ORION 1: Inhibition of PCSK9 Synthesis Via RNA Interference

Inclisiran, an interference RNA, may reduce the volume of PCSK9 inhibitor injections to lower cholesterol, according to the results of the ORION 1 Trial presented Nov. 15 during AHA 2016.

Kausik K. Ray, MD, MPhil, FACC, et al., assessed a range of doses of inclisiran, which could provide qualitatively similar reductions in LDL-C to current approaches, but through quarterly or bi-yearly injections (every three or six months). A total of 501 patients (average age 63, 65 percent male) were randomized in a Phase 2 double blind placebo trial to six doses of interference RNA. About 69 percent of patients had atherosclerotic cardiovascular disease, 24 percent had diabetes, 13 percent were being treated for primary prevention and the rest had familial hypercholesterolemia (5 percent).

At baseline, 81 percent were on statins and 31.7 percent were on the cholesterol-lowering drug ezetimibe. The principal endpoint was percentage change in LDL-C at day 180.

The results of the trial show that inclisiran inhibits PCSK9 synthesis by RNA interference and lowers LDL-C significantly. One dose of 300mg achieved a mean 51 percent LDL-C reduction, while two doses of 300mg achieved a mean 57 percent reduction. Further, inclisiran was found to be well tolerated with no safety issues.

The authors of the study note that "the efficacy, safety and dosing profile of inclisiran are likely to ensure significant and durable reductions in LDL-C and thus potentially impact cardiovascular outcomes."

Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents

Keywords: AHA16, American Heart Association, AHA Annual Scientific Sessions, Cholesterol, LDL, Acute Coronary Syndrome, Cytoplasm, Dyslipidemias, Proprotein Convertases, RNA Interference

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