Findings from a pooled post-hoc analysis of three phase 3 trials demonstrated that treatment with twice-yearly inclisiran reduced low-density lipoprotein cholesterol (LDL-C) regardless of body mass index (BMI).
Inclisiran is a chemically synthesized small interfering RNA that targets proprotein convertase subtilisin-kexin type 9 (PCSK9) messenger RNA. The subcutaneous injectable is being investigated for its ability to lower LDL-C through twice-a-year dosing.
The randomized, double-blind, placebo-controlled, ORION-9 (ClinicalTrials.gov Identifier: NCT03397121), ORION-10 (ClinicalTrials.gov Identifier: NCT03399370), and ORION-11 (ClinicalTrials.gov Identifier: NCT03400800) trials evaluated the efficacy and safety of inclisiran in patients 18 years of age and older with elevated LDL-C despite maximally tolerated doses of LDL-C lowering therapies (eg, statin and/or ezetimibe).
ORION-9 included 482 patients with heterozygous familial hypercholesterolemia; ORION-10 included 1561 patients with atherosclerotic cardiovascular disease (ASCVD); and ORION-11 included 1617 patients with ASCVD or ASCVD-risk equivalents. Patients were randomly assigned to receive inclisiran 300mg subcutaneously on day 1, day 90, then every 6 months or placebo. The primary endpoint was the percentage change in LDL-C reductions from baseline to day 510. Results from these trials showed consistent LDL-C lowering with inclisiran.
To investigate the impact of BMI on the efficacy of inclisiran, a pooled post-hoc analysis was conducted. Findings showed that regardless of BMI, treatment with inclisiran was associated with an LDL-C reduction of approximately 50% compared with placebo. Across all BMI types, reductions in triglycerides (~10%), total cholesterol (~33%), non-high-density lipoprotein cholesterol (~45%), and apolipoprotein B (~40%) were also observed.
The Food and Drug Administration (FDA) is currently reviewing the New Drug Application for inclisiran in the treatment of primary hyperlipidemia (including heterozygous familial hypercholesterolemia) in adults who have elevated LDL-C while being on a maximally tolerated dose of statin therapy.
Upon FDA approval, the Company plans to market inclisiran under the trade name Leqvio.
Leqvio® (inclisiran) reduced LDL-C in people who are overweight or obese. News release. Novartis. November 8, 2020. Accessed November 9, 2021. https://www.novartis.com/news/media-releases/leqvio-inclisiran-reduced-ldl-c-people-who-are-overweight-or-obese.