The Medicines Company, a global pharmaceutical company, and Alnylam Pharmaceuticals, an RNAi therapeutics company, have formed an exclusive global alliance for the development and commercialization of Alnylam's ALN-PCS RNAi therapeutic program targeting PCSK9 for the treatment of hypercholesterolemia.

The Medicines Company will make an upfront cash payment of $25 million to Alnylam. Alnylam may also receive potential development and commercial milestone payments of up to $180 million. Alnylam will be eligible to receive scaled double-digit royalties on global products sales of ALN-PCS products.

The pair will collaborate on the advancement of the ALN-PCS program, which includes ALN-PCS02, an intravenously administered RNAi therapeutic which has completed a phase I trial, and ALN-PCSsc, a subcutaneously administered RNAi therapeutic currently in pre-clinical development. Alnylam will continue the program for an estimated one to two years to complete certain pre-clinical and phase I clinical studies. The Medicines Company is responsible for leading and funding development from phase II forward and commercializing the ALN-PCS program if successful.

"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,” said John Maraganore, Ph.D., 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."

Clive Meanwell, M.D., Ph.D., chairman and CEO of The Medicines Company, said, "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. Clearly we see the complementarity of approaches which increase 'good cholesterol' (HDL-C) and decrease 'bad cholesterol' (LDL-C). We look forward to working with our colleagues at Alnylam."

PCSK9 (proprotein convertase subtilisin/kexin type 9) is a protein that regulates LDL receptor levels on hepatocytes; gain-of-function human mutations in PCSK9 are associated with hypercholesterolemia while loss-of-function mutations are associated with lower levels of LDL cholesterol and a reduced risk of cardiovascular disease. ALN-PCS is a PCSK9 synthesis inhibitor that reduces intracellular and extracellular levels of PCSK9 resulting in lowered plasma levels of LDL-C. MDCO-216 is a naturally occurring variant of a protein found in high-density lipoprotein, or HDL. It is a reverse cholesterol transport agent designed to reduce atherosclerotic plaque burden development and thereby reduce the risk of adverse thrombotic events.

Alnylam has completed a phase I trial of ALN-PCS02 in healthy volunteer subjects with elevated baseline LDL-C. Results showed that administration of a single intravenous dose of drug, in the absence of concomitant lipid-lowering agents such as statins, resulted in statistically significant and durable reductions of PCSK9 plasma levels of up to 84% and lowering of LDL-C of up to 50%. ALN-PCS02 was shown to be generally safe and well tolerated in this study and there were no serious adverse events related to study drug administration. Alnylam has also presented pre-clinical data from its ALN-PCSsc program demonstrating potent knockdown of the PCSK9 target gene with an ED50 of less than 0.3mg/kg after a single subcutaneous dose.