Sunday, December 12, 2010

LCT Gets Commercial Approval In Russia!

I had not planned to make another blog entry until Jan-2011, but I felt that the following news was important, so made an exception.   Happy Winter Solstice everyone!

The official sound track for this blog entry is The Blur's "Song 2":  Woooo-hooooo!

LCT Gets Commercial Approval In Russia!

Background: LCT is developing an encapsulated pig beta cell cure for type-1 diabetes.
Called "Diabecell", it has pig beta cells encapsulated in a special coating.  The coating allows blood sugar in, and insulin out, but does not allow the body's immune system to attack the beta cells.  It also allows nutrients in and waste products out.  This allows the beta cells to naturally grow and to react to the body's sugar by generating insulin which goes into the body's blood system.  Meanwhile, the body's autoimmune attack can not target these beta cells, and you don't need to take any immunsuppression drugs (as you would for a normal beta cell transplantation).  Remember that for decades, diabetics injected pig and cow insulin every day, so the fact that they are transplanting pig beta cells instead of human beta cells should not make anyone nervous.  Different researchers have been working on this kind of system for decades, but LCT is the first group to get government approval for this sort of "bio-artificial" pancreas.

I completely understand that not everyone considers a bio-artificial pancreas to be a cure.  Some people think it is just a good treatment: a much better treatment that we have now.  I've written this blog entry from the point of view of someone who thinks that a bio-artificial pancreas that really works is a cure.  If you don't believe that, just replace the word "cure" with "better treatment" in your mind as you read this.

So What Does This News Mean: My understanding is this means LCT has approval to sell their Diabecells as a commercial medical treatment in Russia.  LCT already has a commercial presence in Russia, so I would expect that in the next few months we will see actual availability of the treatment there.  LCT has said that they are working with two different clinics in Russia. LCT thinks that in the second half of 2011, you will be able to fly to Russia (if you don't live there already) and get this treatment.

What can LCT's Diabecell Do Right Now: In my opinion, the current performance of Diabecell does not make it a cure.  They have reported on less than 16 people, and only 2 of them were insulin free for any length of time, and those two were insulin free for only a few months.  But don't underestimate LCT's Diabecell just because it is not a cure right now:  First, research is about doing more in the future than you are doing right now, and this may grow into a cure over time.  Second, this treatment almost eliminates very low blood glucose episodes, and that is a benefit even without being a cure.  For "brittle" type-1 diabetics, this might prove reason enough to get this treatment.


Just about every one of these discussion points could be expanded to a full blog entry, all by themselves.  I'm just trying to "hit the high points" here.  As you read this discussion, don't forget the central point: these guys have gotten farther along the path of encapsulated beta cells as a future cure of type-1 diabetes than anyone else.  They are the first people to get government approval for something that might, in the future, with some more work, cure type-1 diabetes (at least by my definition of "cure").

Edmunton Protocol vs. Diabecell
In a previous blog I compared Diabecell with Burt's immune system reboot research, but that was unfair because Diabecell works on established diabetics, while the reboot research has only been tested on honeymoon diabetics.  However, a better comparison might be to compare the Edmunton protocol (for beta cell transplants) to Diabecell (for encapsulated beta cell transplants).  Both work on established type-1 diabetes.  Unfortunately, I don't know exactly how successful the Edmunton Protocol is, as used these days, so I can't compare it to Diabecell.  But it would be a great project: a useful head to head comparison of cure rates and durations of these two transplant techniques.

My best guess is that right now, the Edmunton protocol has a much higher success rate (in terms of % of people who don't need to use insulin for some period of time) and a much longer remission rate (length of time they don't need to use insulin).  However, it requires the person to take immune suppession drugs for the rest of their life.  Those drugs have serious side effects, and taking them for years or decades raises the chance of problems in the future (like cancer), and Diabecell doesn't have those side effects.

But I do think that the first commercial impact that Diabecell is going to have is on the Edmunton protocol clinics.  Right now, only a few diabetics get an Edmunton protocol beta cell transplant.  The ones who do are often "brittle" diabetics who experience seizures and are either worried about driving, or worried about "dead-in-bed" or both.  Those diabetics will now have an alternative to the Edmunton protocol, and we will see over the next few years how many of them take advantage of it.

From Here to a Cure
One obvious question is, if the current Diabecell is not a cure, can they make it into one?  And if so, how long will that take?  I think there are two steps needed for Diabecell to become a cure (by my definition):
First, it needs to work better.  Right now, about 90% of the people who get the treatment, continue to need to use insulin.  That's not a cure for me.  
Second, they need their treatment to last longer.  Since it requires an operation, I think it needs to last at least a couple of years.  Five or ten years (or longer) would be reasonable for a cure for me.

The big unknown for me is how hard will it be to improve Diabecell in these two ways.  If it is just an engineering issue, then that is great news: if they can just tinker with it and gradually improve both the success rate and the duration, that would be great.  They could tinker with it for 5 to 10 years and end up with a cure.  On the other hand, there might be a research issue in there that they need to solve.  That would require scientific research and a breakthrough of some kind to make it more successful and last longer.  Research breakthroughs are much harder to predict.  You might get it in a year, or maybe never.

Getting Approval Elsewhere
Another important question is, how quickly will LCT get approval in other places like the US and the EU?  I'm not an expert in government approval, and I know some of my readers know this area much better than I do.  However, I don't think getting approval in Russia is going to speed up the process for getting approval in the US.  I think they are still two or three large clinical trials away from US approval.  Remember, in the end, only 8 people have completed clinical trials with Diabecell, and that only lasted a year.  Eight or twelve more are in the middle of a second trial.  But even if you stretch this to the max, it is still just 20 people for a year or two each.  I'm not sure if that is enough data to even start a phase-III trial (as defined by the US FDA).

This is an important point: LCT got their approval in Russia, because the standards in Russia are much lower than the US and EU.  (I'm sure the LCT guys will have a much nicer way to phrase this.  And I'm sure they will be unhappy that I'm so blunt.)  But, my understanding is that the research they have done to date is no where near enough to get approval in the US or EU, and they are not trying to, right now.  (As I pointed out above, I'm not even sure it is enough to start a phase-III trial.)  Obviously, if you believe that the US FDA and the EU EMEA over regulate and are a bunch of "nervous Nellies" that tie up promising treatments in red tape, well here is your chance to get a treatment that hasn't yet gone though all that approval process.  To be a little crass: nothing bad happened in the first 20 people; your kid (or yourself) can be number 21.

