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

Summary

In a two-part, phase 3 RCT of 141 adolescents with HeFH on maximally tolerated statins, inclisiran reduced LDL-C by 27.1% versus 1.4% with placebo at day 330 (between-group difference -28.5%, p<0.0001) and maintained a mean -33.7% reduction at day 720. Safety was favorable with only mild injection site reactions and no treatment-related serious adverse events.

Key Findings

• At day 330, LDL-C decreased by -27.1% with inclisiran vs 1.4% with placebo; between-group difference -28.5% (95% CI -35.8 to -21.3; p<0.0001).
• Mean LDL-C reduction sustained to day 720 at -33.7% (SD 24.0).
• Safety profile was favorable with mild injection-site reactions and no treatment-related serious adverse events or deaths.

Clinical Implications

Inclisiran can be considered as an add-on for adolescents with HeFH inadequately controlled on statins ± other agents, offering substantial LDL-C reductions with twice-yearly maintenance dosing and a favorable safety profile.

Limitations

• Part 2 was open-label and the trial assessed surrogate endpoints (LDL-C) rather than hard cardiovascular outcomes.
• Predominantly White cohort (91%) may limit generalizability; pediatric patients <12 years were not studied.

Future Directions

Prospective studies should evaluate long-term cardiovascular outcomes, adherence/quality-of-life impacts of infrequent dosing, and effectiveness across diverse populations including younger children.