Update On AAT

I'm about four months behind on reporting on AAT (Alpha 1-antitrypsin)
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. Using AAT to treat type-1 diabetes is based on the idea that treating inflammation can cure/prevent/treat the disease.

Here is a link to my previous blogging:
http://cureresearch4type1diabetes.blogspot.com/search/label/AAT

Recent Clinical Trial Results

Results of a phase-I clinical trial of AAT were recently published.  This trial included 12 people and had no control group (so was not blinded nor was it randomised).  The 12 people were recently diagnosed, and when the study started, were generating some of their own insulin.  The abstract is included (in full) below.  My summary is that the study found several changes to immune cells, when comparing the situation before and after dosing with AAT.  However, no differences were reported in the abstract for A1c numbers or amount of injected insulin.   They did report that C-peptide generation went up or stayed the same for 4 patients; the implication is that it dropped for 8 patients.  To me, that seems pretty normal for honeymoon diabetics, so the effects for C-peptide seem to be very small (or nonexistent).  Because there was no comparison group, it's hard to tell if the treatment improved C-peptide generation or not.

My summary of these results are that they might be important to immunologists who are trying to learn more about curing type-1, but it's not the kind of result that's directly applicable to curing type-1 diabetes.  Particularly: there is no mention of anyone going insulin free for any length of time.  Remember that.  In terms of "clinical results" (ie. the kind of results that would matter to a person with type-1 diabetes: C-peptide, A1c, and insulin usage), the results are either tiny, tiny, or nonexistent.

This result is similar to previously released results from other studies, showing very modest results.  I've blogged about those before, at the link above.

Recent Publicity from Anecdotal Results

Additionally, there have been two "anecdotal reports" on AAT effectiveness, both sourced from Dr. Eli Lewis, who is one of the researchers involved.  One was several months ago, the other just a month or two ago.  I call these "anecdotal" because they are not reported in the scientific literature and have not been peer reviewed.  In general, the media reports far less data than a medical journal would report.  Obviously, none of them can be used to get FDA approval.

The Oct 2013 Report

The first anecdotal report was in the news in October 2013.  It reported on a family where the son was diagnosed with type-1 diabetes.   Six month later, the daughter was diagnosed with type-1 diabetes, but the family contacted Dr. Lewis and was able (with some difficulty) to get an off-label prescription for AAT.  The daughter was given AAT, and was cured of type-1 diabetes.   The daughter did not use insulin for years afterward.  Just recently, after about 3 years without using insulin, the daughter has started to use some, but at an extremely low level.

Obviously, that sounds wonderful; what every newly diagnosed type-1 diabetes patient wants to hear.  The father believes that the AAT helped delay the time when insulin had to be used.

The Feb 2014 Report

Later, in February 2014, Dr. Lewis was quoted in news articles as follows:

Following treatment of eight to 12 weeks with AAT, in several patients, it allowed proper glucose levels to be controlled without the need for any insulin injections for more than two years

We believe we will see similar results in a number of U.S.patients who recently received this treatment outside the trials within several months of diagnosis and are still completely insulin free.

Again: sounds like exactly what a honeymoon cure would be.

You may ask, if this drug is in phase-I trials, how can people in the US get it, outside of the clinical trial?  The answer is that those people are being treated "off label".  Because AAT is approved for one illness (alpha 1-antitrypsin deficiency) a doctor can prescribe it for any illness, even if it is not specifically approved for those other illnesses.  This is a quirk of the USA's drug regulations, but it is an important one.

Discussion

I suspect that we might be seeing a conflict between two different ways of diagnosing type-1 diabetes.  The historical method, which I'll call "method A" is that a child starts peeing a lot, and/or drinking a lot, and/or losing weight (often while being hungry all the time), and generally feeling awful.  The doctor checks BG, which is very high, and the person starts using insulin.  Things get much better relatively quickly.  However, there is another way of being diagnosed, which I'll call "method B".  In method B, the child is showing relatively minor symptoms, or maybe none at all.  But they are given a blood sugar test after a meal, and their BG numbers are over 200, which means they have diabetes.  It used to be that type-1 was diagnosed using method A only.  But now, thanks to TrialNet, and heightened awareness, a few people are diagnosed with method B.    But people diagnosed with method B may not need to start using insulin right then.  We don't know a lot about the natural disease progression in people who are diagnosed via method B.  It may be normal (or at least common) for them to go months or years without insulin even without AAT treatment.

Because I've spoken with the father of the child in the first anecdotal report, I know that child was diagnosed using method B.  She did not use insulin before AAT treatment nor did she need it for years afterwards.  But the key question is: was that because she got the AAT, or was that the normal progression of someone diagnosed with method B?

I don't know if that also happened with the second anecdotal report.  One of the problems with scientific results reported via researcher's quotes in the popular media, is that we don't know the most basic information about what was going on.  In this  case: how were the people diagnosed with type-1 diabetes, and were any of them using insulin before AAT treatment?

