Sunday, November 21, 2010

Snarski Confirms Burt's Phase-I Results

First, a little background.   The "Burt" clinical trial in Brazil is one of the very few clinical trials which has actually cured people of type-1 diabetes.  I know that is a provocative statement, so let me be clear:  Some of the people treated in this trial did not need to use external insulin (yet still had reasonable A1C numbers while eating normal diets) for a long as the study ran.   Some of these people were followed for years.  This was not just a "couple of week" or even a "couple of months" event.  

But, there are important safety issues to consider with this treatment.  Basically, the treatment is to "reboot" the immune system, hobbling the immune system, and then treating it so that when it comes back, it does not attack the body's own beta cells.  There are two serious safety issues here: first, during the time the immune system is down, the patient must stay in an isolation ward in a hospital, and is subject to opportunistic infections.  Second, the act of shutting down the immune system is a big deal, and might cause problems "down the road".  Cancerous tumors are a particular worry.  Neither of these risks is completely unknown.   Very similar immune system "reboots" are used today to treat cancer, and some other autoimmune diseases and their safety is understood.  Never the less, the general level of safety is lower than other possible cures for type-1 diabetes.

So, with all that as prelude:

Snarski Confirms Burt's Phase-I Results
Second trial cures type-1 diabetes, in people, for months, but at what risk?

A Polish team has run a clinical trial very similar to Burt's, and gotten very similar results.  Since Burt's results are the best in terms of curing type-1 diabetes, this is good news indeed! 

The results from the published paper is pretty simple: 8 patients were treated, and 7 of them did not need external insulin again, for as long as they were followed.  They were followed for an average of 7 months (longest was 16 months).  The one who still required external insulin used about 10% of the dose before treatment.  In personal communication this group said that as of November 2010 they had treated 15 patients and that 11 of them had remained off insulin (median remission duration of 16 months).

This team used a protocol very similar to Burt's, although not identical.  However, the entire discussion of safety that applies to Burt applies here as well.

Some Discussion and Opinions

Because of the safety issues, I was interested in how many people volunteered for the treatment.  For this group, 19 patients were offered enrollment, and 8 accepted it.  So that means that basically 40% of the people who had the chance, considered this treatment "safe enough" to try it.  This was an adults only trial, so the people making the decision are making it for themselves (not for their children). I would assume that as this treatment becomes more common, the perceived safety would go up.

The researchers for this trial consider the chance of death from this treatment to be less than 1 in 100 (but are are not specific about how much below it is).

Encapsulated Beta Cells vs. Immune System Reboot: Head to Head Comparison

In terms of results in people, there are two approaches to type-1 diabetes which are head and shoulders above the others: Encapsulated Beta Cells (with LCT in the lead), and Immune System Reboot (Burt and Snarski).  No one else has cured type-1 diabetics for any length of time.  So here is a (slightly irreverent) head to head comparison:

Cure Rates

Encapsulated Beta Cells: less than 20% of the people go into remission for over two weeks.
Immune System Reboot:  more than 80% of the people go into remission for over two weeks.

For patients that did not go into remission, they generally used less insulin (for both treatments).  However, I think the drop was great for the reboot patients, but I don't have detailed data to support that.

Cure Duration
Encapsulated Beta Cells: averages less than 3 months.
Immune System Reboot: averages over 10 months.
Note: these are both very rough estimates!

Cure Safety

Encapsulated Beta Cells: Very safe: no known short term or long term side effects.  Out patient surgery.
Immune System Reboot: Less than 1% chance of death (but how much less?)  Also, very  small additional risk of cancers years or decades after the treatment.  Surgery and hospitalized recovery time, lasting many days.  No serious side effects seen so far.

Experience with the Cure

Encapsulated Beta Cells:  Less than 16 people, Max duration less than 2 years.
Immune System Reboot:  Over 30 people, max duration over 4 years (maybe 6 years in Brazil, I need to get updated information on that trial).
(This includes some personal communication from the Snarski group.)

Snarski Abstract:
Burt Abstract:
Another Abstract:

Dr. E Snarski was kind enough to send me a pre-print of his group's paper, and provide valuable information for this blog posting.  Of course, all mistakes here are my own.  One comment that Dr. Snarski made very specifically was that "we should not yet talk about cure - rather the word remission should be used".  I used the word "cure" in some parts of this posting, but that's me.

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. 

Tuesday, November 9, 2010

Possible Cures for Type-1 in the News (Early Nov)

Below are some updates on research into curing type-1 diabetes.   Remember that I generally only cover clinical trials: research done in people.

AAT (Alpha-1 antitrypsin) Starts A Phase-I Trial

I've blogged about AAT in the past, here:
The good news is that they (finally!) actually started their phase-I trial:
The announced that they were going to start the trial back in June, but this is the actual start of dosing for the first patient.

This 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.  You can read my general comments about all inflammation based cures:

Here is the clinical trial for "part 1" of the trial:
And here is the record for "part 2" of the trial:

Part 1 is 16 people and part 2 is 66.  Both are honeymooner's only (within 100 days of dx).  Together, they are supposed to run from Oct 2010 to Nov 2014, but I'm very hopeful that they will publish their part 1 results sooner than that.  They need to do part 1, before they start part 2.  However, the treatment phase will last at least 2 months, and then each patient will be followed for 2 years, so this is not going to be a quick result.  Part 1 is currently only recruiting in Emory University, Atlanta, Georgia, USA.   Contact: Stephanie Meisner     404-785-8136  However, they hope to recruit in many other places soon, including Barbara Davis Center; University of Colorado, Aurora, Colorado, USA, and (the only California location) University of California San Diego, La Jolla, California, USA.  Based on Dr. Lewis's comments (see below) they might already be recruiting at Barbara Davis Center.

