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Alnylam Reports Preclinical Data from Hypercholesterolemia, Hypertriglyceridemia Programs

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NEW YORK (GenomeWeb) – Alnylam Pharmaceuticals this week announced new preclinical data demonstrating the delivery capabilities of its GalNAc conjugate technology in its hypercholesterolemia and hypertriglyceridemia programs.

Alnylam's GalNAc technology facilitates liver delivery of siRNAs via uptake through the asialoglycoprotein receptors expressed on the surface of hepatocytes. The company has sharpened its focus on the approach, using it in its latest drug candidates including the cholesterol-lowering agent ALN-PCSsc, which targets the PCSK9 gene.

At the Arteriosclerosis, Thrombosis and Vascular Biology 2014 Scientific Sessions, Alnylam researchers presented data showing that a single dose of ALN-PCSsc was sufficient to reduce plasma PCSK9 protein levels by up to 96 percent in non-human primates, with a mean knockdown at nadir of 88 percent at the top dose of 10 mg/kg.

Results also showed a lowering of low-density lipoprotein cholesterol (LDL-C) of up to 77 percent, with a mean reduction of 69 percent at the top dose. The results were observed in the absence of statin co-administration, Alnylam noted.

"Knockdown of PCSK9 and lowering of LDL-C were rapid and durable, with maximal effects lasting greater than 90 days and returning to baseline at approximately 160 days," the company stated. At 10 mg/kg, a greater than 50 percent reduction in LDL-C was maintained for over 90 days. A sustained and clamped knockdown of PCSK9 and reduction of LDL-C was observed across this entire time period.

The company said these data support a once-a-month, and potentially a once-a-quarter, dosing schedule for ALN-PCSsc.

In early 2013, Alnylam signed a deal giving The Medicines Company the market rights to all drugs in its hypercholesterolemia program, including ALN-PCSsc and its predecessor, the lipid nanoparticle-formulated, intravenously delivered ALN-PCS. Under the agreement, Alnylam is responsible for developing cholesterol drug candidates through a Phase I trial, after which The Medicines Company will assume all responsibility for the compounds.

Alnylam said that it expects to file an investigational new drug application for ALN-PCSsc in late 2014 or early 2015.

Alnylam scientists also presented data at the meeting on the company's nascent hypertriglyceridemia drug ALN-AC3, which targets apolipoprotein C-III (apoCIII) and is also delivered subcutaneously using the GalNAc technology.

According to the company, the data show that administration of the drug candidate can knock down ApoCIII levels in mice by up to 95 percent, with a reduction in triglyceride levels of up to 68 percent with durability out to over 20 days.

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