Safety and Lipid-Lowering Efficacy of Inclisiran Monotherapy in Patients Without ASCVD: The VICTORION-Mono Randomized Clinical Trial

Abstract

Background: Inclisiran administration twice-yearly (after initial and 3-month doses) effectively reduces low-density lipoprotein cholesterol (LDL-C) in patients on maximally tolerated statins with atherosclerotic cardiovascular disease (ASCVD), risk equivalents, or heterozygous familial hypercholesterolemia.

Objectives: In this study, the authors sought to evaluate whether inclisiran is superior as monotherapy over placebo and ezetimibe in reducing LDL-C in a primary prevention population without ASCVD.

Methods: VICTORION-Mono (V-Mono), a 6-month, randomized, double-blind, multicenter, placebo- and active-comparator controlled phase 3 trial, assessed inclisiran monotherapy in adult participants (aged 18-75 years) without prior ASCVD, diabetes, or familial hypercholesterolemia, with a fasting LDL-C of 100-190 mg/dL and 10-year predicted ASCVD risk of <7.5% according to pooled cohort equation, who were not receiving any lipid-lowering therapy. Participants were randomized (2:1:1) to inclisiran, ezetimibe, or placebo. The primary endpoint was percentage change in LDL-C from baseline, and key secondary endpoints included absolute change in LDL-C and percentage change in proprotein convertase subtilisin/kexin type 9 (PCSK9) from baseline to day 150. The study did not evaluate twice-yearly inclisiran dosing beyond the first 180 days. Safety was also assessed.

Results: Overall, 350 participants were randomized (n = 174, 89, and 87 to inclisiran, ezetimibe, or placebo, respectively) and received the assigned treatments. The study included a diverse population: 62.6% of participants were female, 10.6% were Black or African American, and 39.7% were Hispanic/Latino. Mean participant age was 46.1 years, mean baseline LDL-C level was 135.4 mg/dL, mean body mass index was 29.8 kg/m², and median 10-year predicted ASCVD risk score was 2.2%. The mean percentage change in LDL-C from baseline at day 150 for placebo was 1.4%, for ezetimibe -11.2%, and inclisiran -46.5%. The difference in the change from baseline with inclisiran vs placebo was -47.9% and vs ezetimibe was -35.4% (both P < 0.0001). Inclisiran treatment also demonstrated favorable improvements in other lipid and lipoprotein(a) levels. Inclisiran was well tolerated, with no new safety concerns.

Conclusions: V-Mono demonstrates for the first time that in patients not receiving lipid-lowering therapy, inclisiran as monotherapy, is superior to both placebo and ezetimibe in reducing LDL-C levels over a 6-month follow-up period and was well tolerated. These findings are consistent with previous observations in statin-treated patients. (Efficacy and Safety of Inclisiran as Monotherapy in Patients With Primary Hypercholesterolemia Not Receiving Lipid-Lowering Therapy [VICTORION-Mono]; NCT05763875).

Keywords: LDL-C; VICTORION-Mono; inclisiran; lipid-lowering therapy; monotherapy; primary prevention.