The LCT press release talks about starting a pivotal study in New Zealand in 2011.  (Pivotal usually means the first phase-III study, designed to provide proof of efficiency and safety. Remember that even after this study, to get US approval they will need to do a second ("confirmatory") phase-III study and get marketing approval.)  So it still feels to me like they are 3-6 years away from approval in either the US or EU.  Although the Russian approval was quicker than I thought it would be, so maybe these guys are just faster than I expected.

Cost and Availability
Dr. Elliot at LCT estimated a cost of AU$ 150,000 per operation to start, which is pretty close to US$ 150,000.  There was no mention of exactly how soon the procedure would be started.  There are issues of training, and of transporting the cells from New Zealand to Russia.  At the start, there will be volume limitations, based on the size of LCT's herd of pigs. With that all said, I assume as more people get the procedure done, there will be economies of scale, and it will get cheaper.  An important part of the economic calculations is how long the implanted cells will work.  After all, $150k once is quite different than $150k every ten years, or every year!  And we don't know how long it will last. 

What's The Big Deal?
One way to look at this news is this: nothing has changed in the research.  The results LCT has today are the same as the results they had yesterday.  The only difference is Russian government approval.  So why is this important news?  I think that part of the answer involves the pace of progress in research vs. the commercial world.  Things happen more quickly in the commercial world.  Economic pressure and competition between companies do that.  This news marks part of the transition for LCT from the world of research to the world of commerce.  Not a complete, black and white conversion from one to the other, but a shifting of importance.  Another part of the answer involves availability.  Up until now, you could only get the treatment as part of a research study.  In the future, anyone with money and desire will be able to get it.  So availability will be controlled by the patients who choose to get the treatment, rather than researchers who choose to provide it. (That's over simplified a little, but you get the idea.)

Newspaper article:
Press release:
Previous blogging on LCT:
Previous status on LCT:

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. 
Email:  To get these blog entries emailed to you join the Google Group:

Monday, December 6, 2010

How to find a clinical Trial

The decision to join a clinical trial is a personal one, which I believe is best made between the person with type-1 diabetes (or parents), and their doctor.  However, I know that some type-1s don't have regular endocrinologists, and also some doctors don't tell their patients about available  trials (for a number of reasons).  Therefore, I've put together this blog on how to find clinical trials, so that people with type-1 diabetes, who want to, can discuss these trials with their medical team.

Non-Honeymooners: Don't think that just because you have established type-1 diabetes, there are no clinical trials worth participating in!  This is not true, on two separate fronts.  First, there are some trials aimed a curing established type-1 diabetes. (LCT, Exsulin, Liraglutide, Xoma 52, are examples.)  Second, there are always lots of trials about better treatments for type-1 diabetics (which I do not cover in this blog) but which can improve the "standard of living" of established type-1 diabetics.

Honeymooners: Many of the studies currently underway that may lead to a cure somewhere down the line, are only recruiting "honeymoon" diabetics.  Usually, people who have had type-1 diabetes for a few weeks or less. (Although this varies study to study.)  So, for trials aimed at curing type-1 diabetes, honeymooners are most in demand.  But the honeymoon time period is also the hardest for type-1 diabetics and their families.  They are getting used to so many new things: blood checks, counting carbs, dosing, needles or pumps or both, etc.  So in that way, it is a bad time to be participating in a clinical trial.  This is a fundamental dichotomy that each family must work out for itself: do you want to participate in a clinical trial soon after diagnosis, or not?

Finally, please don't wait for me to publish a posting calling for volunteers for a specific clinical trial: I don't do that.  I publish when a study starts, but often it is only recruiting at one or two places then.  More recruiting centers often come "on line" in the weeks or months after I post.  So use the web sites described below to see when a trial is recruiting near you.  While I don't push specific clinical trials, I do hope that all type-1 diabetics (both newly diagnosed and long established) consider the available clinical trials.  While the decision to enroll is for each person/family to make themselves, I think it would be a shame not to even consider the possibility.

How To Find Clinical Trials for Type-1 Diabetics

If you are looking for clinical trials, then JDRF already has exactly what you are looking for:
I'm not sure how good the coverage is internationally, but in the US, it seems quite good.

If you can not go to the link above, then go to JDRF's  main page:
and click "Get Involved"
and then "Participate in a Clinical Trial"
and then "Register Now"

It you need to fill out some data, like how old you are, and when you were diagnosed, and some other stuff, and then it matches you up with clinical trials in your area. Pretty sweet!

Although run by the JDRF, it returns clinical trials no matter who is funding them.  You get a list of results, and the trials that are funded by JDRF have a little "JDRF" icon on them.  Once you are registered, it will send you email every now and then telling you about new clinical trials in your area, for your age, and that match your profile.  You configure how often you get these emails.  The emails contain links to simple data pages, that tell you the basics of the clinical trial, where it is being done, the inclusion/exclusion criteria.   All very nicely done.

If you want to do more searching on your own, then you can check out the following web sites:
The Immune Tolerance Network (ITN) is a very interesting organization, which I view as part of the "infrastructure" of diabetes research.  They help researchers organize and run clinical trials aimed at stopping autoimmune attack, and similar subjects within the immune system.  They cover research into type-1 diabetes, and also related autoimmune diseases.  At any one time, they usually have a dozen or so studies going on, and a couple are recruiting all the time. 

Because ITN runs a network of doctors who cooperate in clinical trials, their trials often recruit at many different sites all over the US (and sometimes the world), so you have more chances to enroll.   Their studies are more likely to be available near you.

About ITN:
Type-1 Studies Recruiting Now:
This is the official FDA registration site for clinical trials.  It covers just about everything in the US, and many trials not done in the US are registered here as well.  It contains a lot of information, but is a little clunky to use.  I think it is more designed for research professionals, than random people looking for a trial.  You can search for phrases like "type-1" and "diabetes" and limit your search to studies that are recruiting right now, and even by location where they are recruiting.   Personally, I've found the JDRF site has the same information and is much easier for a patient or parent to use.  But the FDA site has more info, so if you find a trial using the JDRF site, you can look up the same trial on this site, and learn more about it.
This is the UK's official registration site for clinical trials.
This is the UN's official registration site for clinical trials.
You can try this in Australia.

Finally, if you are near a major university or diabetes research center, you might want to "reach out" to them.   I know that UC San Francisco, Stanford, The Barbara Davis center at University of Denver, DRI (in Miami), University of Florida at Gainsville, the Joslin center and Harvard (both in Boston) are all doing multiple studies.

