Positive preliminary results from Alnylam's Phase I ALN-PCS trial on severe hypercholesterolemia

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today the achievement of positive preliminary results from its ongoing clinical trial of ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of severe hypercholesterolemia. ALN-PCS demonstrated statistically significant RNAi silencing of PCSK9 of up to 66% and reductions of up to over 50% in levels of low-density lipoprotein cholesterol (LDL-C), or "bad" cholesterol, a clinically validated endpoint. Alnylam believes that the preliminary results of this study, presented today at the Brigham and Women's Hospital in Boston, also document for the first time major advances in delivery of RNAi therapeutics with second generation lipid nanoparticles (LNPs) in human studies. This Phase I study continues with planned dose escalation, given the favorable safety profile and positive efficacy achieved to date. Additional results of the study are expected to be reported in the first half of 2012.

"We are extremely pleased with these data from our ALN-PCS trial which represent what we believe is the first ever demonstration of efficacy for an RNAi therapeutic toward a clinically validated endpoint, namely LDL-C, a defined risk factor for coronary artery disease and acute myocardial infarction. Indeed, preliminary results from our ongoing study show robust, statistically significant, and dose-dependent lowering of both PCSK9 and LDL-C levels," said Akshay Vaishnaw, M.D., Ph.D., Senior Vice President and Chief Medical Officer of Alnylam. "The RNAi effects were rapid and durable after a single dose, exemplifying a compelling profile for RNAi therapeutics that we have now established in man for two disease programs."

This Phase I ALN-PCS study is being conducted as a randomized, single-blind, placebo-controlled, single-ascending dose study in healthy volunteer subjects with elevated baseline LDL-C (>116mg/dL). The primary objective of the study is to evaluate the safety and tolerability of a single dose of ALN-PCS, with subjects being enrolled into sequential cohorts of increasing doses. Secondary objectives of the study include characterization of plasma and urine pharmacokinetics of ALN-PCS, assessment of pharmacodynamic effects of the drug on plasma PCSK9 protein levels, and evaluation of clinical efficacy as measured by LDL-C levels. This trial is being performed in the absence of statins or other lipid lowering therapy. The findings presented today describe results from the initial 20 subjects enrolled in five sequential dose cohorts ranging from 0.015 to 0.250 mg/kg in a 3:1 randomization of drug to placebo.

In this study, administration of ALN-PCS resulted in a rapid, dose-dependent, and durable silencing of PCSK9 protein levels in plasma of up to 66% relative to baseline, with a statistically significant mean reduction of 60% at day four in the current high dose group of 0.250 mg/kg (p<0.001). In addition, administration of ALN-PCS resulted in dose-dependent reductions in LDL-C of up to 50% relative to baseline, with a statistically significant mean reduction of 39% at day four (p<0.05) at the 0.250 mg/kg dose level. Nadir effects on PCSK9 and LDL-C were achieved rapidly and occurred approximately four days after administration of a single dose. There was also a dose-dependent increase in the proportion of subjects who achieved "target" levels of LDL-C of less than 100 mg/dL (p<0.05), with 100% (6/6) of subjects in the two highest dose groups achieving target and a mean LDL-C of 84.0 mg/dL, as compared with 21.4% (3/14) of subjects achieving target in any other group. Moreover, the effects of a single dose were durable, supporting a once-monthly dose administration regimen expected in future studies. Further, there was no significant decrease in high-density lipoprotein (HDL), or "good" cholesterol levels, consistent with the phenotype observed in human loss-of-function mutations in PCSK9.

To date, ALN-PCS has been shown to be safe and well tolerated in this study and there have been no serious adverse events related to study drug administration. There have been no drug-related discontinuations from the study and no liver enzyme elevations. A mild, transient rash was observed in five subjects, including two who received placebo. The study is ongoing; based on the favorable safety profile and positive clinical activity to date, the company plans to continue dose escalation.

"Cardiovascular disease remains the leading cause of mortality worldwide, with elevated LDL-C defining the major risk factor. It is clear that new therapeutic options are needed for patients who cannot achieve target LDL levels with current drugs," said Christopher Cannon, M.D., Professor of Medicine, Harvard Medical School. "As a key regulator of the LDL receptor, PCSK9 is one of the most important targets in molecular medicine for the treatment of hypercholesterolemia. An RNAi therapeutic targeting this genetically validated gene has the potential to rapidly and durably lower LDL cholesterol, thereby reproducing the effects observed in loss-of-function human mutations associated with significant clinical benefit."

ALN-PCS is an RNAi therapeutic that utilizes proprietary second-generation LNP technology with the MC3 lipid; this study represents the first human results with this delivery platform. The same RNAi delivery formulation is being used for Alnylam's program on ALN-TTR02, an RNAi therapeutic for the treatment of transthyretin (TTR)-mediated amyloidosis (ATTR).

"These data mark an important milestone in our overall 'Alnylam 5x15' efforts, as they are the first to demonstrate safety, tolerability, and clinical efficacy of an RNAi therapeutic utilizing our second generation lipid nanoparticle delivery technology. In this regard, these data strongly support advancement of our ALN-TTR02 program for the treatment of transthyretin-mediated amyloidosis, where we expect to start clinical studies shortly," said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. "It is also notable that these new data round out a remarkable year of clinical achievement, where we demonstrated RNAi proof of mechanism in biopsy samples from our ALN-VSP liver cancer program, showed human proof of concept with robust TTR lowering in our ALN-TTR01 Phase I study, and now demonstrated human clinical efficacy with LDL-C reductions with ALN-PCS. To say the least, we believe these data provide very strong support for our future efforts in developing RNAi therapeutics as a new class of innovative medicines."