Hypercholesterolemia

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.

Some forms of hypercholesterolemia can be treated through dietary restrictions, lifestyle modifications (e.g., exercise and smoking cessation) and medicines such as statins.  However, a large proportion of patients with hypercholesterolemia are not achieving target LDL cholesterol (or ‘bad’ cholesterol) goals with statin therapy, including genetic familial hypercholesterolemia patients, acute coronary syndrome patients, high-risk patient populations (e.g., patients with coronary artery disease, diabetics, symptomatic carotid artery disease, etc.) and other patients that are statin intolerant.  Severe forms of hypercholesterolemia are estimated to affect more than 500,000 patients worldwide, and as a result, there is a significant need for novel therapeutics to treat patients with hypercholesterolemia whose disease is inadequately managed by existing therapies.

We are developing an RNAi therapeutic targeting PCSK9 (proprotein convertase subtilisin/kexin type 9) in collaboration with The Medicines Company.  Inhibition of PCSK9 synthesis through an RNAi mechanism has the potential to lower tissue and circulating plasma PCSK9 protein levels resulting in higher expression of LDL receptor in the liver, and consequently lower LDL cholesterol levels in the blood stream.  Lower LDL cholesterol is associated with a decreased risk of cardiovascular disease, including myocardial infarction and stroke. ALN-PCS therapies are PCSK9 synthesis inhibitors that lower levels of 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). Further, RNAi therapeutics can block PCSK9 synthesis across a wide range of plasma PCSK9 levels, which are known to vary widely amongst individuals and are also elevated in association with statin therapy.

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ALN-PCSsc for the Treatment of Hypercholesterolemia

We previously conducted a Phase 1 trial with ALN-PCS02 – an intravenously administered RNAi therapeutic targeting PCSK9, and published results from this study in The Lancet (Fitzgerald, et al., The Lancet, doi:10.1016/S0140-6736(13)61914-5).  This study provided key human proof of concept for an RNAi therapeutic approach.  Specifically, ALN-PCS02 administration, in the absence of statin co-administration, resulted in a rapid, dose-dependent reduction in plasma PCSK9 of up to 84% relative to baseline and placebo, with a corresponding reduction in serum levels of LDL cholesterol – a clinically validated endpoint – of up to 57% relative to baseline and placebo.  The knockdown of PCSK9 and lowering of LDL cholesterol were also found to be durable, with effects lasting for weeks after a single dose.  Further, ALN-PCS02 showed a similar knockdown of PCSK9 and reduction of LDL cholesterol across the wide range of PCSK9 plasma levels at baseline, confirming that RNAi therapeutics targeting PCSK9 have the potential to provide a consistent response.  ALN-PCS was shown to be generally well tolerated in this Phase 1 study.  These results document the first human proof of concept for an RNAi therapeutic impacting a clinically validated endpoint – that of LDL cholesterol.

We are now evaluating an RNAi therapeutic targeting PCSK9 that utilizes our GalNAc conjugate delivery platform, enabling subcutaneous administration with a wide therapeutic index.  Subcutaneous dosing holds the potential for administration of a therapeutic in patients less invasively than intravenous dosing.  In October 2013, we selected a Development Candidate, ALN-PCSsc, to advance into clinical trials.  Pre-clinical data in non-human primates showed that ALN-PCSsc led to up to 95% PCSK9 knockdown and up to 67% lowering of LDL cholesterol in the absence of statins.  In addition, pre-clinical durability data are supportive of dosing as infrequently as once or twice per month .  These new data with subcutaneous delivery support our belief that the unique mechanism of action for ALN-PCSsc holds great promise for a differentiated and potentially best-in-class strategy for PCSK9 antagonism.  We anticipate submitting an investigational new drug (IND) application for ALN-PCSsc in late 2014 or early 2015.

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In February 2013, we formed an exclusive global alliance with The Medicines Company for the development and commercialization of the ALN-PCS program.  Alnylam is leading the program through the completion of Phase 1.  The Medicines Company is responsible for leading and funding development from Phase 2 forward and commercializing the ALN-PCS program if successful.

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New Pre-Clinical Data on ALN-PCSsc and ALN-ANG Presented at AHA

New Pre-Clinical Data on ALN-PCSsc and ALN-ANG Presented at AHA

We presented new pre-clinical data with RNAi therapeutic programs for cardiovascular disease: ALN-PCSsc, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; and ALN-ANG, an RNAi therapeutic targeting ANGPTL3 for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia. These data were presented at the American Heart Association (AHA) Scientific Sessions held November 16 – 20, 2013 in Dallas, Texas. The data showed that subcutaneous administration of ALN-PCSsc led to an up to 95% knockdown of plasma PCSK9 and an up to 67% reduction of low density lipoprotein cholesterol (LDL-C) – in the absence of statin co-administration. In addition, new results for ALN-ANG demonstrated a greater than 95% reduction of triglycerides and greater than 85% reduction of LDL-C in a rodent model of mixed hyperlipidemia.



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Positive Phase I Clinical Trial Results with ALN-PCS Published in “The Lancet”

Positive Phase I Clinical Trial Results with ALN-PCS Published in “The Lancet”

We have published complete study results from our Phase I trial with ALN-PCS in The Lancet. As reported in the paper, ALN-PCS administration resulted in a rapid, dose-dependent reduction in plasma PCSK9 of up to 84% relative to baseline and placebo, with a corresponding reduction in serum levels of low-density lipoprotein cholesterol (LDL-C) – or “bad” cholesterol – of up to 57% relative to baseline and placebo. The knockdown of PCSK9 and lowering of LDL-C were also found to be durable, with effects lasting for weeks after a single dose.  In addition, ALN-PCS was shown to be generally safe and well tolerated in this Phase I study and there were no serious adverse events related to study drug administration.  This new paper documents the first human proof of concept for an RNAi therapeutic impacting a clinically validated endpoint, namely LDL-C.



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Positive Clinical Results for ALN-PCS, Reported at ATVB 2012

Positive Clinical Results for ALN-PCS, Reported at ATVB 2012

Yesterday, scientists presented positive results from our Phase I clinical trial of ALN-PCS 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%.



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