Two phase 3 studies with siRNA against PCSK9 meet primary endpoints
Positive topline results for ORION-9 and ORION-10 phase 3 studies evaluating inclisiran have been announced. ORION-9 showed durable and potent efficacy and excellent safety in heterozygous familial hypercholesterolemia (HeFH) patients and ORION-10 showed similar results in patients with atherosclerotic cardiovascular disease (ASCVD). Both ORION-9 and ORION-10 met all primary and secondary endpoints. Inclisiran demonstrated tolerability and safety, with no treatment-related liver or renal laboratory abnormalities.
ORION-9 and ORION-10 form, together with ORION-11, the pivotal phase 3 LDL-c lowering studies of this first investigational cholesterol-lowering therapy in the siRNA class. The siRNA directed against PCSK9 is administered subcutaneously twice yearly. As siRNA, inclisiran harnesses the body’s natural process of RNA interference to specifically prevent production of the PCSK9 protein in the liver, which enhances the liver’s ability to remove LDL-C from the bloodstream, thereby lowering LDL-C levels.
ORION-9 and ORION-10 were both placebo-controlled, double-blind, randomized studies that evaluated the efficacy, safety and tolerability of inclisiran sodium 300 mg in 482 patients with clinical or genetic evidence of HeFH and in 1561 participants with ASCVD, respectively. Participants in both studies had elevated LDL-c despite maximum tolerated dose of LDL-c lowering therapies. The primary endpoints in both studies are % change in LDL-C from baseline to day 510 (17 months) and time-adjusted % change in LDL-C from baseline between day 90 (3 months) and up to day 540 (18 months). Key secondary endpoints include the mean absolute change at day 510, the average absolute reduction from day 90 up to day 540, and changes in other lipids and lipoproteins.
Each study participant received inclisiran sodium 300 mg administered as a subcutaneous injection initially, again at three months and then every six months thereafter. The majority of study participants are taking inclisiran or placebo in addition to existing lipid-lowering therapy with a maximally tolerated statin (with or without ezetimibe).
Detailed efficacy, tolerability and safety data from ORION-10 will be presented at the American Heart Association (AHA) Scientific Sessions in Philadelphia on Saturday, November 16 and of ORION-9 on Monday, November 18.
Regulatory submissions for inclisiran are anticipated to occur in the U.S. in the fourth quarter of 2019 and in Europe in the first quarter of 2020. Patients who have completed their respective Phase 3 studies are now enrolling into ORION-8, an open-label, long-term extension study in which patients completing ORION-9, ORION-10 and ORION-11 will receive inclisiran for three years to generate longer-term efficacy, safety and tolerability data for inclisiran.