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: http://cureresearch4type1diabetes.blogspot.com/search/label/AAT
The good news is that they (finally!) actually started their phase-I trial:
http://www.marketwatch.com/story/omni-bio-announces-first-infusion-in-phase-iii-clinical-trial-of-alpha-1-antitrypsin-in-recently-diagnosed-diabetic-patients-2010-10-18?reflink=MW_news_stmp
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: http://joshualevy.pbworks.com/ConceptsAndBackground#Inflammation

Here is the clinical trial for "part 1" of the trial:
http://www.clinicaltrials.gov/ct2/show/NCT01183468
And here is the record for "part 2" of the trial:
http://www.clinicaltrials.gov/ct2/show/NCT01183455


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     type1diabetes@emory.edu.  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:

http://www.healthcentral.com/diabetes/c/248704/108450/inflammatory-2
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: http://www.lctglobal.com/html/blob.php/LCT%20NZ%20Trial%20Update_271010.pdf?attach=0&documentCode=2264&elementId=20084 

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
http://articles.latimes.com/2010/nov/01/health/la-he-diabetes-pancreas-20101101
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. 
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

Possible Cures for Type-1 in the News (late June)

Low Dose Naltrexone starts a Phase-I Trial

Background
Naltrexone was approved in 1984 for use in treating heroin addiction, but was never widely used, because of strong side effects.  The low dosage level is one tenth the dose approved, so it is much lower, and doesn't have these strong side effects. Low Dose Naltrexone (LDN) is undergoing several clinical studies aimed at different diseases.

Here is how the researchers describe this trial:

The purpose of this early study is to see if a drug called naltrexone should be studied more in people with Type I diabetes and hypoglycemia unawareness. This study will show whether naltrexone could reduce hypoglycemia unawareness. The study will also show, by using magnetic resonance imaging (also called MRI), whether naltrexone changes the way blood flows in the brain when a person is experiencing hypoglycemia.

Discussion
I'm not sure if I'm going to follow this trial as a potential cure, because it seems to be focused very specifically on "hypoglycemia unawareness", and that is not a cure.  On the other hand I mention it here, because I know that some people are very interested in Low Dose Naltrexone, and it is the first time LDN has been tried on type-1 diabetes.  Unfortunately, they are going going to be measuring blood flow in the brain, and too-low blood sugar events.  Some people think that LDN might result in lower insulin requirements, and producing more natural insulin.  However, this trial is unlikely to detect that (unless they test for more things than are mentioned in their clinical trial record). 


Clinical trial: http://www.clinicaltrials.gov/ct2/show/NCT01053078
Wikipedia: http://en.wikipedia.org/wiki/Naltrexone 
Facebook group: http://www.facebook.com/group.php?v=info&gid=342192490776 


LCT's DIABCELL: Two Year Delay to General Availability

Dr. Elliot (a major player at LCT) said in a public forum:

"We do not anticipate being in the clinic before 2013 and even then in a very limited way."   Source: http://islet.org/forum/messages/53927.htm

This is a two year delay compared to their previous statement (in a yearly report) saying that they hoped to be doing transplants in Russia by 2011.

Also, LCT made a very nice presentation at ADA, which you can see here:
http://www.asx.com.au/asxpdf/20100628/pdf/31r13z624mnx7g.pdf
The really interesting slides start on page 30 and runs to the end (although slides 22 and 27 aren't bad, either).

Artificial Pancreas Photo
Here is a link to a "puff piece" in a Boston newspaper about the "bihormonal" (glucagon and insulin) AP work:
http://www.bu.edu/today/node/11148
The reason I include it is because it starts out with a big photo of a person with this AP.  Notice the five different "sets" on the person's abdomen.  It's a good reminder of where AP is and is not. How far we have come with an AP, and have far we have yet to go.

Dr. Ward's Artificial Pancreas Trials
This newspaper article describes some AP trials being done in Oregon, USA:
http://www.earthtimes.org/articles/press/an-artificial-pancreas-closer,1359773.html

These guys are testing a bihormonal (glucagon and insulin) AP device, similar to El-Khatib's group in Boston, Massachusetts, USA.  However these guys are using a different computer algorithm to control the hardware.  The key achievements include an average BG of 138 and "nighttime hypoglycemia was reduced nearly to zero".  Testing was for a 24 hour period.  I think that 21 people were involved.  (The newspaper article says "21 experiments".)

Stem Cells
I recently came across a group of 8 stem cells experiments (mostly phase-I) which did not require long term immunosupressives.  So those could be part of a future cure.  For example, if Diamyd, DiaPep, or any of the anti-CD3 treatments currently in phase-III trials pan out in honeymoon diabetics, then these stem cells might extend that cure to people with established type-1 diabetes.  I will devote a future posting to these Stem Cells trials.  With the 3 stem cell trials that I already knew about, that's 11 total. 


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.
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

El-Khatib's Group Announces Phase-I Results

If you are following Artificial Pancreas (AP) research, this announcement has it all: good experimental design, good results, a bright future, and some interesting side discussions.

First, the study:  These guys are testing an artificial pancreas which uses both Lispro insulin and glucagon.  Other AP projects are only dosing insulin.  Obviously, this gives the AP more control, it can dose insulin for highs and glucagon for lows.  The study was 11 patients none of whom generated their own insulin (so honeymooners excluded).  The study ran 27 hours and included 3 meals.

Second, the results: the 11 patients fell into two groups as far a results go, as described in the abstract:

In six subjects, the closed-loop system achieved a mean BG concentration of 140 mg/dl, ... There were no instances of treatment-requiring hypoglycemia. Five other subjects exhibited hypoglycemia that required treatment; 

So basically in the initial trial, it worked completely for six patients, but only partially for the other five.  So then they "tuned" their software, and got these results:

prevented hypoglycemia in both groups while achieving an aggregate mean BG concentration of 164 mg/dl.

