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Blocking PCSK9 synthesis with siRNA shows promise in LDL-C lowering

Jackey Suen
04 Sep 2017
Prof Kausik Ray

Blocking the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) with one to two injections of small interfering RNA (siRNA) provides sustained LDL-cholesterol (LDL-C) lowering for up to 1 year in patients with high cardiovascular (CV) risk and elevated LDL-C levels, the phase II ORION-1 study has shown.

“In contrast to PCSK9 monoclonal antibody treatments which require 12 to 26 injections per year, the investigated siRNA approach requires only one to two injections per year,” explained principal investigator Professor Kausik Ray of the Imperial College London, UK.

Inclisiran, the drug studied in ORION-1, is a PCSK9 messenger RNA-targeted siRNA. It is conjugated to N-actylgalactosamine for targeted delivery to hepatocytes, the major site for PCSK9 production.

The study included 501 patients who had either atherosclerotic CV disease (ASCVD) and LDL-C levels >70 mg/dL despite maximum tolerated statin therapy or LDL-C levels >100 mg/dL without ASCVD. They were randomized to receive a single injection of inclisiran 200 mg, 300 mg or 500 mg, two injections (given on day 1 and day 90) of inclisiran 100 mg, 200 mg or 300 mg, or placebo.

The 6-month outcomes, reported previously, showed that the primary endpoint of LDL-C reduction was greatest in patients who received two injections of inclisiran 300 mg. [N Engl J Med 2017, doi: 10.1056/NEJMoa1615758]

“At 1-year extended follow-up, the overall safety profile remained numerically similar between the treatment groups and placebo groups. No new safety concerns were identified,” reported Ray.

The time-averaged LDL-C reductions at 1 year were 30 percent, 37 percent and 39 percent with one dose of inclisiran 200 mg, 300 mg and 500 mg, respectively, and 30 percent, 40 percent and 46 percent with two doses of inclisiran 100 mg, 200 mg and 300 mg, respectively.

“In patients receiving two doses of inclisiran 300 mg, the mean LDL-C levels on day 270 were similar to that on day 90. The LDL-C levels also remained steady throughout 90 and 270 days, with a time-averaged LDL-C reduction of 51 percent accompanied by a tight interquartile range,” said Ray. “This suggests that inclisiran may be given at a dose of 300 mg on day 1 and day 90, and every 180 days thereafter.”

“With these exciting findings, inclisiran is now being investigated in multiple phase III trials. These include ORION-10 and ORION-11 [3,000 patients with ASCVD or high CV risk], ORION-9 [400 patients with heterozygous familial hypercholesterolaemia (FH)], and ORION-5 [60 patients with homozygous FH],” he noted. “We are also designing a CV safety outcome trial, which will include 15,000 patients with high ASCVD risk.”

“In contrast to PCSK9 monoclonal antibodies, inclisiran inhibits all functions of PCSK9 as it blocks the synthesis of PCSK9,” commented Professor Philip Barter of the University of New South Wales, Sydney, Australia. “A longer and larger study is needed to confirm the safety of inclisiran, as the impact of PCSK9 synthesis blockade beyond LDL-C lowering remains uncertain.”

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