The difference between these results (the clinical trials vs. the anecdotal results) is very troubling to me.  Going insulin free for years is huge news.  But it's not mentioned in the journal article.  Why not?  If those results were seen in the people in the clinical trials, they would certainly be in the paper.  But if they were not seen in the clinical trial patients, then why did the non-trial patients do so much better than the clinical trial patients?

For me, there's no question which source of information to weigh more heavily, right now.  It's got to be the clinical trial results.  Those are the results where we know more details.  Those are the results that were peer reviewed.  Those are the results that the research community will examine.  And, those are the results that the FDA will eventually use to approve new drugs, or (in the case of AAT) new uses for existing drugs.  Unfortunately, for AAT, the clinical trial results are much smaller than the anecdotal results.

I was able to talk with Dr. Lewis about this research, and heard him speak about it to a lay audience.  He believes that the "off label" patients had better results because their doctors could be much more flexible with the dosing.  When you're in a clinical trial, you get the dose that the trial says you get.  That's it.  However, in "off label" use, the doctor can tailor the dosing to each individual person, and how they react to the treatment.  Dr. Lewis believes that this customization of dosing resulted in the much better results he talked about.

Dr. Lewis also made two other points which bear repeating:  First is AAT's great safety profile.  It has been used on a wide variety of people, over a long time, and has a record of safety.  Second, although AAT is an anti-inflammatory, it may work differently than "classic" anti-inflammatories.  Classic inflammation works like this: some cells are damaged, and those cells and nearby cells chemically signal the immune system for help.  The immune system responds with inflammation.  This information attacks foreign and dead cells, but it also damages nearby cells (a sort of "collateral damage").    Dr. Lewis believes that AAT works by helping to save these "bystander" cells from this inflammatory damage, without lowering the entire response.  Classic anti-inflammatories lower the whole inflammation reaction.

What Next?

Kamada, the company that produces AAT is starting a phase-II/III clinical trial in Israel, which I will discuss in a future posting.  This is very good news, of course, because if those anecdotal reports mean what we hope they mean, then the data from the phase-II trial will show it.  The phase-II trial will have a placebo group, and will be much larger than the phase-I trial, so any effect as large as a cure (even a temporary one) will be obvious.

Also, there are several other AAT clinical trials already underway.  The recent publication was one of three similar studies.  So the publication of the other studies, which should happen shortly, will also be informative.

Sources

Below are links to abstracts and press releases on the clinical findings, and news articles on the anecdotal reports.  I did speak with the father of the first anecdotal report, and included some information from him.  He did review this posting to ensure that the information from him was accurate, and that he was comfortable with the amount of information I was making public.  I also emailed with Dr. Lewis, and heard him speak.   As always, all mistakes are my own.

Clinical Trial Results:
http://www.ncbi.nlm.nih.gov/pubmed/24527714
http://press.endocrine.org/doi/pdf/10.1210/jc.2013-3864

Below is the complete "Results" section of the abstract:

Results: No adverse effects were detected. AAT led to increased or unchanged levels of C-peptide responses compared to baseline in four patients. The total content of TLR4-induced cellular IL-1β in monocytes at 12 months following AAT therapy was 3-fold reduced compared to baseline (p < 0.05). Furthermore, at baseline, 82% of monocytes produced IL-1β, but at 12 months post-therapy the level decreased to 42%. Similar reductions were observed using TLR7/8 and TLR3 agonists in monocytes and mDCs. Unexpectedly, the reduction in cellular IL-1β was observed only 9 and 12 months post-treatment but not in untreated diabetics. Improved beta cell function in the four AAT-treated individuals correlated with lower frequencies of monocytes and myeloid DCs producing IL-1β compared to subjects without improvement of islet function (p < 0.04 and p < 0.02, respectively). Conclusions: We hypothesize that AAT may have a beneficial effect on T1D in recently diagnosed patients that is associated with downmodulation of IL-1β.

Researcher's Web Page:
http://www.lewislab.net/Teaching/Lewis_Lab_Friendly_Update_page.html

Oct 2013 Reports:
http://www.jweekly.com/article/full/69881/israeli-doctors-diabetes-treatment-draws-hearty-todah-rabah-from-s.f.-diplo/?fb_action_ids=10151792538577374&fb_action_types=og.recommends&fb_source=other_multiline&action_object_map=%7b%2210151792538577374%22:482058221892936%7d&action_type_map=%7b%2210151792538577374%22:%22og.recommends%22%7d&action_ref_map=%5b%5d
http://www.aabgu.org/media-center/bgu-making-a-difference/targeting-diabetes-from-the-negev.html

Feb 2014 Reports:
http://jewishbusinessnews.com/2014/02/24/first-clinical-trial-of-type-1-diabetes-treatment-has-extremely-positive-results/
http://news.xinhuanet.com/english/health/2014-02/25/c_133140280.htm

Phase-II/III Trial:
http://www.businesswire.com/news/home/20140305005510/en/Kamada-Initiates-Phase-23-Clinical-Trial-Glassia#.UzEZBfldXgc
http://clinicaltrials.gov/ct2/show/NCT02005848


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.