So after tuning there were no more problems with lows, but the average BG was 164.
Now, remember that the current ADA guidelines for BG control is 154.  So the 140 is just within range, but the 164 is just out of range.  (Assuming you have a really accurate BG meter, of course. :-)  So for a phase-I trial this is a great result.

But the actual news is even a little better than averaging 164, because the researchers were able to discover why half the people did so much better than the other half in the first set of results.  The people who did well absorbed lispro insulin in about an hour, while the group that had low BGs absorbed it in about two hours.   One of the things that these researchers found, was that insulin is absorbed at different rates at different times, even by the same person.  So it is not a question that some people absorb it quickly or slowly, it's also that even in the same person, sometimes it will be absorbed quickly and sometimes slowly.  To quote Dr. El-Khatib (per. comm.):

We saw variations in the rate of insulin absorption by as much as 40–50% in some subjects between their first and second visits, as well as in an additional screening test that we ran on each subject.

(Think about this the next time you are wondering why the same dose of insulin has a different effect the next time you use it.)

I saw only three issues in this trial which made me nervous about it's applicability, and two are going to be addressed in research these guys hope to start very soon.  The first issue is activity.  For this test, the patients were lying in bed or sitting in a chair, so that was not realistic.  Second, they were using blood measurements of BG levels, not standard CGM measurements.  Third is the regular use of glucagon.  I discuss these issues below.

Third, the future:  For the one day the experiment was run, for 6 out of 11 people, the algorithm worked.  If these phase-I results carry forward into phase-II, phase-III and general availability, then this algorithm is likely good enough for a commercial AP.  Obviously, I would expect improvements so that phase-II and III would have even better results than these.  But these results by themselves are very good.

This research group is already planning to run follow on trials in Boston.  This first trial was run with very limited activity. But a follow on clinical trial will last longer (two days instead of one), use CGM technology, and more accurately represent real activity.  Patients will be able to move around (although they will be pushing around a pole with equipment on it), and they will spend some time on treadmills to model exercise. After that, there is a third trial, a follow on to the two day test.  In that third trial, people will use the bihormonal AP for a total of 5 days while "out and about" (doing what they would normally do).

Another difference in the future trials will be a partial pre-meal bolus.  This will be based on weight, and given with meals.  The researchers expect that this will keep them below the ADA's BG guidelines, especially patients who absorb insulin more slowly.  So if you know the JDRF "stages" of AP development, this would be a stage 6 AP because it includes glucagon, but a stage 4 AP in that you need to tell it when you are having a meal.  In either case, a big improvement over nothing, which is the kind of AP we (in the US) have now, or stage 1, which is available in parts of Europe.  You can read more about JDRF's stages here:
http://cureresearch4type1diabetes.blogspot.com/2009/09/background-for-artifical-pancreas.html

The use of standard CGM technology, starting in the next trial, is another important step forward, in my opinion.  CGM technology has some real limitations, and one of the big open questions in AP development is this: is current CGM technology good enough to feed a successful AP?  The completed trial doesn't directly address this, because they were using BG measurements from the blood stream, not interstitial spaces where CGMs work.

This work is based on giving Lispro for highs and glucagon for lows.  We have a lot of experience giving people insulin when their BGs are high, but much more limited experience giving people glucagon for lows.  Sure, we all have needles in red boxes, and some have even experimented with "microdoses" of glucagon.  But still, this AP will use glucagon much more than has been done in the past, and that is something that must be tested.

For the software nerds out there: basically, the software to control the pumps has one basic algorithm.  It's this basic algorithm that they are testing, and they are not going to change that. However this algorithm has a couple of parameters which the researchers can change.  Two of these involve how quickly insulin is absorbed, and these are the two that they changed in order to "tune" the algorithm for people who absorbed insulin more slowly.

Finally, a little fantasy of mine:  For one of the big diabetes meetings in 2011 or 2012 (ADA, or EASD, or "Friends For Life") there will be enough successful AP research projects, so the can have a "bake off" right there at the convention.  Each team brings a couple of APs, and some convention goers use them for the duration of the convention.  Then in the last session, they become a panel that discusses the current state of APs from a patient point of view.  Someone can chart their BGs on a couple of slides to get the discussion rolling.   I'd love to get a clinical trial number for that......

Research web site: http://www.artificialpancreas.org/
Abstract: http://stm.sciencemag.org/content/2/27/27ra27.abstract
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT00811317
Full paper: http://stm.sciencemag.org/content/2/27/27ra27.full.pdf?keytype=ref&siteid=scitransmed&ijkey=LwlywxnAol4yc
Extra data: http://www.artificialpancreas.org/uploads/ElKhatib_and_Russell__et_al_SOM_Sci_Trans_Med_2010.pdf

How to Summarize AP Clinical Trial Status

I'm also thinking about how I can summarize an AP clinical trial is just a few lines, that are understandable.  For this trial, I'm thinking about something like this:

A phase-I trial of 11 people over a 1+ day time period which includes meals but not activity.
Results: The algorithm had 6 people averaging BG of 140 and no lows.  After tuning, all 11 averaged BG of 164, and no lows.
Notes: This AP could dose both insulin and glucagon.  Commercial CGMs were not used (blood BGs were).

If anyone has any thoughts on how to summarize AP clinical trials, please do share them with me. 

I would like to thank Dr. Steven Russell (a principal investigator in this research) for answering my questions, and also Dr. Firas El-Khatib (a Co-investigator in this research) for providing additional information.  All mistakes are my own.

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.