ALN-PCS is a small interfering RNA (siRNA) that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis, possibly capable of inducing reductions in LDL cholesterol. The siRNA compound is safe and reduces LDL cholesterol, according to randomized clinical trial results published Oct. 2 in The Lancet .

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The single-blind, phase I trial randomized 32 healthy volunteers with raised LDL cholesterol to single doses of ALN-PCS ranging from 0.015 to 0.400 mg/kg or placebo. The highest dose of ALN-PCS was associated with a mean 70 percent reduction in circulating PCSK9 plasma protein (p<0.0001) and a mean 40 percent reduction in LDL cholesterol from baseline relative to placebo (p<0.0001). The rates of treatment emergent adverse events were 79 percent versus 88 percent in the ALN-PCS and placebo groups, respectively.

"Our results suggest that inhibition of PCSK9 synthesis by RNA interference (RNAi) provides a potentially safe mechanism to reduce LDL cholesterol," wrote the investigators. "These results support the further assessment of ALN-PCS in patients with hypercholesterolemia, including those being treated with statins."

In an accompanying editorial, Drs. John R. Burnett and Amanda J. Hooper, University of Western Australia, Perth, WA, note that moving forward, "larger, multi-dose studies of extended duration without the use of premedication are needed to confirm the safety and efficacy of ALN-PCS and should be helpful in determining the optimum dose and regimen to maximize reduction in LDL cholesterol."

Nevertheless, "PCSK9 inhibition is shaping up to be an effective means of lowering LDL cholesterol in patients with severe or refractory hypercholesterolemia who are not able to tolerate statins or have not reached target concentrations of LDL cholesterol," they add. "Fitzgerald and colleagues' results begin to pave the way for expanded RNAi-based therapeutics for the treatment of hypercholesterolemia."

Also commenting on the article, Christie M. Ballantyne, MD, FACC, chair and moderator of the LDL: Assess the Risk Think Tank occurring later this month, notes, "Fitzgerald and colleagues have published the first study in man that shows that siRNA may have benefit in treatment of a clinically validated endpoint, LDL cholesterol. This phase I study examined a siRNA, ALN-PCS, which targets PSCK9 and showed reductions in PCSK9 levels by up to 70 percent with LDL cholesterol reductions up to 40 percent. Even with the many limitations of the study (small sample size, IV infusion, premedications included steroids, etc.), this is an exciting demonstration that new technologies such as siRNA can be used to for novel targets to potentially impact cardiovascular disease."

Keywords: Healthy Volunteers, Proprotein Convertases, RNA, Small Interfering, Cholesterol, LDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiovascular Diseases, RNA Interference, Hypercholesterolemia, Subtilisin, Single-Blind Method

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