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

Etanercept (ENBREL) Completes a phase-I Trial in New Onset Type 1 Diabetes

This is a "new to me" phase-I study of Etanercept (ENBREL) , which just published it's results last week: http://www.clinicaltrials.gov/ct2/show/NCT00730392 and you can read the abstract of the results here: http://www.ncbi.nlm.nih.gov/pubmed/19366957

This is "give a drug quickly after diagnosis of type-1 diabetes to preserve some beta cell function" type treatment. The drug, Etanercept (ENBREL), is a product of Amgen, who sponsored the research, and is US FDA approved for several self-immunity related conditions including Rheumatoid Arthritis and Psoriasis. You can read more about it here: http://en.wikipedia.org/wiki/Etanercept
Note that although the name is similar, this not Efalizumab which I reported on recently.

The results were solidly good, after 24 weeks:

• HbA1c was lower in the etanercept (5.91 +/- 0.5%) compared to placebo group (6.98 +/- 1.2%)
• The percent change in c-peptide AUC showed a 39% increase in the etanercept group and a 20% decrease in the placebo group
• Insulin dose decreased 18% in the etanercept group compared to 23% increase in the placebo group

So the result in plain English is that the treated patients had, on average, A1C measures 1 lower than the non-treated group. They were generating about 60% more of their own insulin (as measured by c-peptide), and used about 40% less insulin. Overall, very nice results for a phase-I trial.

And before you ask: I don't know if they are planning a phase-II study, and I don't know if this will work on non-honeymooners. I did find two interesting papers that reported that people who had type-2 diabetes and who were treated with Etanercept for rheumatoid arthritis had large drops in their BG numbers. How that maps to people with established type-1 diabetes, I'm not sure. Lastly, although this drug is approved by the US FDA different people may well have different opinions about it's safety. It does carry a black-box warning due to higher rates of infection. (Black-box warnings are the strongest warnings that the US FDA requires on prescription medicines to warn people of potential dangers.)

TNF: Friend or Foe?

This research brings up an interesting conflict in research to cure type-1 diabetes: is TNF a friend or a foe? TNF (tumor necrosis factor) also called TNF-alpha is a protein that kills tumors. It also kills other cells in the body. Several treatments currently in clinical trials for various self-immune diseases are based on interfering with the TNF receptor, and Etanercept is one of these. On the other hand, Faustman holds the opposite theory. Her treatment is based on increasing levels of TNF. The drugs she used on NOD mice (CFA), and in people (BCG) are both expected to raise the level of TNF. Now these two beliefs are not exactly opposite, because Etanercept blocks a TNF receptor, while BCG (and CFA) stimulate the production of TNF itself. However, it is unclear how both Etanercept and BCG can both have a good impact on type-1 diabetes since they effect TNF in opposite ways. If one helps cure type-1 diabetes, the other should make it worse, and visa-versa (at least at first impression). So it is possible to interpret the success of Etanercept as bad news for Faustman. Of course it is also possible that the two work in completely different ways, and TNF is a "red herring" in terms of curing type-1 diabetes.

Here is a link to some discussion of Faustman and TNF:
http://www.faustmanlab.org/docs/mediacoverage/MedPageToday_8-25-08.pdf

Joshua Levy

The short life of Efalizumab (BRiTE) Phase-II Clinical Trial

In early April, I found out about a new phase-II clinical trial, called BRiTE, that tested Efalizumab as a possible honeymoon cure for type-1 diabetes. Efalizumab (tradename "RAPTIVA") is a product of Genentech and is already approved for use on psoriasis and rheumatoid arthritis, which are autoimmune diseases in some ways similar to type-1 diabetes. I was in the process of writing up the summary when the news turned bad.

Later in April, Genentech and the US FDA announced that Genentech was voluntarily withdrawing Efalizumab from the market. I assume that this will mark the end of the type-1 clinical trial as well. Genentech has received 3 reports of progressive multifocal leukoencephalopathy (PML) in people treated with RAPTIVA. This disease is caused by a virus and is almost always fatal (survivors are often brain damaged), and is very rare.

This is a cautionary story for our testing process for new treatments. As the US FDA has said:

Raptiva was approved for the treatment of moderate to severe plaque psoriasis in 2003. There were no cases of PML seen in the clinical trials that supported the approval of Raptiva. At the time of approval, a total of 2,764 patients had been treated with Raptiva. Of those 2,764 patients, 2400 had been treated for three months, 904 for six months, and 218 for one year or more.

Since the approval of Raptiva (efalizumab) in October 2003, the FDA has received reports of three confirmed cases and one possible case of progressive multifocal leukoencephalopathy (PML) in patients who were 47 to 73 years of age who were using Raptiva for the treatment of moderate to severe plaque psoriasis. Two of the patients with confirmed PML and one patient with possible PML died. All four patients were treated with Raptiva continuously for more than three years. None of the patients were receiving other treatments that suppress the immune system while taking Raptiva.

Notice that there is no discussion of clinical testing lasting longer than 2 years, and that the people who got PML had all been taking the drug for over 3 years. The testing that RAPTIVA got is pretty much the same testing that the various type-1 cures currently under development are getting.

And you may want to think back to the bravebuddies discussion of a few months ago ("Ask the FDA to better serve diabetes patients" and "COMMENT ON FDA PETITION", when people were complaining about extra testing that the FDA wanted to require to make sure drugs approved for diabetes did not cause heart problems. Those drugs were getting approved with less than 1 year of testing, and people were howling that the FDA wanted two years or maybe more!)

This is also something to remember if an immunity drug based cure becomes available. If one does we will all be asking ourselves the same question: should my child be first in line to get this cure? It's now been FDA approved, should I get it for my kid right now, or wait. And if I wait, how long? These are not going to be easy questions to answer.

My understanding is that Efalizumab lowers the autoimmunity by targeting a specific type of T-cells, called CD11a. Several other treatments for type-1 diabetes which are currently in clinical trials work by targeting specific types of T-cells, although I don't know of any other drug that targets CD11a cells specifically. ToleRx and MacroGenics both target CD3 cells, while Pescovitz's research targets CD20 cells, and Faustman is targeting certain CD8 cells.

Here is the Clinical Trial record for the type-1 test: http://www.clinicaltrials.gov/ct2/show/NCT00737763
And a press release of the withdrawal: http://www.raptiva.com/raptiva/index.jsp?p=Raptiva&fr=yfp-t-501&toggle=1&cop=mss&ei=UTF-8

Joshua Levy