Wednesday, April 25, 2012

Possible Cures for Type-1 in the News (April-2012)



Kamada Announces Something On Their Phase-I Trial of AAT

I know the headline is vague, but the news is vague.  This is what they said:
The trial found stabilization and even improvement in diabetes measures of the patients, and a high safety profile in the 20 children and adolescents tested.
Diabetes measures in most of the patients showed stabilization and even slight improvement.
Notice that no actual numbers are provided, and not even what they were measuring!  In my experience, this is a new high-mark in terms of vagueness.   However the safety information is nice.  AAT is already approved for another use, so it has some assumption of safety.  But, that other use is a rare one, so more safety information is important.  Here is a piece of solid news, which was also included, and which I'm happy to hear:
The company expects to publish the final report on the clinical trial in late 2012.

AAT is an anti-inflammatory drug, which the body makes naturally, and which is already FDA approved for people who have a rare condition where a person don't make enough of it on their own. In addition to this trial, there are 2 or 3 other clinical trials underway testing AAT on type-1 diabetes. And this is part of a more general anti-inflammation technique to try to cure type-1 diabetes. Most researchers believe that inflammation is a result of the body's immune attack on it's own cells. That is, the underlying immune problem causes inflammation and also causes beta cells to die (which causes the symptoms of type-1 diabetes). However, some researchers believe that the underlying immune problem causes inflammation, and that this inflammation kills the beta cells, which then causes the symptoms of type-1. The difference is that, in the second model, if you stop the inflammation you can stop the symptoms of type-1 diabetes (the high BG numbers and the low C-peptide numbers). That is a big difference. But this second model is still a minority opinion.

Previous blogging on AAT: http://cureresearch4type1diabetes.blogspot.com/search/label/AAT

Diamedica Plans to Start a Human Trial of DM-199 


Diamedica has talked about starting a human trial of their DM-199 drug in the past, but I've not blogged about it, because I didn't see any activity.  However, in their most recent press release (URL below) they do say that they have submitted the IND (Investigative New Drug) paperwork.  This is the first step to starting a clinical trial.  So even though I have not seen anything on the FDA's Clinical Trials web site, I'll provide some background here.

This quote is from their web site:

DM-199 Type 1 diabetes - is a novel recombinant protein which has been found to target the three main aspects of Type 1 diabetes by increasing regulatory T cells, reducing insulitis and improving glucose control in [tissue] studies, specifically:
  • Halts autoimmune attack - significant dose dependent delay in onset of diabetes in NOD mice leading to a 12x increase in C-peptide (a primary clinical endpoint) to 5-6 nM. [Delays and reduces the onset of type-1 diabetes when given during and before the honeymoon phase.]
  • Proliferates beta cells - 1,277% increase in insulin producing beta cells, restoration of blood insulin to near normal levels. [Treated mice generate a lot more insulin of their own, almost as much as non-diabetic mice.]
  • Improves glucose control - 291% increase in peak glucose infusion rate ... and a 1.6% improvement in HbA1C (measure of blood glucose levels) in a ZDF rat model. [ZDR rats are an animal model of type-2 diabetes. Photo below.  Obviously, A 1.6 improvement in HbA1C would be a great treatment, even if not a cure, if we can do the same in type-1.]
  • Human clinical trial - proof of concept - in a Phase 2a clinical trial with first generation DM-99, glucose levels were lowered by up to 48% after a meal [I have not been able to find a description for this study, or the results, anywhere. I'm not sure if this was done on type-1 or type-2 diabetics.]


Press release: http://www.diamedica.com/news/diamedica-provides-update-dm-199-dm-204-and-appoints-mr-ed-rady-senior-consultant-licensing-par

More info on ZDR rats: http://www.criver.com/en-us/prodserv/bytype/resmodover/resmod/pages/zdfrat.aspx


Background

DM-199 is recombinant protein, a new and improved version of DM-99. DiaMedica has previously done research in animals on DM-99, and they believe that all those good results will also apply to DM-199. It looks to me that all future research will be in DM-199, but they will continue to cite older research on DM-99, to support DM-199 safety and effectiveness.

