Exsulin: New Phase-I Research Almost Ready to Start (for Non-Honeymoon Type-1 Diabetes)

The Exsulin company is hoping to start Phase-I human trials in June 2009 (so right soon now). They are testing a new formulation of INGAP called Exsulin, a drug designed to regrow beta cells in the pancreas.

Their Phase-I clinical trial is small, short, and open to people who have had type-1 diabetes for more than 2 years, so we should have some results soon. It is a three group design. One group gets nothing, one gets a full dose, the other gets a half dose. They are checking for all the right stuff: C-peptide, fasting glucagon, fasting glucose, total daily insulin dose, and HbA1c. They are using two sites Montreal and Rochester.

This is described on their web site:
http://www.exsulin.com/underway.html

INGAP (now renamed Exsulin) has a 12 year history of research. NOD mice trials worked well, but human trials didn't show much success (sound familiar?) The phase-I study is described here: http://www.clinicaltrials.gov/ct2/show/NCT00034255. The phase-II study is described here: http://www.clinicaltrials.gov/ct2/show/NCT00071409. It was funded by Proctor and Gamble but the results were not good enough to move forward.

The original developers of INGAP got back rights to it after P&G didn't like the phase-II results. Their analysis of the results convinced them that INGAP was helping grow new beta cells, but that those new cells were being killed off too quickly to help the patient. (Maybe because of the body's immune system, or maybe because of inflammation, or maybe for some other reason.) So it is natural for them to pair Exsulin with another drug to treat the other problem, and see if both together can cure type-1 diabetes. But the research they are starting now is just Exsulin, not paired with anything.

Joshua Levy

DiaKine starts Phase-I clinical trials on Lisofylline (LSF)

DiaKine is about to start it's first clinical trial in a research program aimed at curing type-1 diabetes. Their treatment is Lisofylline (LSF), an anti-inflammatory drug that (in NOD mice) has prevented type-1 diabetes and (when given with exendin-4) cured existing type-1 diabetes.

Previously (in May 2008) DiaKine has formed a joint project with Kinexum Metabolics, to run a human trial (phase-II) using both of their drugs together (LSF and INGAP). The combination had already given good results in NOD mice. That trial was supposed to start in "late 2008". Kinexum Metabolics has since changed it's name to Exsulin (not INsulin, but EXsulin. Get it?) I can't find any record of the LSF+INGAP trial starting, but each company is testing it's own stuff seperately, so maybe after that, they'll test them together. I know a lot of people are interested in an anti-inflammatory and a beta-cell growing combination therapy, and obviously these two companies are interested in that, also. In any case, this trial is LSF only, not the combo they talked about earlier.

The current trial involves 8 people, and is supposed to start in May 2009 and be done by December 2009.

This research is being done in New Jersey.

You can read a news article here:
http://www.earthtimes.org/articles/show/diakine-therapeutics-diabetes-immune-modulator-drug-set-for-human-clinical-trial,821004.shtml

The US FDA's clinical trial record is here:
http://clinicaltrials.gov/ct2/show/NCT00896077

And the official press release is here (and is better than most):
http://www.diakine.com/assets/news20090512.pdf

The press release talking about LSF+INGAP together is here:
http://www.diakine.com/assets/news20080506.pdf

I want to thank the Wainscoat family for bringing this to my attention.

Joshua Levy

NovImmune to enter Phase-II with NI-0401 (Another CD3 targeted drug)

It looks like NovImmune (a Swiss company) will start phase-II trials of NI-0401, a CD3 targeted drug "this quarter" and hope to have results in 2011 "at the earliest". The trial is expected to be multi-site and have between 100 and 200 patients enrolled, making it pretty big for a phase-II. The drug has already completed a phase-I clinical trial for Crohn's disease, another diseases where the immune system attacks it's own body. I can't find any record of a phase-I trial for this drug in type-1 diabetes, so I assume they are using their safety data from the Crohn's testing to justify a phase-II trial for type-1 without a separate phase-I.

News article is here:
http://www.bioworld.com/servlet/com.accumedia.web.Dispatcher?next=bioWorldHeadlines_article&forceid=50851

If treatments targeting CD3 sound familiar, that is not surprising. There are two other CD3 targeted treatments already in human trials. ToleRx's Otelixizumab (in phase-III trials now), and MacroGenics's Teplizumab (in phase-II trials now).

More information on ToleRx (Otelixizumab previously TRX4) :
http://cureresearch4type1diabetes.blogspot.com/search/label/Otelixizumab
http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials#TRX4alsoknownasChAglyCD3byToleRx

More information on MacroGenics (Teplizumab):
http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials#MacroGenics

Joshua Levy

Haller Cord Blood trial, results from Phase-I and Starting Phase-II

Haller at University of Florida is running a research program to transfuse into honeymoon diabetics their own (previously frozen) umbilical cord blood. Umbilical cord contains stem cells and also a lot of a specific type of T-cell (part of the immune system) called T-regulators. These cells help to regulate the immune system, and since type-1 diabetes is caused by a lack of immune regulation, this seems like a reasonable thing to try. Especially since more and more people are "banking" their children's umbilical cords at birth. The Phase-I study was focused on two possible paths to a cure: adult stem cells would migrate to the pancreas and help grow new beta cells, and/or T-regulators would help suppress the bad immune response. It appears that the adult stem cells path did not pan out, and the phase-II trial only discusses the T-reg mechanism, and not the adult stem cell mechanism.