Some of the information in this blog entry comes from a "sticky" Diabetes Daily thread:

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.  I have no relationship with any person or company running any clinical trial or recruiting for any clinical trial.
Email:  To get these blog entries emailed to you join this Google Group:

Wednesday, December 1, 2010

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

Here are various news items on possible cures for type-1 diabetes which are in human trials, and related items:

Diamyd Completes Enrollment of their Second Phase-III Trial

Since this study follows people for about 15 months, it is very reasonable to expect that it will complete in mid 2012.  Since this is the second phase-III trial, if successful, market approval might come in 2013 or 2014.  Diamyd is a vaccine like treatment designed to teach the body's own immune system to stop attacking it's own beta cells.  The company's description is this: "Diamyd® is thought to induce tolerance to GAD, thereby intervening in the autoimmune attack and preserving the capacity to produce insulin in patients with autoimmune diabetes".  Remember, the phase-III trials are only in honeymoon diabetics.

Press release:

Leptin Starts a Phase-I Clinical Trial, but as Treatment, not Cure

I have blogged in the past about Leptin:

And here is the press release for the new news:

Back in 2008 Leptin was presented (in the news, at least) as a possible cure, but by April 2010 it was presented as a possible new treatment.  This most recent news makes it clear that it is a possible treatment for type-1 diabetes, not a cure.  I don't expect to cover this research moving forward.  Remember that even as a treatment, it takes 10 years to move through the regulatory process and get approved.

Single case of Putting Type-1 into Remission for One Year
This is a single patient report (not a research study).  The patient had two diseases: ITS and type-1 diabetes.  To treat ITS, she was given Rituximab about 15 months after being diagnosed with type-1.  The result was that her type-1 diabetes went into remission for 11 months.  (No need for external insulin during that time).   This is reported here:

Obviously, this is interesting.  Especially since there has already completed a phase-II study on type-1 diabetics, and got good results there, too.  (Although I'm embarrassed to say that I've not blogged on the specific results of that study.)

Rituximab targets the CD20 part of the immune system's B cells (different from the pancreas's beta cells) to try to prevent the autoimmune attack. B cells are part of the body's immune system and communicate with the T cells, which actually attack the body's  beta cells in the pancreas.  By targeting the B cells, it is hoped this treatment will stop or lower the attack of the "bad" T cells.

Comment: Most treatments aimed at stopping the autoimmune attack are very focused on stopping the "bad" T cells which directly attack the beta cells in the pancreas.  This treatment (if successful) opens up a whole 'nother way to stop the attack: by targeting the immune systems communication and support system, the B cells.

I have previously blogged on Rituximab here:
And reported status here:

Cautionary Note: Possibly Faked Phased Clinical Trial Data
This news article made me very nervous; the impact could be to many other clinical trials. 
Here is the article:

The basic summary is this:  MannKind is developing an inhaled insulin doing several clinical trials in foreign countries, using contract clinical trial companies.  (These are companies that specialize in just doing clinical trials for other companies.  They don't develop drugs.  They do testing of other company's new drugs.)  A MannKind employee claims that some of the data reported by the contract clinical trial company in Russia is obviously false.  All patients had the exact same blood pressure.   Since FDA relies on these studies to do approvals, this is a big deal.  This one case impacts MannKind, but the general problem could effect others treatments as well.  Did that contract clinical trial company do other trials for other drugs?  Is the problem limited to one company, or does Russia have systematic problems that put all Russian clinical trials at risk?  You get the picture: it's bad.

Omission from Previous Blog Entry
In my last blog (comparing Burt's treatment with LCT's) I did not include the fact that LCT's clinical trials were all people with established type-1 diabetes, while Burt's were all honeymooners (people with recent onset type-1 diabetes).  This is a serious omission.  Working on established type-1 diabetes is a huge advantage over honeymoon type-1 diabetics, and that is a strong point in LCT's favor that was not included in the comparison.  I'm sorry for this omission.

General Background Information

All "Animal Models" are not Equal
This is an interesting blog entry about "animal models" used to test type-1 cures:

General Background for Understanding Type-1 Research
This article describes the immune system in general, what is meant by "honeymoon" and other useful words and ideas, but the Teplizumab clinical trial it talks about has since been stopped.  Also the phase-I/phase-II/phase-III description is for new drugs or treatment.  Already approved drugs or treatments can follow a slightly different path.

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.

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. 

Thursday, October 21, 2010

Possible Cures for Type-1 in the News (Mid Oct)

Here is another collection of news from the last few weeks.

Teplizumab (by MacroGenics / Eli Lilly) Fails in phase-III Trials

It appears that MacroGenics lead phase-III trial of Teplizumab has failed.  Here are some quotes from their press release:
The Data Monitoring Committee concluded that the primary efficacy endpoint of the study, a composite of a patient’s total daily insulin usage and HbA1c level at 12 months, was not met 
Following careful evaluation of the Data Monitoring Committee’s recommendations for [this clinical trial], based on the lack of efficacy, [MacroGenics and Eli Lilly] have decided to suspend further enrollment and dosing of patients in two other ongoing clinical trials of teplizumab in type 1 diabetes: the Protégé Encore Trial, a second Phase 3 trial of the same design as Protégé, and the SUBCUE trial, a Phase 1b trial that is exploring the subcutaneous administration in patients with type 1 diabetes.

Obviously, this is a huge blow to this drug as a possible cure for type-1.  MacroGenics might try to salvage this drug by reanalyzing the data from this experiment to see if there was a subpopulation which was helped.  But it is a long shot.

Another ominous question is what about similar drugs also under development?  Teplizumab is a monoclonal antibody targeting CD3 T-cells.  There are two other drugs in that category currently in clinical trials: Otelixizumab and NI-0401.  I don't know if Teplizumab failed because attacking CD3 is the wrong technique, or there was a problem specific to that one drug.  I hope the latter, because if it is the former, all three of these drugs will fail.  

The President and CEO of ToleRx (developers of Otelixizumab) has a blog ("The Green Chair") which you can read here:
His whole blog entry on this is worth reading. Here is his quote on this particular issue:
Next, I’d like to underscore some of the reasons why we continue to have a strong belief in our lead product candidate, otelixizumab. Otelixizumab’s biochemical structure is fundamentally different from other anti-CD3 monoclonal antibodies, such as teplizumab.  We believe this unique molecular structure is inherently important in mediating or delivering the “right” signals to T cells, and it is these signals, we believe, that are responsible for the effects, both in efficacy and tolerability, that were observed in our previous clinical trials. 
ToleRx expects to publish their phase-III results in the second quarter of 2011.

