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Alnylam Reports Positive Preliminary Clinical Results for ALN-PCS, an RNAi Therapeutic Targeting PCSK9 for the Treatment of Severe Hypercholesterolemia

Alnylam Initiates Phase I Clinical Study of ALN-PCS, an RNAi Therapeutic Targeting PCSK9 for the Treatment of Severe Hypercholesterolemia

Hypercholesterolemia

ALN-PCS: Hypercholesterolemia

Alnylam is developing ALN-PCS, an RNAi therapeutic for the treatment of hypercholesterolemia, or high levels of cholesterol in the blood. Hypercholesterolemia contributes to many diseases, most notably cardiovascular disease - the leading cause of death in the U.S.

ALN-PCS is a systemically delivered RNAi therapeutic targeting the gene proprotein convertase subtilisn/kexin type 9, or PCSK9, a genetically validated target involved in the metabolism of LDL cholesterol (LDLc), or "bad" cholesterol. Our RNAi therapeutic has the potential to lower tissue and circulating PCSK9 levels resulting in higher LDL receptor levels in the liver, and subsequently lower LDLc levels.

Pre-clinical data with ALN-PCS have shown specific silencing of PCSK9 mRNA and PCSK9 serum protein levels of up to 90%, with an ED50 (the dose that provides a 50% silencing effect) of approximately 0.06 mg/kg for both mRNA and protein reduction. These studies have also demonstrated a greater than 50% reduction in levels of LDLc, which is rapid and durable, lasting for weeks after a single dose.

In September 2011, Alnylam initiated the Phase I clinical trial with ALN-PCS. Positive preliminary results from this study were presented in early January 2012. The Phase I 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). Results presented were from the initial 20 subjects enrolled in five sequential dose cohorts ranging from 0.015 to 0.250 mg/kg and is being performed in the absence of statins or other lipid lowering therapy. 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. 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. This Phase I study continues with planned dose escalation, given the favorable safety profile and positive efficacy achieved to date.

We believe that the preliminary results of the ALN-PCs Phase I study also document for the first time major advances in delivery of RNAi therapeutics with second generation lipid nanoparticles (LNPs) in human studies. ALN-PCS employs a proprietary Alnylam second-generation lipid nanoparticle formulation, specifically that using the MC3 lipid.

The Phase I trial of ALN-PCS is being conducted in the U.K. as a randomized, single-blind, placebo-controlled, single-ascending dose study, enrolling approximately 32 healthy volunteer subjects with elevated baseline LDLc (>116mg/dL). The primary objective of the study is to evaluate the safety and tolerability of a single dose of ALN-PCS, with patients being enrolled into five sequential cohorts of increasing doses ranging from 0.015 to 0.25 mg/kg. Secondary objectives include characterization of plasma and urine pharmacokinetics of ALN-PCS, and assessment of pharmacodynamic effects of the drug on plasma PCSK9 protein and LDLc levels measured from serial blood samples prior to and following dosing.

Preliminary Phase I Results
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). This trial is being performed in the absence of statins or other lipid lowering therapy. Data available to date 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.

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. 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 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, 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.

Severe hypercholesterolemia is a condition characterized by very high levels of cholesterol in the blood which is known to increase the risk of coronary artery disease, the leading cause of death in the U.S. Most forms of hypercholesterolemia can be treated through dietary restrictions and medicines such as statins. However, a large proportion of patients with hypercholesterolemia are not being met by statin therapy including genetic familial hypercholesterolemia patients, acute coronary syndrome patients, and other patient populations that are statin intolerant or statin resistant; severe hypercholesterolemia is estimated to affect more than 500,000 patients worldwide. As a result, there is a significant need for novel therapeutics to treat patients with severe hypercholesterolemia whose disease is inadequately managed by existing therapies.