So the basic status is that Haller has completed a phase-I trial, and gotten good results, and has started a phase-II trial.

The Phase-I Trial
It is supposed to involve 23 patients and run from April 2005 to July 2010, however the data I've seen covered 8 patients and was published in June 2007, so it is an interim result.

That said, the results were good: a few months after the transfusion, the treated kids had an average A1C 1 point lower than untreated (7 compared to 8), they used about 2/3 as much insulin per kg of body weight as the untreated patients, and they generated more C-peptide in response to food (meaning they generated more of their own insulin).

For the phase-I trial:
http://cordblood.cryosite.com/UserFiles/File/Cord%20Blood%20and%20Diabetes.pdf Nice summary
http://www.ncbi.nlm.nih.gov/pubmed/18358588 Phase-I Results Abstract
http://cordblood.net/cbrblog/haller-abstract.pdf Phase-I Results Whole Paper
http://clinicaltrials.gov/ct2/show/NCT00305344 Phase-I US Clinical Trial Record

The Phase-II Trial
It involves 15 patients (10 get treatment, 5 are the control group), and is scheduled to start March 2009 and finish collecting data by March 2012.

More details are described here:
http://clinicaltrials.gov/ct2/show/NCT00873925 Phase-II US Clinical Trial Record

My thoughts on this line of research are here; these are all personal opinions:
First, I think it is pretty limited in direct application, since it requires banked cord cells and is a honeymoon treatment. But I'm always hopeful that they might learn something that could be applied more broadly.
Second, I'm very interested in how long the effect lasts. Is it permanent, or does it go away over time?
Third, I think their "phase-II" experiment is tiny. Only 15 patients makes it smaller than some phase-I experiments that I've followed, and that's not a good sign.
Forth, this research "feels" to me like basic research where they're trying to better understand how adult stem cells and T-regulator cells might help type-1 diabetics, by experimenting on people. Rather than research on a short, straight line path to a cure.

Thanks to Ellen over at www.childrenwithdiabetes.com for pointing the phase-II trial out to me.

Joshua Levy

Quick Updates: Faustman, Diamyd, and LCT

Quick Update on Faustman
http://www.necn.com/Boston/Health/2009/03/26/Cure-for-diabetes-may-not-be/1238100563.html
This is a very fluffy TV news segment on Faustman, with no new information in it, except that results of her human trials should be published "by 2010". Previously, the target was mid-2009, and before that, late 2008.

Discussion on Faustman
There is no way to know if this is bad news for the research or not, because there is no way of knowing the cause of the delay. Human trials are often delayed because it takes longer than expected to recruit people (a good reason), but sometimes they are delayed for more complex analysis required to see a small benefit, not seen in the quicker data analysis (a bad reason).

Quick Update on Diamyd
http://www.marketwatch.com/news/story/diamydr-study-published-europes-leading/story.aspx?guid={16C4F628-8E2A-4E83-B0FB-0A514E053449}&dist=msr_2
http://www.springerlink.com/content/f612483413663654/fulltext.pdf
This is a five year follow up on Diamyd's phase-II clinical trial of their GAD65 treatment on LADA patients. Sometimes called "type 1.5" LADA is immunity based diabetes that effects older people. So the results seen here are likely to be relevant to type 1 diabetics. The results were good, especially in avoiding insulin use. The 47 patients got several different doses. The best dose seemed to be 20ug. At the start of the trial, none of the patients required insulin. For the 20ug dose, only 14% of the people required insulin after 5 years. For the no-dose group, 64% required insulin. Put another way, of the 11 people who did not get GAD65, 7 of them required insulin at the end of the study. Of the 7 people who got 20ug, only 1 did. The 20ug group, had very slightly better C-peptide numbers at the end of the trial than at the beginning, while the no-dose group had worse C-peptide numbers at the end. That suggests that the GAD65 prevented the destruction of beta cells.

Discussion on Diamyd
One of the big issues in type-1 cure research is this: If the immune system stops attacking it's own beta cells, will the body's beta cells naturally regrow without further help? This research suggests to me that the answer is no. C-peptide is created when the body makes insulin. If you look at the patient's C-peptide numbers, the no GAD group's declined, which is what you'd expect from an immune system continuing to attack the beta cells. However, in the groups that got the treatment, the C-peptide numbers basically stayed the same, not going up or down. That suggests that the beta cell attack stopped, but that no new beta cells were regenerated by the body.

Quick Update on LCT
http://www.lctglobal.com/downloads/cms_media_resources/2009-05-04-Clinical%20Announcement%20FINAL%20%205May09.pdf
LCT now has two patients who don't require external insulin right now.

Discussion on LCT
This is basically the same news we've heard before from LCT. Some people given their treatment do not require insulin for a few weeks or a few months. This is good news, to be sure, but it is the same news we already knew of their work. In my mind, the big issue with their cure is how long the implanted cells last, and I don' t think the data announced here addresses that issue.


A personal note: I'm in the middle of an internal transfer at work. This is something that I've wanted for a long time, but in the short term, it means less time to read and comment on research. When I first started this blog, I was hoping for about 2 postings per month, but April was much busier than that. But I doubt I'll have time to make as many postings in May and through the summer.

Joshua