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The Medicines Company and Alnylam Form Strategic Alliance to Develop and Commercialize RNAi Therapeutics Targeting PCSK9 for the Treatment of Hypercholesterolemia

Alnylam Reports Positive Clinical Results for 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 results from this study were presented in April 2012. The Phase I study was conducted as a randomized, single-blind, placebo-controlled, single-ascending dose study in healthy volunteer subjects with elevated baseline LDL-C (>116mg/dL). A total of 32 subjects were enrolled into six sequential dose cohorts ranging from 0.015 to 0.400 mg/kg. Results showed that ALN-PCS, 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%. The effects of a single dose of ALN-PCS support a once-monthly dose administration regimen for future studies. Importantly, ALN-PCS demonstrated consistent clinical activity toward both PCSK9 and LDL-C independent of baseline levels of PCSK9, highlighting the unique mechanism of action for a PCSK9 synthesis inhibitor.

ALN-PCS was shown to be safe and well tolerated in this study and there were no serious adverse events related to study drug administration.

In early 2013, The Medicines Company and Alnylam announced an exclusive global alliance to advance the ALN-PCS program. The collaboration includes program 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 while funded by The Medicines Company for an estimated one to two years to complete certain pre-clinical and Phase I clinical studies. The Medicines Company will then lead and fund development from Phase II forward and commercialize the ALN-PCS program if successful.

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.

Phase I Study-Updated Clinical Results
The Phase I study was conducted as a randomized, single-blind, placebo-controlled, single-ascending dose study in healthy volunteer subjects with elevated baseline LDL-C (greater than 116mg/dL). A total of 32 subjects were enrolled into six sequential dose cohorts ranging from 0.015 to 0.400 mg/kg in a 3:1 randomization of drug to placebo. This trial is being performed in the absence of statins or other lipid lowering therapy Administration of ALN-PCS resulted in rapid, dose-dependent, and durable reductions in LDL-C of up to 50% relative to baseline and placebo, with a statistically significant mean reduction of 41% (p<0.01) at the 0.400 mg/kg dose level. In addition, ALN-PCS administration resulted in rapid, dose-dependent, and durable knockdown of PCSK9 protein levels in plasma of up to 84% relative to baseline and placebo, with a statistically significant mean reduction of 68% in the highest dose group of 0.400 mg/kg (p<0.0001). 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). ALN-PCS was shown to be safe and well tolerated in this study and there were no serious adverse events related to study drug administration. There were no drug-related discontinuations 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.