I haven't found any comment by Novimmune (makers of NI-0401).

Prior to this news, there were four treatments in phase-III of clinical trials aimed at curing type-1 diabetes.  And phase-III is the last stage before market approval. Teplizumab was one of these, and Otelixizumab is another.  NI-0401 is in phase-II clinical trials.    If you're a "glass is half empty" kind of person, you can say that this news has lowered the number of phase-III possibilities by 25%, and cast a pall over another 25%.  If you're a "glass is half full" kind of person, you can say that 5 years ago he had only one drug in phase-III trials, and even after this news, we still have three.  For myself, I would point out that over 30% of treatments in phase-III trials end up failing for one reason or other.  So of the four we had, we should expect 1 or 2 to fail.  And now, 1 has.

News article:
Press release:
Biz news article:

Sitagliptin and Lansoprazole Start a Phase-II Clinical Trial
I had previously blogged about this trial here:
but at the time they were planning the trial, but now they have started it:
These are two drugs currently used for type-2 diabetes, but this trial is aimed at using them on people who have type-1 diabetes.

Another Encapsulated Beta Cell Cure in Human Trials
I've been following LCT (encapsulated pig beta cells) for years, and just last month I found a second encapsulated beta cell trial (that one using human cells).  Now this month I found a third group doing encapsulated beta cell trials in people. Thanks to kisiliz (of CWD) for pointing this out to me:

Unfortunately, the results of this phase-I study of about 14 people. (4 of whom were actually treated) were not good.  C-peptides were detected only immediately after the implantation.  Although slight amounts of generated insulin could be detected years later, Insulin usage and BG numbers did not change.  Basically, it was a proof of concept, but no practical impact.  However, this study was just published in 2009, so they might well improve things, and move forward.

This makes for a total of three encapsulated beta cell research teams active right now, and that's a good sign.

Below is Animal Research, so Years Away from Human Trials
I don't usually blog about research that has not started human trials, but I thought the following two research areas were particularly interesting.  Remember that anything that has not yet started clinical trials is well over 10 years away from general availability, and has a less than 50/50 chance of ever even starting human trials:

Alternate Artificial Pancreas Design
I would describe this as a "cool hack" (which is a software engineering way of saying "a really elegant design, which solves a complex problem in a simple way").  You can think of it as a hybrid of self dosing insulin and an implanted device.  If you prefer, you can think of it as an artificial pancreas with no moving parts or computer software.

The trick is as follows: you create an artificial pancreas, which is nothing more than an insulin reservoir, a chemical barrier, and a tube so the insulin (once it gets past the barrier) goes directly into the liver.  The barrier is key.  It reacts to the BG levels in blood to either let more insulin out, or less insulin.  This is very much like the "self dosing" insulins being researched by SmartInsulin and others, but it is different in that the "self dosing" chemistry is in a barrier which is separate from the insulin itself.  I don't know if this is a better or worse approach (than combining the self dosing chemistry into the insulin), but it is different.  And I believe that in early research, different is good,  because we don't care how many fail, just that one succeeds.  Sending the insulin straight to the liver is an interesting refinement as well.  Naturally generated insulin goes to the liver very quickly, before it circulates through the blood or is deposited in the fat cells under the skin.  So dripping the insulin into the liver should result in faster response, and in a sense is a more natural flow.  Injecting insulin in the fat just below the skin is very easy to do, with almost no training, which is why we do it, but that does not mean it is the best from a biological point of view, just that it is the most practical.

Since there are no batteries, moving parts, electronics, etc, this type of artificial pancreas should be much easier to care for as an implanted device, and have fewer parts that can break or need to be replaced.   Only insulin will need to be added.  Unfortunately, I have not found any published animal research on this device, but I haven't looked very hard (and I'm not so familiar with the tools to search for animal trials, as I am for human trials.)

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, September 28, 2010

Possible Cures for Type-1 in the News (Sept)

An Encapsulated Human Islet Transplant Cure in Phase-I
For the last many years, I have thought that LCT was the only company actively doing clinical trials on an encapsulated islet cell cure for type-1 diabetes.  However, I recently found this clinical trial record:

These guys are testing human encapsulated islet cells (so not pig cells, as LCT is using).  They started in November 2008 and ending in December 2013, and includes 15 people.  They're doing this one trial in two phases, the first phase is only open to people who have already had an organ transplant (which I'm sure is delaying the study, since it takes a long time to recruit people like that). They call their device a "Monolayer Cellular Device", and the work is being done in Belgium

News on Otelixizumab by Tolerx
I have two tidbits on Tolerx's Otelixizumab.  The first is from news article which was discussing the start of their DEFEND-2 clinical trial, which is a confirmatory phase-III trial.  So that is the last stage before FDA approval.  So, as the quote shows below, Tolerx is starting to look to eventual approval:
If the trial [DEFEND-2] is successful, the company plans to send the drug candidate to the U.S. Food and Drug Administration in 2012.
Obviously that is good news.  For comparison, Diamyd was talking about starting the approval process in 2011, and LCT at one time was 2011, but more recently was 2013.  To the best of my knowledge we have never started the marketing approval process for a non-insulin drug to target type-1 diabetes.  So having three possible starts in the next 3 years is great.  Although that is tempered by the fact that only one of these treatments has been tested on established diabetics, and none of them represents a cure so far.

The other piece of news is a little more technical.  Here is the key quote:
The new research findings support existing data suggesting that otelixizumab may work in patients with new-onset type 1 diabetes by blocking the function of T killer/effector cells that mistakenly attack and destroy insulin-producing beta cells, while simultaneously stimulating T regulatory cells that are thought to protect against future T killer/effector destruction. Clinical data from the recently completed DEFEND-1 Phase 3 study and the ongoing DEFEND-2 confirmatory Phase 3 study will be evaluated in light of these new findings to determine whether this dual effect of otelixizumab is consistent with results from patients who have received otelixizumab.
 Press release:

What this means is that they believe that their experiments show that Otelixizumab works in two different ways.  First, it blocks the bad killer T-cells.  The cells that are directly attacking the pancreas.  Second it increases the actions of the regulatory T-cells, which are cells designed to control killer T-cells.  That is potentially a powerful combination (although it will be interesting to see how long it lasts).  Another interesting piece of data is how selective is it?  Attacking the bad killer T cells is one thing, but it would be even better to NOT attack the good killer T cells.  The press release implies that it is selective, (which would be great) but this is a case where we need to see the numbers, to see exactly how selective it is. 

