Bristol & Isis: Stop Making Sense

Bristol-Myers Squibb must have missed the memo about the obsolescence of antisense therapies in light of RNA interference advances. The pharma is paying Isis Pharmaceuticals--a prolific and formidable conjuror of IP and drug candidates--$15 million upfront for exclusive rights to the biotech's PCSK9 antisense research program for prevention and treatment of hypercholesterolemia.

Bristol will pay all the bills associated with the discovery, development and commercialization deal, which will focus on Isis' second-generation PCSK9 inhibitors and backup compounds. Isis will also get at least $9 million in research funding over the next three years, up to $168 million in development and regulatory milestones, and high-single-digit to low-double-digit milestones on sales of any drugs. Solid figures for a realtively new discovery program that barely warrants a mention in Isis' own corporate materials.

Did Bristol pay over the odds for such an early stage program? Not necessarily: the deal's financials are roughly in line with its last pre-clinical deal in the space, a more traditional small molecule adventure with Exelixis back in 2005. This time the target (longwindedly, proprotein convertase subtilisin kexin 9) is a protease that helps to regulate levels of LDL cholesterol. Too much PCSK9, too much LDL cholesterol (just why is still undetermined).

And PCSK9 has proven impossible to modulate using small molecules or protein therapeutics, which is why it has drawn attention in the nucleic acid therapy crowd, namely Alnylam Pharmaceuticals and partner UT Southwestern. The RNAi company considers PCSK9 the most intriguing cardiovascular target out there, and aims to file an IND for an injectible PCSK9 inhibitor this year. If Bristol felt the same way about the target, they didn't have many options.

But wait, you say. Statins are cheap, orally available, and generally work well at lowering LDL cholesterol. All true--but Alnylam is targeting the several hundred thousand patients (out of the millions on statin therapy) whose LDL remains out of control despite statin therapy.

Going after a smaller, unsatisfied segment of a massive market like the statins with a specialty therapy may pay off handsomely for biotechs like Alnylam. It will be interesting to see whether Bristol (which has signed two excellent, risk-hedging, biotechy out-licensing deals this year with AstraZeneca and Pfizer) can further embrace the biotech ethos and do the same.

If so it may also take a close look at Isis' apolipoprotein B-100 inhibitor, ISIS 301012, a compound we picked as one of our top-10 licensable cardiovascular projects a few months ago. That Phase II candidate, also being tested as an LDL lowerer against a traditionally undruggable target, ought to land a much more lucrative deal than PCSK9, Isis CEO Stanley Crooke told Reuters today.