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.

Etanercept (ENBREL) Completes a phase-I Trial in New Onset Type 1 Diabetes

This is a "new to me" phase-I study of Etanercept (ENBREL) , which just published it's results last week: http://www.clinicaltrials.gov/ct2/show/NCT00730392 and you can read the abstract of the results here: http://www.ncbi.nlm.nih.gov/pubmed/19366957

This is "give a drug quickly after diagnosis of type-1 diabetes to preserve some beta cell function" type treatment. The drug, Etanercept (ENBREL), is a product of Amgen, who sponsored the research, and is US FDA approved for several self-immunity related conditions including Rheumatoid Arthritis and Psoriasis. You can read more about it here: http://en.wikipedia.org/wiki/Etanercept
Note that although the name is similar, this not Efalizumab which I reported on recently.

The results were solidly good, after 24 weeks:

• HbA1c was lower in the etanercept (5.91 +/- 0.5%) compared to placebo group (6.98 +/- 1.2%)
• The percent change in c-peptide AUC showed a 39% increase in the etanercept group and a 20% decrease in the placebo group
• Insulin dose decreased 18% in the etanercept group compared to 23% increase in the placebo group

So the result in plain English is that the treated patients had, on average, A1C measures 1 lower than the non-treated group. They were generating about 60% more of their own insulin (as measured by c-peptide), and used about 40% less insulin. Overall, very nice results for a phase-I trial.

And before you ask: I don't know if they are planning a phase-II study, and I don't know if this will work on non-honeymooners. I did find two interesting papers that reported that people who had type-2 diabetes and who were treated with Etanercept for rheumatoid arthritis had large drops in their BG numbers. How that maps to people with established type-1 diabetes, I'm not sure. Lastly, although this drug is approved by the US FDA different people may well have different opinions about it's safety. It does carry a black-box warning due to higher rates of infection. (Black-box warnings are the strongest warnings that the US FDA requires on prescription medicines to warn people of potential dangers.)

TNF: Friend or Foe?

This research brings up an interesting conflict in research to cure type-1 diabetes: is TNF a friend or a foe? TNF (tumor necrosis factor) also called TNF-alpha is a protein that kills tumors. It also kills other cells in the body. Several treatments currently in clinical trials for various self-immune diseases are based on interfering with the TNF receptor, and Etanercept is one of these. On the other hand, Faustman holds the opposite theory. Her treatment is based on increasing levels of TNF. The drugs she used on NOD mice (CFA), and in people (BCG) are both expected to raise the level of TNF. Now these two beliefs are not exactly opposite, because Etanercept blocks a TNF receptor, while BCG (and CFA) stimulate the production of TNF itself. However, it is unclear how both Etanercept and BCG can both have a good impact on type-1 diabetes since they effect TNF in opposite ways. If one helps cure type-1 diabetes, the other should make it worse, and visa-versa (at least at first impression). So it is possible to interpret the success of Etanercept as bad news for Faustman. Of course it is also possible that the two work in completely different ways, and TNF is a "red herring" in terms of curing type-1 diabetes.

Here is a link to some discussion of Faustman and TNF:
http://www.faustmanlab.org/docs/mediacoverage/MedPageToday_8-25-08.pdf

Joshua Levy