Both Tolerx (Otelixizumab) and MacroGenics (Teplizumab) Start Separate Subcutaneous Trials
Both Tolerx and MacroGenics are starting clinical trials designed to test their respective drugs when given subcutaniously.   The current clinical trials for both drugs require an IV (drip into a blood vein).  Those can not be done at home.  However, these studies are checking to see if the respective drugs can be injected just under the skin (called Subcutaneously, or SubQ).  That is how insulin is injected.  So if these clinical trials are successful, that means people would be able to inject themselves at home, rather than go to a clinic and have a nurse do it.

These are both phase-I studies and both are still recruiting new patients.
The Teplizumab study has 71 people, and should complete in July 2012, and is honeymoon only.  You must be within 1 year of diagnosis.
The Otelixizumab study has 28 people, and should complete was supposed to finish in July 2010. This study is not limited to honeymoon diabetics, but you must have A1C numbers above 9%, you must generate a little C-peptide.  If the study shows that the drug has the same (or similar) effect when injected like just under the skin as they see with IV drips, then I would love to see how it effects long established diabetics. 

Clinical trial record: Teplizumab
Clinical trial record: Otelixizumab

Testing C-Peptides: Fasting as good as Stimulated?
A little background: When your body makes insulin, it also makes a small molecule called C-Peptide.  This is very important to diabetes research, because if a researcher sees insulin in a person's blood, there is no way to know if that insulin came from an injection or from internal production.  However, C-peptide only comes from internal insulin production.  So when someone measures if a drug helps insulin production, what they really do is measure C-peptide.  Years ago the US FDA adopted this standard, so that in order to get a new drug approved to help a diabetic produce more insulin, the drug company must show evidence that the new drug increases C-peptide levels.  (Paradoxically, measuring insulin is considered a second rate way to testing insulin production, because the type-1 diabetic might have injected more insulin for any number of reasons.)  C-peptide is the gold standard of measuring insulin production.

But there are two ways to measure C-peptide: fasting and after a meal (which is sometimes called a "challenge" or "stimulated").  The fasting one is quicker and easier to do (at least for the researchers, the patient may prefer a meal :-) )  But the meal one is considered a better measure of effectiveness.   Basically, a fasting C-peptide measure tells you how well your body creates "basil"  (ie. no food) insulin.  While the meal test tells you how well your body creates "bolus" insulin (in response to food).  The meal one is considered better, but the fasting one is easier.  

The summary of this poster session is that the results of the two different tests are linked.  So that doing a fasting test predicts what will happen for a meal test, and doing a meal test predicts what will happen for a fasting test.  If confirmed by other trials, this will make it cheaper and easier to do clinical trials in the future (especially for large numbers of people) since you will only need to do a fasting test.

Press release:

Novocell Terminates Encapsulated Islet Transplant Clinical Trial
Years ago, Novocell was developing an encapsulated islet cell transplant cure, similar to LCT, although my memory was that they were using human islet cells, not pig cells.  In any case, the research did not move forward.  They started a phase-I clinical trial in 2005, but in 2006 they stopped recruiting for it.  I think that it has been moribund ever since, but they just (April 2010) officially terminated it.

The company recently changed it's name to ViaCyte, and is working on an encapsulated islet cure called "Pro-Islet".  They are doing animal ("pre-clinical") studies, so I'm not following it as yet.

Final End of TT-223
A few days ago, Transition Therapeutics announced the end of clinical research for TT-223:
Transition Therapeutics announced today [17 Sept 2010] that a clinical study of gastrin analogue TT-223 in combination with a Lilly proprietary GLP-1 analogue in patients with type 2 diabetes did not meet its efficacy endpoints. Given these findings, there will be no further development of TT-223.
Press release:

My translation: Even when we mixed it with another drug, it still did not work well enough to move forward.

So that's about as dead as you can get.  (Although INGAP went through this same process and was later "reborn" by the original developers who thought it had a future even though their big pharma backers did not.  Those guys are still doing clinical trials of INGAP (renamed Exsulin) and who knows what will happen?)

A little history:
TT-223 was one of the possible cures in existence when I started tracking them on my original web status page.  They were initially funded by JDRF, but then Eli Lily took over development from Transition Therapeutics, the small company that JDRF had funded.  JDRF got it's money back at this point because their funding was no longer needed, and they then reinvested it in something else.  But Eli only continued the type-2 testing, not the type-1 testing.  So almost exactly a year ago I blogged about this, and said that TT-223 was dead as far as a cure for type-1 (at least until someone started testing it again in type-1 diabetics).  You can read that post here:
At that point I stopped following TT-223.  However, an alert reader continued to follow them, and so when they issued the press release above, that reader forwarded it to me.  Thanks!  You know who you are.

Rituximab in the Real World
I have previously blogged on Rituximab (sold as Rituxan):
This drug is already approved for use in the US for certain diseases, and there was a recently published article on it's safety as applied to rheumatoid arthritis, which is an autoimmune disease of the same general family as type-1 diabetes.  You can read that here:

News coverage:

This study was based on a registry of over a thousand French citizens who were treated with Rituximab and who were followed up for at least a year.  So this is a much bigger study than the Phase-I study for type-1 diabetics, which was less than 90 people for 1 year. 

There were two interesting results, from my point of view:

First, the overall rate of serious infection was about the same in this trial as it had been in the trials that were used to get approval for the drug in the first place.  That's good news, because those approval trials generally exclude patients who have "co-morbidities" (that is: something else wrong with them).  On the other hand, real world use include patients who have several different diseases.  (Especially rheumatoid arthritis.)  And having more than one disease raises the chance of serious infection, and that is exactly what this study was looking at.  So it is good news that the side effects were no worse for real world use as for experimental use.

Second, the serious infection rate was much higher (about 5 times as high) for people who had "low IgG levels".  So the authors of the study suggest that people getting Rituximab get tested for that before each dosing.  Other co-morbidities that were associated with a higher chance of serious infection included chronic lung disease and/or cardiac insufficiency and extraarticular involvement. (Which are not common in type-1 diabetics, and especially not young ones.)

I think this is good safety news for this drug. Both because it shows it is safe when used "as-is", but also because it provides a clear path to even higher levels of safety via a simple screening process. 

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. 

