Teva Ups Stake in Co. Pursuing Heat Shock Therapy to Stop Autoimmune Diabetes

Last week (June 14, 2010), Israeli drug giant Teva Pharmaceutical Industries Ltd., a company perhaps best known for being the largest manufacturer of generic drugs sold in the U.S., announced that it had exercised an option to raise its ownership stake (to 16%, up from 10% previously) in a company known as Andromeda Biotech (see here and here for more about the latest development). It should be noted that in spite of it's dominace in generics, Teva is not exclusively a generics drug developer/manufacturer, the company also some has its own branded drugs in neurosciences, respiratory and biologics/specialty products, some of which are blockbusters in their own right, even though a majority of it's products (and revenues) are derived from generics.

Although the Teva investment is a general stake in a biotech company, the primary product being developed by Andromeda is a drug that's been in development for well over a decade now (perhaps 15 years or so if I'm not mistaken), known as DiaPep 277®, which is a contraction of the term 'diabetes' and 'peptide' plus some numbers. DiaPep 277 has been treated something like a hot potato over the past decade, as the rights to the drug back in 1997 were then owned by a pharmaceutical company known at the time as Aventis (now Sanofi Aventis), which also makes Lantus and Apidra insulin analogues. At some point (in 2004), Aventis decided that investing more money into DiaPep 277 might be detrimental to it's mega cash-generating insulin business, so they cancelled any further development when the initial contract expired.

A short while after, another Israeli firm named Andromeda Biotech (which has nothing to do with outer space, galaxies, or constellations, but the name is certainly memorable) was formed in 2007 and picked up the rights to the drug, which is a subsidiary of specialized investment firm based in Israel known as Clal (which reportedly means "inclusive" in Hebrew if my sources are correct) Industries and Investments, and it's biotechnology unit (CBI) believed that DiaPep 277 still had sound business potential as a possible autoimmunity treatment for type 1 diabetes and that the science behind it was promising, therefore made some investments (to the tune of somewhere around $10-$15 million) to keep development moving ahead.

A few years ago, the folks at Clal then convinced drug giant Teva to invest in DiaPep 277 (see here for the latest announcement) even though Aventis had dumped it, and in 2009, Teva acquired the worldwide rights to market Diapep 277 if and when it is ever approved. Teva initially made an investment, with options to expand it's ownership stake contingent upon certain development hurdles being met, thus the latest announcement.

What is DiaPep 277? Good question. Here's Some Background.

DiaPep 277 is a synthetic peptide (fragment) consisting of 24 amino acids which are derived from a sequence of the human heat shock protein 60 (Hsp60). This is a protein that's generated naturally by the body when stressed. In 2002, Diabetes In Control had a fairly decent overview written in laymen's terms, and you can view that here. For some additional background, you may also read this brief write-up by immunologist Professior Irun Cohen at the Weizmann Institute of Science, although I didn't find it answered any additional questions about exactly how the treatment works. But Dr. Cohen happens to be a native of Chicago and studied at Johns Hopkins University, so presumably he's pretty knowledgable on the subject matter.

At a very basic level, it is believed that DiaPep 277 somehow modulates the body's immune system (although relatively few details on exactly how it does this have been published, so details are clearly lacking), thus preventing the destruction of pancreatic beta cells that secrete insulin and therefore helps to preserve their natural function. It appears that it may work best in newly-diagnosed patients, but it's much less clear if it has any applicability to longstanding patients. Still, if it works, it could be promising autoimmunity treatment, increasing the number of different options available to doctors and patients.

In many respects, if DiaPep 277 is approved, this treatment would perform a very similar function as MacroGenics' teplizumab or Tolerx's otelixizumab anti-CD3 antibody treatments are supposed to (both of which are now recruiting for their own Phase III human clinical trials): stopping the immune system attack on the pancreatic beta cells, thereby preserving functionality and hopefully setting the stage to restore endogenous insulin production either via some kind of transplant (such as islets), or beta cell regeneration, or some combination thereof. In medical research lingo, this would be described as one component of a "biological cure" for type 1 diabetes, but really two (or more) elements would be required to restore insulin independence.

