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

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today positive results from its Phase I clinical trial of ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of severe hypercholesterolemia. ALN-PCS is a PCSK9 synthesis inhibitor that reduces intracellular and extracellular levels of PCSK9 resulting in lowered plasma levels of low-density lipoprotein cholesterol (LDL-C), or "bad" cholesterol. The new data were presented at the American Heart Association's Arteriosclerosis, Thrombosis and Vascular Biology 2012 Scientific Sessions held in Chicago. Results showed that administration of a single dose of 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 new data also highlight continued improved efficacy and tolerability for Alnylam's second-generation lipid nanoparticle (LNP) delivery technology.    

"We are very excited by these new ALN-PCS data that demonstrate robust clinical efficacy for this PCSK9 synthesis inhibitor. Indeed, we believe the unique mechanism of action for ALN-PCS, which inhibits the synthesis of PCSK9 in liver cells thereby reducing both its intracellular and extracellular functions, provides a differentiated strategy for PCSK9 antagonism. This mechanism of action for ALN-PCS results in potent and durable LDL-C reductions and consistent clinical activity across a wide range of baseline PCSK9 plasma levels, including individuals with very high PCSK9 levels," said Akshay K. Vaishnaw, M.D., Ph.D., Senior Vice President and Chief Medical Officer of Alnylam. "These new results show very robust, statistically significant, and dose-dependent lowering of both PCSK9 and LDL-C levels in a single dose study performed in the absence of statin co-administration. In addition, ALN-PCS treatment was well tolerated at all dose levels studied to date indicating the potential to even further dose escalate in future studies."

"Cardiovascular disease remains the leading cause of mortality worldwide, with elevated LDL-C a major modifiable risk factor. A substantial number of patients cannot achieve target LDL levels with current drugs, such as statins, and it is clear that new therapeutic options are needed," said Daniel J. Rader, M.D., Director of Preventive Cardiovascular and Associate Director of the Institute for Translational Medicine and Therapeutics at University of Pennsylvania. "As a key regulator of the LDL receptor, liver-expressed PCSK9 is one of the most important and best validated new targets in molecular medicine for the treatment of hypercholesterolemia. An RNAi therapeutic targeting PCSK9 expression in the liver has the potential to rapidly and durably lower LDL cholesterol, thereby reproducing the effects observed in loss-of-function human mutations that are associated with significant clinical benefit. I am very encouraged by the ALN-PCS data generated to date and look forward to continued studies that highlight the unique mechanistic approach of PCSK9 synthesis inhibitors, including the potential magnitude and durability of LDL-C response when ALN-PCS is co-administered with statins."

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). The primary objective of the study was to evaluate the safety and tolerability of a single dose of ALN-PCS. Secondary objectives of the study included assessment of pharmacodynamic effects of the drug on plasma PCSK9 protein levels and evaluation of clinical efficacy as measured by LDL-C levels. 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.

In this study, 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). 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. There were no drug-related discontinuations and no liver enzyme elevations. There was also no significant change compared to baseline in levels of high-density lipoprotein (HDL), or "good" cholesterol, consistent with the phenotype observed in human PCSK9 loss-of-function mutations.

"These data mark yet another important milestone in our overall 'Alnylam 5x15' efforts, as they demonstrate continued safety, tolerability, and robust clinical efficacy of an RNAi therapeutic targeting a liver-expressed disease gene utilizing our second generation lipid nanoparticle delivery technology," said Barry Greene, President and Chief Operating Officer of Alnylam. "In particular, these new data strongly support continued advancement of ALN-TTR02, an RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR), which employs the same second generation LNP delivery formulation as ALN-PCS. Dosing in our ALN-TTR02 clinical study has recently been initiated and we are on track to report data in the third quarter of this year."