Monday, September 13, 2010

JDRF Funding Research for a Cure 2010

Note: I forgot one study in the original (Sept-13) version of this blog entry, but this updated (Sept-15) version includes that study and updates the counts and percentages.  I'm sorry for the oversight.

In the US, we are starting the "Walking Season" when JDRF asks us to walk to raise money for cure. So I'd like to do my part, by reminding you all how important JDRF is to the human trials of potential cures for type-1 diabetes, which I track. 

Let me give you the punch line up front: 73% of the treatments currently in human trials have been funded by JDRF. (And the number is 85% for the later phase trials!) This is an amazing impact; one that any non-profit should be proud of.

One new complication (which I am very happy to have!) is that there are now more studies which combine two different drugs into one treatment.  In general, I give funding credit, if the organization in the past funded any component of a combination treatment, or if they are funding the current combined treatment. Also, I list experiments separately if they use at least one different drug.  For example, There are currently about six different trials going on for Diamyd's GAD65, both phase-III and phase-II, however all of these are covered by the one listing in the phase-III section.  However, the clinical trial using Diamyd's GAD65 and lansoprazole and sitagliptin together gets it's own listing, in the phase-II section.

Last year, I didn't think there were enough  trials aimed at established (non-honeymoon) diabetics, to mark them separately, but this year, I think there are.  The trials marked E/NH below include patients who have had type-1 diabetes for more than one year, and so are out of the honeymoon period.  Other treatments might end up helping established diabetics, but these are the ones being actively tested right now. I was surprised at how many there are.  There is a general belief that all the current clinical trials are for honeymoon diabetics, or that JDRF's funding is somehow only going to curing honeymooners.  It is true that none of the phase-III studies are aimed at established type-1 diabetes, but phase-II contains 37% non-honeymoon trials, and phase-I contains 50% (with JDRF funding 81% of the non-honeymoon trials).

Cures in Phase-III Human Trials
Summary: there are 4, and all of the treatments have been funded by JDRF.
  • Diamyd's GAD65
  • TolerRx's CD3
  • MacroGenics's CD3
  • Andromedia's DiaPep227 
All of these treatments have more than one study active right now.

Cures in Phase-II Human Trials
Summary: there are 16, and 13 of them have been funded by JDRF, either directly or indirectly through ITN. Here are the treatments that have been funded by JDRF:
  • Abatacept by Orban at Joslin Diabetes Center
  • Diabecell by Living Cell Technologies    (E/NH)
  • Diamyd's GAD65 and lansoprazole and sitagliptin
  • Exsulin (previously INGAP) by Exsulin    (E/NH)
  • Kineret / Anakinra by Mandrup-Poulsen at Steno Diabetes Center
  • Liraglutide at Hvidovre University Hospital   (E/NH)
  • PROCHYMAL by Osiris Therapeutics
  • Rituximab by Pescovitz at Indiana
  • Sitagliptin by Garg    (E/NH)
  • Sitagliptin and Lansoprazole at Sanford Health
  • Thymoglobulin (also known as ATG) by Gitelman
  • Umbilical Cord Blood Infusion by Haller at University of Florida
  • Xoma 52 by Xoma Corp  (E/NH)
Not funded by JDRF:
  • Atorvastatin (Lipitor) by Willi at Children's Hospital of Philadelphia
  • Brod at University of Texas-Health Science Center
  • NI-0401 by NovImmune

Cures in Phase-I Human Trials
Summary: there are 13, and 7 of the are funded by JDRF and 6 are not. Here is the list funded by JDRF:
  • ATG and GCSF by Haller at University of Florida    (E/NH)
  • BHT 3021 by Bayhill Theraputics    (E/NH)
  • CGSF by Haller at University of Florida
  • Trucco at Children’s Hospital of Pittsburgh    (E/NH)
  • IBC-VS01 by Orban at Joslin Diabetes Center
  • Proleukin and Rapamune by Greenbaum at Benaroya Research Institute    (E/NH)
  • Lisofylline by DiaKine
Not funded by JDRF:
  • ATG and autotransplant by Burt at University of Sao Paulo
  • BCG by Faustman at MGH
  • CGSF and autotransplant by Esmatjes at Hospital Clinic of Barcelona  (E/NH)
  • Encapsulated Islets at University clinical Hospital Saint-Luc    (E/NH)
  • Etanercept (ENBREL) by Quattrin at University at Buffalo School of Medicine
  • Pioglitazone by Wilson at Stony Brook 
This summary does not include Artificial Pancreas research, which I discuss separately.
Nor does it include the last group of eight stem cell trials.

Summary of all Trials
33 in total
9 not funded by JDRF
So 73% of the human trials currently underway are funded (either directly or indirectly) by JDRF. Everyone who donates to JDRF should be proud of this huge impact; and everyone who works for JDRF or volunteers for it, should be doubly proud.

It is important to remember, however, that although there are four treatments in Phase-III trials, we are not close to a cure for established type-1 diabetes.  None of the treatments in Phase-III trials resulted in cures during their Phase-II trials. They all extended or increased the honeymoon phase in some way.

We have a long way to go, and that is where JDRF comes in.
    Compared to Last Year

    In 2009 there were 4 treatments in Phase-III trials, in 2010 there are 4 (no growth).
    In 2009 there were 10 treatments in Phase-II trials, in 2010 there are 16 (growth of 60%, but see the discussion below).
    In 2009 there were 13 treatments in Phase-I trials, in 2010 there are 13 (no growth).

    Obviously, there is not the same level of growth as there was last year.  I'm not sure if that is because last year had unusually large growth, or if this year has unusually small growth, or if we are hitting "equilibrium" in our clinical trials of possible cures.   I'll discuss that in more detail in a future post, as time permits.

