Highlight
Based on the results of the ORION-16 trial, the following key highlights emerge regarding the use of inclisiran in the pediatric population:
1. Potent Efficacy: Inclisiran achieved a significant placebo-adjusted reduction of 28.5% in LDL cholesterol at day 330 in adolescents already on maximally tolerated lipid-lowering therapy.
2. Sustained Impact: The open-label extension (Part 2) demonstrated a mean LDL-C reduction of 33.7% from baseline at day 720, confirming the long-term durability of the siRNA approach.
3. Favorable Safety Profile: The safety and tolerability of inclisiran in adolescents were consistent with adult data, with no serious treatment-related adverse events and manageable, mild injection site reactions.
4. Simplified Adherence: The infrequent dosing schedule (twice yearly after the initial doses) provides a critical alternative for improving treatment compliance in adolescent patients.
Background: The Clinical Burden of HeFH in Youth
Heterozygous familial hypercholesterolaemia (HeFH) is an autosomal dominant genetic disorder characterized by severely elevated levels of low-density lipoprotein (LDL) cholesterol from birth. This lifelong exposure to hypercholesterolemia leads to the premature development of atherosclerotic cardiovascular disease (ASCVD). If left untreated, individuals with HeFH face a significantly higher risk of myocardial infarction and other cardiovascular events in early adulthood.
While statins and ezetimibe remain the first-line pharmacologic interventions for pediatric HeFH, a substantial proportion of adolescents fail to achieve recommended LDL-C targets. This shortfall is often due to the severity of the genetic mutation, intolerance to high-dose statins, or the significant challenge of medication adherence in the teenage years. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as a revolutionary class of therapy in adults, but there remains a pressing need for effective, long-acting options in the pediatric space to mitigate the cumulative ‘cholesterol burden’ early in life.
Study Design: The ORION-16 Framework
ORION-16 was a two-part, phase 3, randomised, multicentre clinical trial designed to evaluate the efficacy and safety of inclisiran in adolescents (aged 12 to <18 years) with HeFH. The trial was conducted across 51 sites in 26 countries, underscoring its global relevance.
Patient Population
Participants were required to have a confirmed diagnosis of HeFH and elevated LDL-C levels despite being on maximally tolerated statin therapy, with or without other lipid-lowering agents. The baseline characteristics showed a median age of 15.1 years, with a balanced gender distribution (53% female).
Interventions and Dosing
In Part 1 (a 1-year double-blind phase), 141 patients were randomly assigned in a 2:1 ratio to receive either 300 mg of inclisiran sodium or a placebo. Doses were administered subcutaneously on day 1, day 90, and day 270. In Part 2 (a 1-year open-label extension), all patients, including those previously on placebo, received inclisiran on a maintenance schedule.
Endpoints
The primary endpoint was the percentage change in LDL cholesterol from baseline to day 330. Secondary endpoints included changes in other lipid parameters (such as total cholesterol, ApoB, and non-HDL cholesterol) and the assessment of safety and tolerability over the 2-year study period.
Key Findings: Efficacy and Safety Outcomes
The results of ORION-16 provide robust evidence for the clinical utility of inclisiran in the adolescent population.
Primary Efficacy Results
At day 330, the least squares mean percentage change in LDL-C was -27.1% in the inclisiran group, compared to a slight increase of 1.4% in the placebo group. This resulted in a statistically significant between-group difference of -28.5% (95% CI -35.8 to -21.3; p<0.0001). This magnitude of reduction is clinically meaningful, especially as it was achieved on top of standard-of-care therapies.
Long-term and Secondary Outcomes
In the open-label portion of the study, the efficacy of inclisiran was not only maintained but appeared to strengthen, with a mean percentage change in LDL-C of -33.7% from baseline at day 720. Similar improvements were noted in other atherogenic lipid markers, including apolipoprotein B and non-HDL cholesterol, which are critical indicators of cardiovascular risk in HeFH.
Safety and Tolerability
Inclisiran was generally well tolerated. The most common adverse event associated with the study drug was injection site reactions, occurring in 16% of the inclisiran group versus 6% in the placebo group during Part 1. These reactions were classified as mild, transient, and did not lead to any treatment discontinuations. Crucially, there were no treatment-related serious adverse events, no deaths, and no evidence of adverse effects on growth or pubertal development, which are paramount concerns in pediatric pharmacology.
Mechanistic Insights: siRNA and the PCSK9 Pathway
Inclisiran represents a shift in how we approach PCSK9 inhibition. Unlike monoclonal antibodies (such as evolocumab or alirocumab) which bind to circulating PCSK9 protein, inclisiran is a small interfering RNA (siRNA) that utilizes the body’s natural RNA interference (RNAi) mechanism. It is conjugated with N-acetylgalactosamine (GalNAc) to ensure targeted delivery specifically to hepatocytes.
Once inside the liver cell, inclisiran binds to the RNA-induced silencing complex (RISC) and directs the cleavage of the mRNA encoding PCSK9. By preventing the synthesis of the PCSK9 protein at its source, inclisiran increases the recycling and expression of LDL receptors on the hepatocyte surface. This leads to enhanced clearance of LDL cholesterol from the bloodstream. Because the RISC complex is stable and long-lived, a single injection can suppress PCSK9 production for several months, allowing for a twice-yearly dosing regimen.
Expert Commentary: Addressing the Adherence Gap
The clinical management of adolescents with chronic conditions is notoriously difficult due to the psychological and social transitions inherent in this age group. In the context of HeFH, daily oral medications or even bi-weekly injections can lead to ‘treatment fatigue,’ resulting in suboptimal lipid control during a window of time where lowering cholesterol has a profound impact on lifetime cardiovascular risk.
The most significant advantage of inclisiran identified by clinical experts is its dosing frequency. A maintenance schedule of one injection every six months aligns well with routine semi-annual clinical follow-ups. This ‘office-administered’ approach ensures 100% adherence to the therapy, removing the burden of daily or bi-weekly administration from the adolescent and their family.
However, it is important to note that while the percentage reduction in LDL-C is impressive, it is slightly lower than the 50% reductions typically seen in adult populations. This may be due to differences in baseline LDL-C levels, background therapy intensity, or the specific genetic landscape of the pediatric cohort. Future studies may be needed to determine if dose optimization or combination with newer agents (like angiopoietin-like 3 inhibitors) is necessary for the highest-risk pediatric patients.
Conclusion
The ORION-16 trial successfully demonstrates that inclisiran is an effective and safe lipid-lowering therapy for adolescents with HeFH. By providing sustained LDL-C reduction through a unique siRNA mechanism and an infrequent dosing schedule, inclisiran addresses both the biological and behavioral challenges of treating young patients with severe genetic dyslipidemia. These findings support the inclusion of inclisiran in the pediatric treatment armamentarium, potentially transforming the trajectory of cardiovascular health for children born with HeFH.
Funding and ClinicalTrials.gov
The ORION-16 trial was funded by Novartis Pharma. The study is registered at ClinicalTrials.gov under the identifier NCT04652726.
References
1. Wiegman A, Peterson AL, Bruckert E, et al. Efficacy and safety of inclisiran in adolescents with heterozygous familial hypercholesterolaemia (ORION-16): a two-part, randomised, multicentre clinical trial. Lancet Diabetes Endocrinol. 2026 Mar;14(3):233-242. doi: 10.1016/S2213-8587(25)00351-1.
2. Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia. N Engl J Med. 2020;382(16):1520-1530.
3. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34(45):3478-3490.
4. Gidding SS, Champagne MA, de Ferranti SD, et al. The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association. Circulation. 2015;132(22):2167-2192.