Here is a newspaper report and a press release based on good results (in animals) with DM-99:
http://diamedica.com/news/diamedica-announces-positive-final-results-type-1-diabetes-study
http://www.marketwatch.com/story/diamedica-announces-positive-final-results-in-type-1-diabetes-study-2010-10-14-114750?reflink=MW_news_stmp

And here is some literature by the company itself:
http://www.diamedica.com/sites/default/files/DiaMedica-may-hold-Holy-Grail-for-diabetes-biotuesday-Feb-6-2011.pdf

This drug is currently in phase-II trials for type-2 diabetes, but has not yet been tested in people for type-1 diabetes. The animals studies are clearly aimed at type-1 diabetes, and they claim both beta cell regeneration and lowering the autoimmune attack.


Victoza (Liraglutide) Starts Another Phase-II (but as a treatment)


Liraglutide is a GLP-1 analog which is sold under the name Victoza and is approved for use in type-2 diabetics in the USA, the EU, and elsewhere. (The most common GLP-1 analog is Byetta.) In addition, there is active research to see if this drug will help type-1 diabetics. My current option is that this research is aimed at providing a better treatment, rather than a cure for type-1. However, this posting gives a summary on the research, since there is quite a bit going on.

Here are the studies ongoing:
NCT01206101 phase-II 50 people March 2012 - Jan 2015 Novo Nordisk
NCT01536665 phase-II 42 people Feb 2012 - Sept. 2012 Novo Nordisk
NCT00993720 phase-II 30 people Oct 2009 - Oct 2010 Hvidovre University Hospital
NCT01299012 phase-I 10 people Oct 2010 - June 2011 University at Buffalo

But what do we know right now?

Here is the results section from the study:
In all fourteen patients, mean fasting and mean weekly glucose concentrations decreased significantly after one week from [an average of] 130 to 110 and from [an average of] 137.5 to 115 respectively. Glycemic excursions also improved significantly at one week. The mean S.D. of glucose concentrations decreased from 56±10 to 26±6 mg/dl (p<0.01) and the CV decreased from 39.6±10 to 22.6±7 (p<0.01). There was a concomitant fall in the basal insulin from 24.5±6 units to 16.5± 6 units (p<0.01) and of bolus insulin from 22.5±4 units to 15.5± 4 units (p<0.01).
From my point of view, the results are underwhelming.  People who already have great control (BGs of 130?  that would be great!) dropped about 20 points.  I'm not sure taking a second drug (a once a week injection) to go down 20 points is worth it.   Now, if the impact is actually 15%, that's a little different, but it's still not a big result (in my opinion).  Now the use of insulin dropped about 30%, and that is a pretty big result.

Abstract:  http://www.eje-online.org/content/early/2011/06/06/EJE-11-0330.abstract

Wikipedia: http://en.wikipedia.org/wiki/Liraglutide
News: http://medicine.buffalo.edu/news_and_events/news.host.html/content/shared/smbs/news/2012/02/dandona-ada-liraglutide-120.detail.html

Public Citizen has officially petitioned the US FDA to remove Victoza from the market.  I would love to write up a full blog on why they think it's dangerous, and why the FDA thinks it's safe, and the trade offs and assumptions involved.  It is a great "teachable moment."  But I doubt I'll have time.  For now, Victoza is on the market.

Discussion of Phases

You might notice that of the four studies going on right now, three are phase-II and one is a phase-I, but that the phase-I study actually started after one of the phase-II studies. Furthermore, Victoza was approved for use in the USA in January 2010, so at least two of the studies could have been phase-IV ("post approval studies").  So why weren't they?  I'm not sure the official answer, but my unofficial answer is simple: researchers have great leeway to call a study phase-I, II, III, or IV as they wish.  Different researchers choose different phase numbers to try to manage expectations.

Discussion of Money

One of the interesting things about this research, was the cost.  The press release from the University of Buffalo says that the ADA is putting in about $600,000 and the study will enroll about 45 people.   For comparison, Dr. Faustman's BCG trial, cost about $10,000,000 and dosed 3 people (according to the published information).   So that means that Dr. Faustman's trial cost over 200 times as much (if compared on a dosed patient by dosed patient basis).  Remember that in both cases, the drug being used was already approved for use for another disease, and in both cases, it has already been used in type-1 clinical trials.

Can Propecia / Finasteride Cause Type-1 Diabetes?

I was recently asked if Propecia / Finasteride could cause or trigger type-1 diabetes.
Propecia is a trade name for Finasteride, and is commonly used for male-pattern baldness.  It changes the way the body processes testosterone (a "male" hormone).

