RNA interference drug lowered LDL in early-stage study

A single dose of ALN-PCS, a small interfering ribonucleic acid drug candidate that works by blocking production of PCSK9, lowered LDL in healthy volunteers as compared with placebo, according to results of a phase 1 study.

Investigators tested ALN-PCS (Alnylam Pharmaceuticals) in 32 healthy adult volunteers (75% men) with elevated LDL who had not received any lipid-lowering therapy in the 30 days before recruitment. For the randomized, single blind, placebo-controlled study, 24 participants received one dose of IV ALN-PCS in doses ranging from 0.015 mg/kg to 0.4 mg/kg and eight participants received placebo.

The primary endpoint was the safety and tolerability of ALN-PCS. Similar proportions of participants in both groups reported mild or moderate adverse events (ALN-PCS, 79%; placebo, 88%). The most common adverse event was rash that may have been related to premedications administered to all participants. One participant assigned a 0.045-mg/kg dose was diagnosed with bilateral pulmonary emboli and deep vein thrombosis 3 days into the study, but the safety review committee determined the diagnosis was not related to the drug.

Participants assigned the highest dose of ALN-PCS, 0.4 mg/kg, experienced an average 70% reduction in circulating PCSK9 compared with those assigned placebo (P>.0001), and an average 40% reduction in LDL from baseline compared with placebo (P>.0001).

The study represents the first demonstration of the effect of an RNA-interfering drug on a clinically validated endpoint in humans, according to the researchers.

“If successfully developed, this class of drugs could be an alternative for the one in five people who are resistant to statins, or be combined with statins to produce even greater effects for the many others for whom the current first-line treatment does not lower cholesterol enough,” Kevin Fitzgerald, PhD, of Alnylam Pharmaceuticals, said in a press release.

In a related editorial, John R. Burnett, MD, PhD, and Amanda J. Hooper, PhD, both of the University of Western Australia in Perth, wrote that the findings “begin to pave the way for expanded [RNA interference]-based therapeutics for the treatment of hypercholesterolemia.

“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,” they wrote. “Since statins upregulate PCSK9, potentially limiting their effectiveness, combination treatment with the addition of a PCSK9 inhibitor could enhance the LDL-lowering effect of statins alone.”

For more information:

Burnett JR. Lancet. 2013;doi:10.1016/S0140-6736(13)61910-8.

Fitzgerald K. Lancet. 2013;doi:10.1016/S0140-6736(13)61914-5.

Disclosure: The study was funded by Alnylam Pharmaceuticals. Thirteen of the 20 researchers are employees of Alnylam Pharmaceuticals. The other researchers, Burnett and Hooper report no relevant financial disclosures.