Because AAT is already approved for use in people, it could start out at as a phase-II trial or even a phase-IV trial.  Both parts of this trial are labeled "phase-II" but since AAT has never been used on type-1 diabetics before, and part 1 only has 16 people, I prefer to think of part 1 as a phase-I clinical trial, and part 2 as phase-II.

In addition to all that, thanks to a anonymous but alert reader over at CWD, I can include a link to the following web with discussion by Dr. Lewis, who is deeply involved in AAT research:
Be sure to read both page 1 and page 2, and most especially Dr. Lewis's answers to the many comments.  Also remember that he is covering both type-1 and type-2 in different parts of his text and helping transplants (rather than directly curing type-1) in some parts, so you need to understand the context of the question to understand his answer.
He is really positive about this.  Of course, everyone should be positive about their own research.  :-)

I would be particularly careful about his answer to question 9.  Especially during the honeymoon phase, you might get that kind of result from luck.  It's important to remember that's just one personal testimonial.  It is the kind of thing that motivates a clinical trial, but not a replacement for a clinical trial.  Finally, if anyone who does medical research professionally has any thoughts on his answer to question 13, I'd be interested in your opinions; especially the "AAT activity" part.

LCT Update

Basic summary is that they have now dosed 10 out of the planned 12 person clinical trial in New Zealand. (LCT refers to this a phase-II trial, and it is their second one, but it's also much smaller than other phase-II studies: 12 people, instead of the 50+ people that is common.)  The longest follow up was for one year.  The first 4 people got 10ku/kg and have been followed for 30 or more weeks, the second group of 4  got 15ku/kg and have been followed for 8 or more weeks, and the last group of 4 got 20ku/kg and are still being dosed.  

The first group's average insulin needs dropped by about 30%, but no one was reported to have gone "off insulin" for any length of time.  Both first and second groups had a large drop in low blood glucose episodes.

Press release: 

Some Discussion and Opinions
This news definitely feels like more of the same.  Normally, more of the same (repeating your results) is a good thing.  And it may be a good thing here, also.  However I'm a little nervous that the dosage has gone up a lot: 5ku/kg to now 15ku/kg, but the results have not gotten better.  (At least that I can see from their published data.) Part of that is that the early 5ku/kg guys, some of them got extra transplants.  But still, whatever is happening, it does not look like simple giving more islets is going to result in big improvements.  At least not in a straight forward (linear) way.

The last group from this last clinical trial got the highest dose so far: 20ku/kg, and their data has not been reported on at all.  I hope that they do better than the earliest 5ku/kg group.  (Meaning at least 25% go insulin free for some period of time, for example.) 

El-Khatib Artificial Pancreas Update

Here is an "feel-good" article about the artificial pancreas being developed at Boston University
This is an artificial pancreas which is unique in that it can dose insulin if the person goes high, and glucagon, if the person goes low.  Obviously, this gives it some interesting advantages over an AP that can only dose insulin.

This is the paragraph which summarizes where they are right now:

So far, Damiano's team has tested its algorithm in 15 people in one- to two-day experiments. The first trial, in which they tested adults for 27-hour stretches, demonstrated that safe and effective glucose control was feasible with the two-hormone artificial pancreas. In the second trial, currently underway, they are testing the system in children and adults for 51 hours and have included an exercise component. (Since exercise can lead to increased risk of hypoglycemia, this adds an additional level of challenge to the algorithm's decision-making process.) Because the trial is ongoing, the team is hesitant to draw early conclusions, but Damiano says that they are very encouraged by the results.
And where they hope to be in the future:
Damiano says he hopes to be performing out-patient trials by 2012 and estimates that the device could be on the market by 2015.

There was one wrinkle to this research, which I had not known before:

One of the hitches, however, is that glucagon is not yet approved by the Food and Drug Administration for long-term use because it breaks down in solution. Several companies are tackling that problem. In the meantime, since a system that uses only insulin is likely to be FDA-approved sooner, Damiano's team is working on an insulin-only system as well.
Some Discussion and Opinions

The "out patient" trials they refer to in 2012, mean wearing the AP outside of the hospital.  Right now, all testing is done in a hospital.  Also, I think the 2015 date for FDA approval is a little optimistic.  From a regulatory point of view, they would need to do phase-II trials, phase-III trials, and get marketing approval, all within five years. (And that's separate from the scientific work of developing an AP that worked, and the engineering work of figuring out how to produce it!  Nor is it counting separate approval for long term glucagon,)

Personal Notes
I want to thank everyone over at BB for their huge outpouring of support.  You guys have no idea how many emails I got; it felt wonderfully supportive. 

I feel that my blog looks a little "old", so I'm going to update how it looks sometime this month.  So don't be surprised if it suddenly changes it's look, and then changes again to something else!  If anyone has ideas on improvements to how the blog looks, or the static text on the blog page, now would be a great time to email me or leave a comment.

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.