Where Things Currently Stand With DiaPep 277

DiaPep 277 is now already conducting Phase III human clinical trials at 40 sites in Europe, Israel, and South Africa (but NOT the U.S. or Canada, at least presently, although I believe they've announced recruiting plans for a North American leg of the second part of it's Phase III trials). Based on where things now stand with DiaPep 277's trials, it's fair to say that DiaPep 277 is roughly at the same phase of development as the Macrogenics and Tolerx treatments are, in spite of nearly 15 years of testing and repeated changes in ownership. However, I should point out that for the Phase III trial, a total of 456 newly diagnosed adult and adolescent patients with type 1 diabetes have already successfully been recruited to the study for a treatment period of 2 years (the trial is scheduled to end sometime next year -- in 2011). However, this is not enough trial participants for U.S. or European regulatory approval, thus a second leg of the trial has been added which will presumably increase the number of trial participants needed to ensure the trial results can meet U.S. and European regulatory requirements.

Adromeda Meeting Development Hurdles Means Teva's Investment Will Grow

Apparently, some of the development hurdles Teva had in it's agreement with Andromeda appear to have been met, thus the recent announcement that Teva would increase it's stake in the company, albiet only marginally (an increase of 5%, but for a startup, it's nevertheless a very important and significant source of funding).

Questions on DiaPep's Prospects?

Josh Levy, who writes a blog called "Current Research into a Cure for Type-1 Diabetes" that I follow writes that DiaPep 277 was the earliest possible type 1 cure to go into Phase III human clinical trials (way back in 2005, if I'm not mistaken), and he's always been a bit more pessimistic than I have been about the prospects for this autoimmunity treatment. He argues that the early results were "not very promising, but they added more people to the trial".

Josh and I differ somewhat in how we have interpreted the published trial result information that has been released (at least in the public domain) to date. As I understood it, the reality was that they began the trial with fewer people than regulators in the U.S. and Europe require, but when the results turned out as expected, they then expanded the number enrolled in the trial to meet the U.S. and European approval requirements. There could be any number of reasons why they started with fewer research participants, but one of the most likely is money -- it's far cheaper to start a trial with fewer participants. According to an update I read a while back on Andromeda's website (see here), the following was reported:

"Based on the phase II clinical trials, a phase III clinical trial at 40 sites in Europe, Israel, and South Africa was designed and is currently being conducted.

The study involves 400 patients which includes adults and adolescents for a treatment period of two years.

An interim analysis was performed on 137 patients who completed 12 months of treatment, of which 100 of them completed 18 months of therapy.

An Independent Data Monitoring Committee (IDMC) carefully reviewed the findings from the trial and recommended proceeding with the study as originally designed.

The results showed that no significant drug related adverse events, serious adverse events or lab abnormalities were reported and that there are no safety concerns in continuing the study.

In the study, it was observed that when comparing a population similar to those who participated in the phase II studies, the effect of the drug was similar.

The observed trend of the effect may become more significant once a larger sample size is analyzed.

It was recommended to test a larger number of patients to confirm the effect observed in the current analysis.

In addition, it was recommended to proceed with the study without any change to the design and continue the enrollment of new patients."

Press Releases Written By Non-Native English Speakers Might Skew Understanding

Josh zeroed in on the statement "In the study, it was observed that when comparing a population similar to those who participated in the phase II studies, the effect of the drug was similar" but this does not actually disclose the results of the trial itself. I believe Josh may have assumed that to be the case. He concluded that the results of DiaPep 277 were similar to a placebo, rather than the results being similar to results observed in trial participants in the Phase II trial, which was how I interpreted this statement. I will say that sometimes, when a press release is done by a non-native English speaker (even those whose command of the English language is quite good), some ways of expressing certain elements can be somewhat peculiar and subject to misunderstanding. We have seen how this can occur when a recent BP executive named Carl-Henric Svanberg, whose native language is Swedish, recenly gave a press conference after BP's 4-hour meeting with President Obama at the White House about the massive oil spill into the Gulf of Mexico and clumsily stated that BP cares about "small people" which was widely seen as condescending and rude when his intent may not have been meant that way.