    Another issue, is that the growth in phase-II trials is partly due to my including several clinical trials of drugs which are used to treat type-2 diabetes and are being tested on type-1 diabetes.  Some of these drugs have shown success at lowering insulin requirements for type-1 diabetics, but I'm not sure if they are possible paths to a cure.  They may just be better treatments.  My plan on these is to wait about 9 more months and make a decision at that time if they are possible cures or just possible treatments.  If they are not cures, I'll remove them from my comparison.  The studies in this group include:
    • Liraglutide at Hvidovre University Hospital
    • Sitagliptin by Garg    (E/NH)
    • Sitagliptin and Lansoprazole at Sanford Health 
      • I give an organization credit for funding a cure if it funded that cure at any point in it's development cycle.
      • I use the term "US Gov" for all the different branches and organizations within the United States of America's federal govenment (so includes NIDDK, NIAID, NICHD, etc.)
      • The ITN (Immune Tolerance Network) has JDRF as a major funder, so I count ITN as indirect JDRF funding.
      • I have made no attempt to find out how much funding different organizations gave to different research. This would be next to impossible for long research programs, anyway.
      • Funding of research is not my primary interest, so I don't spend a lot of time tracking down details in this area. I might be wrong on details.
      • I don't work for the US Gov, JDRF, or any of the other organizations discussed here. I'm on the Research Information Committee of the San Francisco Bay Area chapter of the of JDRF and an adviser to JDCA. I also own stock in several of the companies discussed here.
      This is an update and extension to blog postings that I've made for the last two years:

      Please think of this posting as being my personal  "thank you" note to all the JDRF staff, volunteers, and everyone who donates money to research a cure for type-1 diabetes:  Thank You!

      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, August 31, 2010

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

      GCSF (Neulasta/Pegfilgrastim) Starts a Phase-I Clinical Trial
      This is straight forward trial where GCSF is given to people in the honeymoon phase of type-1 diabetes.  It is interesting for many of the same reasons that the ATG+GCSF trial is interesting (see older post on ATG+GCSF).  Both of these trials are being done at the University of Florida, and Dr. Michael J. Haller is involved in both.

      Clinical Trial Record:

      There is a second GCSF clinical trial being done at the University of Padova (Padova, Padua, Italy), but it is not aimed directly a curing type-1 diabetes.  Although I don't understand it fully, it appears to be more basic research into GCSF effects on people with type-1 diabetes.  Clinical trial record is here:

      A Little Discussion: Why a GCSF only Trial?
      One obvious question that came to mind when I saw this GCSF only clinical trial, done at the same place and time, and by the same researcher as doing the ATG and GCSF trial, was: why do both?  I mean, if GCSF works, then certainly ATG and GCSF will work, and clinical trials are a lot of work and expense.

      The answer to this question (for me) has to do with with three separate, but related goals:
      1. We want to cure type-1 diabetes. (Cure Product Development.)
      2. We want to learn how drugs effect type-1 diabetes, so we can find a cure.  (Basic research.)
      3. We want the FDA to approve clinical trials which lead to points 1 and 2.
      If you only look at point 1, then a GCSF-only trial (when a GCSF+ATG trial is also ongoing) might sound like a waste of time.  As a parent of a child with type-1 diabetes, I often focus only on point 1.  However, product development flows out of basic research, so points 2 and 3 are also important.  It may turn out that studying GCSF alone will help create a cure in the future, or that the FDA might require more knowledge of GCSF alone before it will approve some future clinical trial, which leads to finding a cure.

      In the past I have blogged about not understanding how  Sitagliptin alone, or Sitagliptin and Lansoprozole combined, could cure type-1 diabetes.  However, it may be that these clinical trials will be valuable, because of points 2 or 3 above.  They might be the basic research or FDA required background that eventually leads to a cure, even if they are not the cure themselves.

      LCT Announces Completion/Extension of their Phase-II Trial
      LCT has announced these things in August:
      1. Their phase-II trial has been extended with 4 new patients who will get dose 20k u/kg dose.  The phase-II study now includes 4 who got 10k u/kg, 4 who got 15k u/kg and these 4.  This is a 50% expansion of their study, at 33% higher dose.
      2. The first four patients have seen a benefit of fewer (or elimination) of low BG episodes.  Only two such events, compared to nineteen, so almost a 90% drop.
      3. They plan "commercial launch" in 2013, and "global reach though partnership".  They seem to be assuming that the operation will cost about $150k (I think this is US$, but not sure.)
      4. They have also laid out the following time line for getting to commercial availability, which is the most detailed that I've seen:
      • 2011: Continue phase-II trials, get approval for phase-III trial (They use the term "pivotal".)
      • 2012: Complete phase-III, report on results.
      • 2013: "Approval and revenue"
      That's their plan, and I hope they make it.  I see the following issues for them to overcome.  First, they need to have a cure.  Right now, the longest they have had anyone insulin-free is 32 weeks, and only two people (out of twelve) have been insulin free for any number of weeks.    Obviously they need to improve both of these numbers.  (Although, if you view them as a treatment to help brittle diabetics, then their results might be good enough already - depending on how long they last - but that wouldn't be a cure.) Second, they need to treat enough people to get their approvals.  Right now, they have treated a total of 16, with 4 more on the way.  That is far fewer patients than any other phase-II trial that I know of.  A more common count is 20-30 in the phase-I trial, 80-120 in phase-II, and 300 in a phase-III "pivotal" trial, and then a second phase-III trial for confirmation.  (Basically all the drugs in phase-III trials have followed that path.)  LCT is running at about 1/3 the size in their phase-I trial, and 1/10 the size in their phase-II.

      Press release:
      Corporate Overview:
      This corporate presentation contains a lot of information on where they are, what they plan to do in the future, and how they plan to make money.  It is targeted at investors, after all.

      NovImmune has started a phase-II for NI-0401
      This company is very hard for me to follow, because they don't issue many press releases, don't have the clinical trial records, that most other researchers have, and it is just generally hard to find information on them.  The  are a small, relatively new company and their lead product (the one farthest along is the drug development process) is NI-0401 which is and anti-CD3 drug, generally similar to the Teplizumab and Otelixizumab

      Their recent corporate literature makes it clear that NI-0401 has started a phase-II clinical trial for type-1 diabetes.  Unfortunately, I have not been able to find clinical trial records for either the phase-I or phase-II trials, so I have no ideas how many patients are involved, if they are honeymoon or not, or any other of the most basic information about the study.  Even worse, I can not find any published results for the phase-I study in type-1 diabetics.  (I did find results for their phase-I trial on Crohn's disease, but not tyoe-1.)

      Corp presentation:

      AP News: Faster Insulin
      Below is a link to a JDRF press release on their project to created faster acting insulin (mostly to help their Artificial Pancreas project):
      I normally would not cover it, because it doesn't talk much about results or progress, however I did want to mention it because it is much broader and contains more context than your usual press release.

