ALN-PCS Phase 1 Clinical Trial Shows Positive Results

(RTTNews) - Alnylam Pharmaceuticals Inc. (ALNY) and The Medicines Company (MDCO) announced positive initial results from their ongoing Phase 1 clinical trial with ALN-PCSsc at ESC Congress 2015 in London.

ALN-PCSsc is an investigational RNAi therapeutic targeting PCSK9. PCSK9 is a genetically validated protein regulator of LDL receptor metabolism, being developed for the treatment of hypercholesterolemia. In contrast to anti-PCSK9 monoclonal antibodies or MAbs that bind to PCSK9 in blood, ALN-PCSsc is a first-in-class investigational medicine that acts by turning off PCSK9 synthesis in the liver.

In the Phase 1 study, subcutaneous administration of ALN-PCSsc resulted in an up to 83% lowering of LDL-C, with an up to 64 ± 5% mean maximum reduction, comparable to published results for anti-PCSK9 MAbs.

The Phase 1 trial of ALN-PCSsc is being conducted in the U.K. as a randomized, single-blind, placebo-controlled, single ascending- and multi-dose, subcutaneous dose-escalation study. Enrollment in the study has been completed, but the study is ongoing with continued data collection and subject follow up. The study was designed to enroll up to 76 volunteer subjects with elevated baseline LDL-C, with subjects randomized 3:1, drug: placebo. The study was performed in two phases: a single ascending dose phase and a multiple dose phase. The MD phase also includes subjects both on and off statin co-medication. The primary objective of the Phase 1 study is to evaluate the safety and tolerability of ALN-PCSsc. Secondary objectives include assessment of clinical activity as determined by knockdown of plasma PCSK9 levels and lowering of serum LDL-C levels, as well as pharmacokinetics of ALN-PCSsc. Twenty-four patients were assigned to either receive placebo or one of five doses of ALN-PCS ranging from 25 milligrams to 800 mg. Those who received doses of at least 100 mg saw their LDL drop at least 40%, it dropped as much as 78% at the 500 mg dose. More importantly, 140 days after the treatment was given, patients still had an average LDL reduction of about 40%.

The study also gave 45 subjects multiple doses of either ALN-PCS or placebo. These patients had maximal LDL reductions of 80% and average LDL reductions of 50% to 60%. The durable effects of ALN-PCSsc support a once quarterly, and possibly bi-annual, low volume subcutaneous dose regimen for evaluation in further clinical studies. Additional Phase 1 clinical activity results, including further durability data for PCSK9 knockdown and LDL-C lowering effects, as well as changes in exploratory biomarkers such as total cholesterol, apoB, non-HDL-C, and Lp(a) - are planned to be presented at a future date.

ALN-PCSsc was found to be generally well tolerated, with no clinically significant drug-related adverse events to date. There were no serious adverse events or drug-related discontinuations. All adverse events were mild or moderate in severity. At higher drug exposures of 500 mg or greater, four subjects receiving ALN-PCSsc reported mild, localized injection site reactions that resolved without medical intervention. There were also no clinically significant changes in renal function tests.

The lead development responsibility for ALN-PCSsc will now transition from Alnylam to The Medicines Company, who together will be advancing ALN-PCSsc in the ORION development program, a comprehensive global clinical development plan designed to support ALN-PCSsc regulatory approval and market access worldwide. ORION will begin with an initial Phase 2 study that is expected to start by end of 2015. Further, the companies expect that Phase 3 clinical trials will begin in 2017, and that ORION will include a comparative study of ALN-PCSsc with anti-PCSK9 MAbs.

Alnylam and The Medicines Company are collaborating in the advancement of ALN-PCSsc per the companies' agreement formed in early 2013. As per the terms of the agreement, Alnylam will complete certain pre-clinical studies and a Phase 1 clinical study of ALN-PCSsc and The Medicines Company is responsible for leading and funding development from Phase 2 forward as well as potential commercialization.