Alnylam seeks CTA clearance to initiate ALN-PCS Phase I clinical trial for severe hypercholesterolemia

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it has filed a Clinical Trial Application (CTA) with the Medicines and Healthcare products Regulatory Agency (MHRA) to initiate a Phase I clinical trial with ALN-PCS, an RNAi therapeutic for the treatment of severe hypercholesterolemia. Upon receiving clearance of the CTA, Alnylam plans to initiate the Phase I trial and expects to present initial safety, tolerability, and clinical activity data from this study by the end of this year.

“a major scientific breakthrough that happens once every decade or so”

"The filing of this CTA marks an important milestone in our Alnylam 5x15 product efforts, as it is the first program using our second generation lipid nanoparticle technology to enter clinical testing, where we aim to have important safety, tolerability, and clinical activity data by year's end. Moreover, we are excited about the potential for ALN-PCS to make an impact in the treatment of severe hypercholesterolemia as this RNAi therapeutic targets both intracellular and extracellular PCSK9, a target validated by human genetics that is known to play a central role in LDL cholesterol metabolism," said Akshay K. Vaishnaw, M.D., Ph.D., Senior Vice President and Chief Medical Officer of Alnylam. "We continue to execute on our Alnylam 5x15 initiative, which is focused on advancing innovative RNAi therapeutics that address genetically defined targets and diseases with high unmet medical need. ALN-PCS represents the second of such programs, following ALN-TTR01 which is currently in a Phase I trial with data expected later this quarter."

ALN-PCS is a systemically delivered RNAi therapeutic targeting the gene proprotein convertase subtilisin/kexin type 9, or PCSK9, a target validated by human genetics that is involved in the metabolism of low-density lipoprotein cholesterol (LDLc, or "bad" cholesterol). ALN-PCS targets both intracellular and extracellular PCSK9, thereby phenocopying the human genetics observed in loss of function or null human PCSK9 mutations (N. Engl. J. Med. (2006) 354:1264-1272; Am. J. Hum. Genet. (2006) 79: 514-523), without any adverse effects on high-density lipoprotein (HDL, or "good" cholesterol) levels. An RNAi therapeutic targeting PCSK9 has the potential to lower tissue and circulating plasma PCSK9 protein levels resulting in higher LDL receptor levels in the liver, and subsequently lower LDLc levels. Lower LDLc is associated with a decreased risk of cardiovascular disease, including myocardial infarction. Pre-clinical data from the ALN-PCS program have shown specific silencing of PCSK9 mRNA in the liver, and plasma PCSK9 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.

As per the filed CTA, the Phase I trial of ALN-PCS is expected to be 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.

ALN-PCS is an RNAi therapeutic that utilizes proprietary Alnylam second-generation lipid nanoparticle (LNP) technology, specifically that using the MC3 lipid.