I had not heard of any connection between them, and searched my "usual sources" and did not find any evidence that the drug could cause, or could trigger, type-1 diabetes.  It is sometimes given at the same time that adults are often diagnosed with type-2 diabetes, but that has nothing to do with type-1 diabetes, and there is no evidence of causality or association.  Diabetes is not listed as a possible adverse effect in drug's "package insert".  And I could not find any case reports of a link, nor any research studies showing a link in people.  I didn't check in animals.

I was able to find an FDA briefing document on Finasteride given for a kind of cancer.  This dose was five times larger than the dose for hair loss, and in a very large study (20,000 people total), the levels for "Diabetes Mellitus" for both treated and placebo groups were the same (but no separation between type-1 and type-2, unfortunately).  So again: no connection.

Wikipedia: http://en.wikipedia.org/wiki/Propecia
Side Effects: http://www.drugs.com/sfx/propecia-side-effects.html

Health Blogger Could Be Jailed for Giving Health Advice While Unlicensed
Read all about it here:
http://www.theatlantic.com/technology/archive/2012/04/health-blogger-could-be-jailed-for-giving-health-advice-while-unlicensed/256288/
http://www.carolinajournal.com/exclusives/display_exclusive.html?id=8992

Note that this guy describes himself as a type-1 diabetic and so the reporter for "The Atlantic" does as well, but others refer to him as a type-2.  He was diagnosed in middle age, he was on Actos prior to dx (which suggests that his doctor thought he was type-2) and there is no mention of antibody tests.  On the other hand he had a BG of 700+ when diagnosed. Anyway, the gist of his blog is that carbs are bad and that nutritionists are wrong for suggesting that people eat more of them.  That's a whole can of worms in itself, but the reason I'm posting this is much more because of the "blogger might be charged with a misdemeanor crime" aspect of it, then exactly what the blogger is saying.


Notes on this Blog

I have two pieces of news about this blog:

First, I've got a large non-blog event happening in my life right now, so I'm expecting fewer blog postings in the next six months or so, compared to the number in the past. In the past, I often did 2-3 per month, but I'm expecting 1 or 2 per month, and maybe only 1 every two months for the next 6 months or so.

Second, I'm planning on turning off anonymous commenting on my blog in the next few weeks. If you just read email or by posts on internet forums, then this will not effect you, but if you read my blog directly (URL is at the bottom of this posting), then you will no longer be able to comment anonymously there.

I'm not making this change because I've gotten bad anonymous comments. If you look at my comments you can see anonymous ones that are good and that are bad. The same is true of the named, non-anonymous ones. I'm making this change because I have come to believe that anonymous comments are bad for the internet and bad for society (as the two merge). People who would never be vandals out in the open, might, if they think they are anonymous. So although my blog doesn't see a lot of that, I'm turning it off anyway. It is a statement that I think anonymity on the net is not a good thing. If you are not willing to put your name behind it, you shouldn't do it. Fake names are bad enough, but total anonymity is worse.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement. 
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

6 comments:

miki steiner said...

Hi Joshua,
Thank you for an important blog. I started reading it several months ago when my son was diagnosed with T1D. I often talk to my son's doctors about the clinical trials you discuss and get more information. BTW my son is in the KAMADA clinical trial. Thanks you, Michal

Shiyam said...

Hi Joshua, Thanks for your T1 research updates. Will you please blog us your opinion on the below news article:

http://www.freepatentsonline.com/5886029.html

Joshua Levy said...

Shiyam: I don't have time to do full research and a full report, but here are some very quick thoughts:

1. I don't care about patents. Patents don't mean it worked. They don't mean anything, really, except that the person wants to make money off an idea. But I track results, not desires. And a patent is a mark of desire (desire to make money) not the mark of success.

2. It looks to me like this patent was issued in 1997 or 1999. If so, that means the idea is a failure. Why? Because it has been over 13 years since the patent was issues and no one has been cured. If someone had been cured, we all would have heard of it. It would be huge news. The patent holder would be rich. But no news means it has failed. 13 years is more than enough time for animal research to become human research. But it has not happened. Sign of failure.

3. The results mentioned are all in rats. This has two problems. First, I don't put much weight in animal results. Second, the best animals are NOD mice. Typically I only track research done in people, specifically because animal cures so rarely pan out.

Joshua Levy

diabetes said...
This comment has been removed by a blog administrator.
Symptoms of diabetes said...

Great info! Thank you!

lukesdday said...

Thanks for digging into AAT - have been seeing vaguely optimistic articles about it.
And best of luck with the major event! Sounds ominous - hope it's not.