my gut reaction is that if there is clear good news, then it will show up even in a 60 person study.  The only danger is that with 60 people, the results will not be clear.  But my belief is that if they are not clear with 60 people, then the answer is "no".  I think it's unlikely that a drug which is so-so with 60 people is going to show as a cure with 120 or 180 people.

Of course, another question is, do these changes mean that Kamada thinks the drug is working, or do they mean Kamada thinks the drug is failing?  My answer to that is "I don't know".  The trial is double blind, so officially Kamada should not know anything about the outcome.  Even if they did, good results could motivate them to speed things up, but so could bad results (to lower expenses). I don't see a good way to "read meaning" into a shorter trial.

In the non-scientific world, it could mean that the company is running low on money, or that it is harder than expected to recruit people for the study.  As originally designed, this study would require 180+ honeymooners to enroll in one country: Israel.  That's a lot of fish to pull out of a small fishing hole.  (My very "back of the envelope" calculations suggest that about 350 people are diagnosed with type-1 in Israel per year, so you'd need to get about half of them to enroll.  If you recruited for two years then "only" 1/4 of everyone diagnosed in the entire country would need to sign up. That is hard.)

Press release: http://www.businesswire.com/news/home/20151202005422/en/Kamada-Update-Alpha-1-Antitrypsin-Development-Newly-Diagnosed

About the inhaled version (being tested for a different disease):
AAT is already approved as an intravenous injection for treating AAT deficiency.  This is not the same type of injection as insulin; it generally requires a trip to a clinic for treatment.  However, Kamada is also testing an inhaled form to treat AAT deficiency.  If this is approved, and if AAT is found to work for type-1 diabetes, then having different forms will be convenient.  They have finished enrolling their inhaled AAT study, which is a good milestone:
http://www.businesswire.com/news/home/20151208005129/en/Kamada-Completes-Enrollment-U.S.-Phase-2-Study



Albiglutide Starts a Phase-II Trial

Albiglutide (tradenames Eperzan and Tanzeum) was approved in both the USA and the EU in 2014. It is a Byetta-like drug, designed to be used once per week, so the dosing is more like Victoza.  Like both of those drugs, Albiglutide is part of a large class of drugs called GLP-1 inhibitors.  All of these drugs are commonly used by people with type-2 diabetes.  It is not clear to me why it would cure type-1, but GlaxoSmithKline is testing it in type-1 diabetics, and it might improve A1c numbers.

This trial involves about 68 people, of whom 51 will get the drug and 17 will be in the placebo group.

The trial will take about 17 months per person.  Two months of pre-treatment screening, 12 months of treatment, and three months of post treatment monitoring.  They started in November 2014 and hope to finish by December 2016.

They will be recruiting people at about 29 different sites, in five different countries (France, UK, Germany, Italy, and Spain).  See the complete list in the clinical trial record below.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02284009
Wikipedia: http://en.wikipedia.org/wiki/Albiglutide

My plan is to follow this study, and see if this drug turns out to be a promising treatment, a promising cure, or neither.  If it doesn't show cure potential, I will stop covering it.

If this drug does prove useful in curing (or even treating) type-1 diabetes, there are several other widely available drugs in the same category which could be tested (some are available for off label use immediately). In addition to Victoza and Byetta there are: Bydureon, Dulaglutide, and Lixisenatide.

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.