      Most press releases just cover one piece of news for one line of research, but this press release gives a lot more useful context to the search for faster acting insulin.  Basically, it starts out with a goal.  The goal is to get faster acting insulin, mostly because it will make creating an artificial pancreas easier, and make the resulting pancreas better.  (Obviously,  it will also help everyone who uses insulin with meals, which is basically all type-1s.)  The simplest way to speed up insulin (and the way done in the past) is to create a new form of insuilin which is faster than the currently available forms.  And JDRF is funding Dr. Buckingham at Stanford to test one of those.  Another way is to find a faster pathway into the body.  So JDRF is funding Dr. Zisser testing of AFREZZA, which is inhaled insulin; the hope is that inhaled equals faster.  A third idea is to use microneedles to deliver insulin faster (JDRF is working with BD on this one).  A fourth is a port-system which puts insulin from a standard pump directly into a person's liver.  Since insulin mostly effects the liver, this could speed up the effectiveness of pumped insulin.  (JDRF is working with Roche on this.)  Finally, there is a post-pump insulin warmer which might also speed up insulin effectiveness.  (JDRF is funding Dr. Tamborlane of Yale to test this for InsuPatch.)

      My Opinions.....
      The whole point of research is that you don't know which projects are going to pan out and which are not.  This press release shows how JDRF is trying many different possible paths to faster insulin.  Some of those paths seem like good ideas to me.  Others seem very inventive, if a little strange.  Others don't strike me as unlikely to succeed.  I'm sure other people looking at the same list will expect different research to fail and succeed than I do.  That is why JDRF is funding all of them.  No one knows which will pan out.  I believe that this whole project is part of JDRF's "glucose control" research area, and that whole section includes about 6% of their funding.  So even though it sounds like a lot of different research projects in different areas (and it is!), all together it is only a few percentages of JDRF's total investment.   It doesn't even begin to touch the 33%+ aimed at immune therapies or the 40% aimed a regrowing beta cells.

      JDRF Page on Spending:

      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. 

      Monday, August 23, 2010

      Possible Cures for Type-1 in the News (mid-Aug)

      Sitagliptin and Lansoprazole Preparing for a Phase-II Clinical Trial
      This trial is giving two drugs (both of which are already in use) to people with type-1 diabetes in their honeymoon phase.  The hope is that it will preserve some beta cell function.  This study is not yet recruiting patients.  They hope to recruit 54 patients and finish in April 2014. Sitagliptin is the generic name for Januvia, and Lansoprozole is the generic name for Prevacid.

      A Little Discussion: I still don't understand why this is supposed to preserve beta cells.
      When I blogged about the Sitagliptin only clinical trial, I said that I didn't understand why it might help type-1 diabetics; and I still don't.  With this trial, I don't understand why adding a antacid like Lansoprozole would help type-1 diabetics, either.  On the other hand, Januvia is available now for type-2 diabetes with a prescription, and Prevacid is available "over the counter" and as a generic.  So if this pans out, you will be able to get this as an "off label" use without waiting for further FDA approvals.

      For me, a far more interesting trial, which I have blogged about before, is being run by the NIH, and which uses Diamyd plus Sitagliptin and Lansoprozole.  That one I understand: Diamyd stops the autoimmune attack by retraining it, and the other two drugs reverse beta cell damage or develop new beta cells.  You can read about that study here:
      and I think they have upped the enrollment to 7 since I wrote that blog entry.  On the other hand, if this Sitagliptin and Lansoprozole only study lays a scientific foundation for more studies where they pair it with something to stop the autoimmune attack, that would be valuable.

      News article:
      Clinical Trial Record:

      Other Phase-II trial of Sitagliptin:
      Blogging on Sitagliptin:
      Wikipedia for Sitagliptin:
      Wikipedia for Lansoprazole:

      Delay in Trucco's Phase-I Trial
      Trucco's clinical trial is one of the first ones that I ever followed in my "status" web page.  That was years before I started my blog.  I've never blogged on it, because there has never been news.  Basically, they remove dentric cells, which are part of the immune system, treat those cells, and then put them back in the patient (the same patient where they came from).  This trial only enrolls people who have had diabetes for more than five years, so honeymooners are excluded.  It is a safety only study: they are not measuring any BG, A1C, insuline usage or C-peptide numbers.  If it turns out safe, then they plan to start a honeymooner only study to see if it improves any of those things. 

      Now, finally, there is news.  In June 2010, Trucco's group updated their clinical trials record as follows:

      Estimated Enrollment: 15
      Study Start Date: March 2007
      Estimated Study Completion Date: June 2011 (previously had been mid-2010)
      Estimated Primary Completion Date: December 2010 (previously had been mid-2009) 
      So this is basically a one year slip.

      Web status page: 
      Year old newspaper article:
      Scientific Overview:
      (Includes a nice diagram on page 8, even if the rest is highly technical.)

      One Possible Cure, but not yet in Clinical Trials.
      Some researchers in India are working with a "release as needed" injected insulin.  This is broadly similar to SmartInsulin.  A single injection of this new insulin, called Supramolecular Insulin Assembly II (SIA-II) resulted in good blood glucose levels (which they call "physiologic glucose levels") for over 100 days in animals.  I'm very much looking forward to what this does in people.  But remember: drugs generally take 10+ years to go through human trials, and less than half of the drugs successful in animals ever go on to human trials.  (Since this is an Insulin it might be slightly faster than 10 years, but not much.)

      News report:

      Another benefit of this drug, is that it puts pressure on the SmartInsulin developers.  In turn the SmartInsulin developers put pressure on the SIA-II developers.  I'm a firm believer that competition pushes both groups of developers to move faster, so I'm all for it.  It sounds to me like both SmartInsulin and SIA-II are close to starting human trials, but SmartInsulin is closer.

      Discussion: What is a Cure?  Is this a Cure?
      This drug (and also Smart Insulin) can start off an interesting parlor conversation about what is a cure?  Are treatments like SmartInsulin or SIA-II cures?   Obviously, each of us must make up their own mind about what is and is not a cure.  But in my mind, a treatment that required one injection every 3 months, and no blood glucose checks, no dietary limitations (no counting carbs), with no long term side effects and a normal life expectancy.  Personally, I would call that a cure, even though it requires an injection every 3 months, and even though you would have type-1 "on the inside".  It would be a functional cure.  Your opinion may differ.

      News from Cerco Medical
      I don't really cover Cerco Medical, because they have not yet started human trials for their "islet sheet", which is an encapsulated beta cell cure generally similar to LCT's  Diabcell.  However I know people are interested in it, and this is the most specific news I've heard about when they are hoping to start a clinical trial:
      His [Scott R. King, president of Cerco Medical] company is planning to begin human testing in 2012 or 2013.  
      This comes from a newspaper article, which is mostly about Artificial Pancreas work in Oregon:

      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.