Talk about bad timing. You could almost feel sorry for Genzyme signing a $1.9 billion development and commercialization deal with Isis for mipomersen just days before ENHANCE data shook up the long-held belief that lower LDL equals better cardiovascular outcomes.
Mipomersen is based on the same lower-is-better lipid theory, after all. In fact, the drug targeting apolipoprotein B-100 has been shown to reduce cholesterol and other atherogenic lipids by more than 40 percent beyond reductions achieved with current standard lipid-lowering drugs.
Given the uncharted regulatory environment post-ENHANCE, we weren’t surprised to hear that Genzyme and Isis are pushing back their development timeline for mipomersen. IN VIVO speculated as much in February, and sure enough FDA is requesting more data to support an NDA filing than the firms had originally banked on.
The revised development plan calls for filing in 2010, not 2009, for an initial indication in homozygous familial hypercholesterolemia – a rare, orphan drug indication. It is the planned filing for a broader indication in patients with high cholesterol at high risk of cardiovascular events, including heterozygous FH, that could face a more significant delay, until 2012 or potentially beyond.
While FDA has guided Genzyme and Isis that reduction of LDL-cholesterol is an acceptable surrogate endpoint for accelerated approval for patients with hoFH, the agency is requesting two carcinogenicity studies to be included in the filing, rather than the one the firms had been planning to have completed in time for the submission.
For the broader indication, FDA is requesting a cardiovascular outcomes trial, three words that would send a tremor through even the most deep-pocketed big pharma. Outcomes data means long, expensive trials. Take for example Merck/Schering’s ongoing outcomes trial for Vytorin, IMPROVE IT, which is enrolling 18,000 patients with data anticipated in 2012.
Genzyme and Isis management are assuring investors that they can run a significantly smaller outcomes trial given the high-risk patients that will be enrolled, but that remains to be seen.
The one outcome that is clear is that the cost of developing mipomersen just went up.
And that leads to yet another snag: the transaction hasn’t officially closed. It’s expected to this quarter, but before the door shuts on the deal, there may still be an opening for Genzyme to re-negotiate. Both chief execs were less than forthcoming when asked about re-negotiating, which makes us think some changes are likely.
One line item Genzyme might look to gain an edge on is the development costs. Under the original agreement, Genzyme is responsible for paying all but $75 million of the development costs, meaning it would bear the brunt of the outcomes trial.
The deal also includes a pretty hefty upfront payment - $325 million – but the bulk of the regulatory and commercial milestones hedge Genzyme’s risks. Only $50 million of the $825 million in development and regulatory milestones are related to the homozygous FH indication, with the rest of the allotted payments falling to a heterozygous FH indication, a non-FH indication and approval of a follow-on product.
Read more about mipomersen and the latest regulatory setback at “The Pink Sheet” DAILY.
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