Genzyme Taps RNAi Therapeutics for TTR Amyloidosis

Orphan disease gold miner Genzyme has just partnered Alnylam’s promising TTR amyloidosis drug candidate, giving it the right to commercialize resulting medicines in Japan and ‘other Asia-Pacific countries’.  In addition to a healthy $22.5M upfront, Alnylam stands to receive the customary development milestones and actually high royalties for a post-phase I program, plus Genzyme bears responsibility for the regulatory process in the licensed territories.

The basis for this deal, as also expressly stated in the press release, were the potent, ~90% knockdown efficacies obtained in the (single) dose-ranging ALN-TTR02 phase I study (for review, see 'Simply SNALP').  Critically, it was Tekmira’s SNALP delivery technology that made these results possible and catapulted Alnylam’s market cap by ~300M (50% increase in share price) at the time the phase I results were announced this summer.  I should add, however, that in addition to ALN-TTR02, the preclinical subcutaneously administered candidate ALN-TTRsc has been included in the deal. 

Clearly, if they are really serious about the competitiveness of the subcutaneously administered GalNAc-siRNA conjugate, Genzyme has got to be hoping that there won’t be a repeat of the mipomersen (antisense) injection site reaction fiasco which, in addition to the liver fat and immune stimulation issues, is endangering the approval for mipomersen even in the very high unmet medical need population of homozygous familial hypercholesterolemia.  In this case, the adverse event that could drastically lower the deal value soon after its close comes in the form of the Tekmira litigation risk (note: Genzyme is ISIS' partner on mipomersen and should know, also about the strength of the competing subQ ISIS-TTRRx program which is partnered with GSK).  

In case you are wondering what I am alluding to: less than a month after Genzyme invested more than $300M in ISIS and their hypercholesterolemia candidate mipomersen, the FDA issued a Partial Clinical Hold due to significant safety signals with the systemic phosphorothioate oligonucleotide, according to last week’s Briefing Documents for the mipomersen Advisory Committee meeting.   The risk in the TTR case, of course, is the pending litigation with Tekmira, involving the critical RNAi delivery technology enabling the ALN-TTR02 results, its manufacturing and other (e.g. 2’-O-methyl) IP associated with the TTR amyloidosis program.  You would expect that Genzyme would have at least waited for another month or so before closing the deal (trial date in November).  

I doubt that the deal value would have been much higher without the overhang given the size of the Asian TTR market.  But then, of course, nothing can surprise me here any more and a resolution to the Alnylam-Tekmira troubles may already have been hammered out.  A clue may be how Tekmira responds to the news.  If there is tonight a we-are-pleased-that-Genzyme-has-partnered-ALN-TTR02-for-which-we-provide-the-delivery-technology-PR, then it's probably nothing to get excited about.  But if there is silence, then maybe the real news may come with a slight delay.  

Talking of Tekmira, this company, as it is customary in biotech sub-licensing, is likely to receive a partial payment out of the $22.5M upfront (plus a cut of the future income stream related to ALN-TTR02).  Another partnership implication is that Alnylam has talked to Takeda, and Takeda declined on ALN-TTR.  As you remember, in 2008 Takeda forked over $150M to Alnylam, also for being the exclusive Asian partner for 5 years with a right of first refusal for Alnylam drug candidates in the Asian territories.   You’ve got to wonder how comfortable that conversation was, especially after handing over some of that for the ‘technology transfer’.  There might be even less room to hide from Genzyme, as I believe Genzyme and Alnylam may be sharing one building now.

Sarepta Fails to Report Meaningful Dystrophin Expression Data, Falls Behind Prosensa

Restoring truncated, yet largely functional dystrophin in Duchenne Muscular Dystrophy (DMD) by exon skipping is a promising approach to this devastating disease.  For this, however, to have any meaningful therapeutic impact, it has been estimated that one would have to achieve about 20% of wild-type (probably somewhat higher for truncated versions) dystrophin levels in all muscle fibers.

Releasing 48-week data from one of the most manipulated clinical trials that I have seen, Sarepta Therapeutics just reported that treatment with their exon-skipping antisense morpholino eteplirsen resulted in 34-52% dystrophin-positive muscle fibers.  Impressive? I can’t tell, but what is more worrisome is that I don’t know why the company does not tell either.

Percent muscle fibers expressing dystrophin does not mean equal amount of dystrophin restored.

In a New England Journal of Medicine paper last year, Sarepta’s competitor Prosensa (with partner GSK) reported in a similar-sized study that in 10 out of 12 patients, the percent of fibers expressing dystrophin following treatment with their exon skipper PRO051 was between 60 and 100%.  Yes, 60-100% and nost just 34-52% as in Sarepta's case.

What is more, the immunofluorescence intensity and Western blot data in the Prosensa study showed that those fibers expressing dystrophin did so at much reduced levels compared to healthy muscle, on the order of 5-20% (overall bulk levels).  In other words, it is quite likely that the ~50% of fibers that express dystrophin in the Sarepta study together express at most 3-10% of normal dystrophin, well short of what is expected to be therapeutic.  It is also possible, however, that Sarepta’s assay is very sensitive such that even fibers with just 1% or so of wild-type signals were counted in. 

Given that stating the percent fibers expressing any dystrophin is almost meaningless, you have to wonder why Sarepta has not presented the data.

But then you ask, then why did the lame start to walk in the study (à 6 minute-walk-test data)?  Actually, I don’t believe that this was shown in the study either.  Just because this is a devastating disease in children does not mean that rigorous trial design and execution can be entirely done away with.  Yet, in this already tiny 12-patient, single-center (!), and open-label (!) study, the company wisely discarded the worst responders early on allowing the 6 MWT numbers to be 'statistically significant'.   There seemed to be more subgroup analyses presented than patients in the study.  If I were a regulatory agency, I would strongly consider refusing to even just look at the 6 MWT data.

Why am I writing this?  First of all, I am obviously trying to find any shares to short.  And second of all,  what really irks me is that as orphan drugs become more and more popular in drug development, a number of companies are doing away with rigorous science, drive aggressive patient recruiting and disease awareness campaigns (best if a pediatric indication is involved), and expect the rest of us to subsidize the enormous costs of these drugs.  Fine, if the drugs worked, but not for placebos.  Wait another 5-10 years and there will be an enormous backlash and those that need access to these drugs will suffer the most.