Efficacy and safety of inclisiran in adolescents with heterozygous familial hypercholesterolaemia (ORION-16): a two-part, randomised, multicentre clinical trial.

Abstract

Inclisiran, a small interfering RNA targeting hepatic PCSK9, was previously studied in various adult patient populations, but it has not yet been assessed in paediatric patients with heterozygous familial hypercholesterolaemia (HeFH), a genetic disorder characterised by elevated LDL cholesterol. The ORION-16 study aimed to evaluate the efficacy and safety of inclisiran treatment in adolescents with HeFH. ORION-16 was a two-part (1-year double-blind, 1-year open-label), randomised, phase 3 trial at 51 sites across 26 countries. In Part 1, adolescents (aged 12 to <18 years) with HeFH and elevated LDL cholesterol on maximally tolerated statin treatment with or without other lipid-lowering therapy were randomly assigned 2:1 (via interactive response technology) to either inclisiran sodium 300 mg subcutaneously or placebo (administered on days 1, 90, and 270); in Part 2, all patients received inclisiran (days 360 [only patients previously assigned to receive placebo], 450, and 630). The primary endpoint was the percentage change in LDL cholesterol from baseline to day 330, assessed in all randomly assigned patients. Safety was assessed in all patients who received at least one dose of study drug. Endpoints in Part 2 were analysed in all patients who entered and received at least one dose of study drug in Part 2. ORION-16 is registered at ClinicalTrials.gov (NCT04652726) and is completed. Between Feb 17, 2021, and Dec 14, 2022, 141 patients were randomly assigned (93 to inclisiran, 48 to placebo; median age 15·1 years [IQR 13·4-16·8]; 75 [53%] female; 128 [91%] White). In Part 1, the least squares mean percentage change in LDL cholesterol from baseline to day 330 was -27·1% in the inclisiran group and 1·4% in the placebo group, with a between-group difference of -28·5% (95% CI -35·8 to -21·3; p<0·0001). In Part 2, at day 720, a mean percentage change in LDL cholesterol from baseline of -33·7% (SD 24·0) was observed. Inclisiran was well tolerated, with a safety profile comparable to studies in adults. Injection site reactions were more frequent with inclisiran (15 [16%] of 93 patients) than with placebo (three [6%] of 48) in Part 1 (13 [9%] of 139 in Part 2); all were mild and did not lead to study drug discontinuation. There were no treatment-related serious adverse events, and no deaths during the study. In adolescents with HeFH, inclisiran was effective in lowering LDL cholesterol, with sustained efficacy over 2 years, and was well tolerated. These results support inclisiran as a potentially useful addition for the treatment of adolescents with HeFH, providing an infrequent dosing regimen. Novartis Pharma.