Primary and secondary efficacy endpoints met with siRNA against PCSK9News - Aug. 27, 2019
Positive topline results from the first pivotal phase 3 clinical trial evaluating the efficacy, safety, and tolerability of inclisiran to decrease LDL-c through twice-yearly dosing have been announced. The ORION-11 study of inclisiran sodium 300 mg met all primary and secondary endpoints with efficacy consistent with findings from phase 1 and 2 studies. The trial showed that inclisiran was well tolerated and confirmed that the safety profile was at least as favorable as that demonstrated in the ORION-1 Phase 2 and ORION-3 open label extension studies.
Inclisiran is the first cholesterol-lowering therapy in the siRNA (small-interfering RNA) class. As a siRNA, inclisiran harnesses the body’s natural process of RNA interference to specifically prevent production of the PCSK9 protein in the liver. This enhances the liver’s ability to remove LDL-C from the bloodstream, thereby lowering LDL-C levels. In phase 2 studies, inclisiran provided clinically significant LDL-C reductions greater than 50% in addition to the effects of statins and/or ezetimibe, and LDL-C reductions were sustained throughout the six-month dosing interval.
ORION-11 is a pivotal phase 3, placebo-controlled, double-blind, randomized study to evaluate the efficacy, safety, and tolerability of inclisiran sodium 300 mg administered subcutaneously in 1,617 patients with atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents and elevated LDL-C despite maximum tolerated dose of statin therapy (with or without ezetimibe). The international study was conducted at 70 sites in seven countries (ex-US). 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 primary endpoints are percentage change in LDL-C from baseline to day 510 (17 months) and time-adjusted percentage change in LDL-C from baseline after day 90 (three 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.
Detailed efficacy, tolerability and safety data from ORION-11 will be presented during a late-breaking science session at the ESC Congress 2019, Paris, on Monday, September 2 at 8:30 am CET. The sequential release of topline phase 3 data readouts for the ORION-9 and ORION-10 studies are expected to continue later in the third quarter in advance of anticipated regulatory submissions 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 9v) are now enrolling into ORION-8, an open-label, long-term extension study, in which patients will receive inclisiran for three years to evaluate the efficacy, safety and tolerability of long-term dosing of inclisiran.