What We Know And Don't Know About DiaPep 277

The simple reality is that not every detail from these drug trials gets published, particularly if those trials have no U.S. arm to them (which has indeed been the case with DiaPep 277, therefore they won't show up on the clinicaltrials.gov website). Josh cited an article from an Israeli newspaper which claimed that "The reason is that the interim result does not provide statistically significant results about the effectiveness of DiaPep 277" which he concluded meant there were not statistically significant results, thus in one of his more recent updates on this treatment, he also claimed that they "changed the way they analyzed the data, and are hoping for good results", but "So far, I have not seen any good news type results from this study, but Andromeda seems very positive, and Teva has put in over [U.S.] $15 million over the last year, so they think that something is there. I just do not see it myself."

That's true, but I don't believe we can draw any solid conclusions based on data we don't see. Frankly, I don't believe Teva would have invested $15 million in something that looked questionable at best, nor would the company increase it's investment, but again, without seeing any specifics, it's quite hard to reach any conclusions. But I can say that the details on the trials have been very hard to come by (Josh Levy doesn't have any referenced on his blog, and I'm not aware of any, either, so aside from those on Andromeda's website, many of which are more than a few years old, the details are few and far between). But, I will say that sometimes studies may appear to show the worst, but when the data is re-examined shows something else, and Andromeda concluded that it was indeed worth proceeding to the next phase of trials.

Re-Examining Data Happens Frequently in Clinical Trials

Consider another recent example of where re-examining trial data turned the results of a trial completely around. As I wrote (see here) in January 2010, Biodel, Inc., which has a new, rapid-acting insulin (and a non-analogue!) called VIAject now pending approval (a decision from the FDA is expected by later this year) in the U.S. and Europe, but a leg of it's Phase III clinical trial in India nearly ended what looks to be the first-ever rapid-acting regular insulin. What happened? The short story is that VIAject trials took place in the U.S., Germany and India. The U.S. and German results were exactly as anticipated, proving the new insulin met the clinical trial results, but this was not the case with the Indian results. After closer examination, the reason was because the blood test results in the Indian trial were tainted by the hot India temperatures. The FDA suggested to the company that they re-examine the data, and when an identifiable subset of blood samples from the Indian trial was excluded from the results, the company found that the Indian trial results were indeed comparable to those in the U.S. and Germany trials. This example shows that re-examining clinical trial results occurs often, and can sometimes can change the outcome from what seems dubious to strongly in the opposite direction. It is not simply about spinning results, but looking at items that may not be apparent to the casual observer, and I don't believe we know enough about DiaPep 277 to draw any conclusions at this time.

Expert Feedback

To get some perspective on the use of this heat shock protein therapy to arrest beta cell destruction, I reached out to some authorities on this subject, some of the immunologists and other experts at the University of Miami Miller School of Medicine's Diabetes Research Institute (DRI).

Several people at the DRI were familiar with DiaPep 277 (in fact, the DRI Executive Director of Medical Development Gary Kleiman said that he was aware of this work/company 15+ years ago), but that they too haven't seen much in the way of solid data on the subject. When I asked if there was any additional data that had been published in the medical or scientific journals on this treatment, Dr. Alberto Pugliese responded by indicating that there was very little he could add since he was not aware of any new published or new unpublished data that might add to the known information. Clearly, the work has been ongoing for some time, but only selected tidbits of information have made it into the public domain. For that reason, we must trust that the research being done is reliable and will satisfy regulatory authorities if and when it is finally submitted for approval. The countdown, however, is on because Teva and Andromeda indicate that the first segment of the Phase III clinical trial will be wrapped up in 2011, and they are presently recruiting for the second Phase III clinical trial. In the interim, watching Teva's moves may be an infrequent but reliable indication as to whether key (and importatnt) milestones are being met, and this latest investment suggests that is indeed happening. We'll just have to stay tuned for more!