Alnylam Pharmaceuticals and The Medicines Company have formed an exclusive global alliance to develop and commercialize Alnylam’s early-stage RNAi-based cholesterol-lowering drug for the treatment of hypercholesterolemia, a leading contributor to cardiovascular disease.

The companies will collaborate to advance Alnylam’s ALN-PCS program, which uses RNA interference to silence the PCSK9 protein that regulates low-density lipoprotein receptor levels on liver cells to keep levels of LDL cholesterol low and reduce the risk of cardiovascular disease. The program includes two candidates: an intravenously administered RNAi therapeutic that has completed an early-stage trial with positive results; and a subcutaneously administered drug in preclinical testing.

Alnylam will get $25 million upfront and potential development and commercial milestone payments of up to $180 million. Alnylam will also be eligible for double-digit royalties on all global sales of products resulting from the collaboration. Alnylam will be responsible for advancing the two investigational compounds through early-stage development, after which The Medicines Company will take over all development and commercialization responsibilities.

“For Alnylam, this new partnership enables the advancement of ALN-PCS, an important program within our Alnylam 5x15 product development and commercialization strategy focused on RNAi therapeutics directed toward genetically validated targets,” says John Maraganore, CEO of Alnylam. “We believe that the ALN-PCS program holds great promise for the development of a significant therapeutic option for patients with hypercholesterolemia, and that the unique mechanism of action for ALN-PCS could provide a differentiated and potentially best-in-class strategy for PCSK9 antagonism.”

Cardiovascular disease is a leading cause of mortality worldwide and high LDL cholesterol levels are a major modifiable risk factor. The PCSK9 protein is a hot target for cardiovascular disease risk modifying drugs, with several large pharmaceuticals advancing programs that are much further ahead than Alnylam’s program. Sanofi and Regeneron Pharmaceuticals’ compound has completed two late-stage trials and is being tested in a third trial. Roche and Pfizer both have investigational compounds in mid-stage development. The difference between these drugs and Alnylam’s is that they are monoclonal antibodies that inhibit the activity of PCSK9 after it has formed while Alnylam’s drug silences the expression of a gene to inhibit the formation of PCSK9 in the first place.

RNA interference raised hopes for an effective new class of therapeutics in the mid-2000s, but that was soon dashed by problems with half life and targeted delivery of RNAi-based therapeutics. But improved delivery systems using lipid nanoparticles has rekindled the field. In the past year, Alnylam entered into licensing agreements for the development of pipeline compounds with Arrowhead Research in hepatitis B, Ascletis in liver cancer in China, Genzyme in amyloidosis, and Monsanto for the development of RNAi based products for agricultural use.

The Medicines Company markets Angiomax, an anti-clotting drug used to open clogged arteries during stent procedures. The company originally licensed Angiomax from Biogen Idec where it was invented by Maraganore, now the CEO of Alnylam. It is currently developing a drug that is a “turbocharged form of HDL,” or good cholesterol with the potential to modify the disease through reverse cholesterol transport, says Clive Meanwell, chairman and CEO of The Medicines Company.

“We have seen that PCSK9 gene silencing can substantially reduce LDL-cholesterol in patients and has epidemiological and disease mechanisms studies suggest this can further reduce the risks of the world’s number one killer, coronary artery disease,” says Meanwell. “Clearly we see the complementarity of approaches which increase ‘good cholesterol’ and decrease ‘bad cholesterol’.”