Safety and Efficacy of Inclisiran in Patients With Heterozygous Familial Hypercholesterolemia – Results from the Phase 3 Trial
Trial Summarized by: Mrinali Shetty, MD | Reviewed/Approved by: James de Lemos, MD
Placebo-Controlled, Double-Blind, Randomized Trial to Evaluate the Effect of 300 mg of Inclisiran Sodium Given as Subcutaneous Injections in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH) and Elevated Low-Density Lipoprotein Cholesterol (LDL-C)
ORION-9 assessed the efficacy and safety of inclisiran in patients with heterozygous FH.
ORION-9 met all primary and secondary efficacy endpoints. A 50% (70.6 mg/dL) observed LDL-C lowering was observed at day 51. A 45% time-adjusted LDL-C lowering was observed between day 90 and day 540.
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Purpose: To evaluate the safety and efficacy of inclisiran, a drug in the siRNA class, compared to placebo in patients with heterozygous FH with high LDL-C while on maximally tolerated statin dose.
Trial Design: N=482. Phase 3, international (8 countries, 54 sites), double-blinded, placebo-controlled, randomized study. 482 patients with heterozygous FH randomized 1:1 to inclisiran 300 mg or placebo. 18-month follow-up. Median age 56 years.
Co-Primary Endpoints: % LDL-C change from baseline at day 510 and time-adjusted avg. % change from day 90 to day 540.
Results: In patients with heterozygous familial hypercholesterolemia and on maximally tolerated statin dose, twice-yearly inclisiran safely reduced LDL-C approx. 50%.
|% LDL-C change from baseline
|% change in LDL-C from baseline
(time adjusted avg)
|Reduction in LDL-C with inclisiran versus placebo||50%
Heterozygous Familial Hypercholesterolemia (HeFH) is a common and clinically challenging entity. The genetic disorder affects 1 in 250 individuals and there are an estimated 30 million people with HeFH worldwide. The highly elevated LDL-C burden since birth puts them at an accelerated risk for atherosclerotic cardiovascular disease. Yet over 90% of patients are not identified or poorly diagnosed. Management is by primary prevention of ASCVD through LDL-C lowering therapy. Traditionally this has been done with the use of high intensity statin therapy, ezetimibe and PCSK9 inhibitors.
Inclirisan is a small interfering double-stranded RNA therapeutic which interferes with PCSK9 production in the liver. Dose-finding and PD modeling showed a durable and potent effect of the drug with LDL-C lowering by 53% using 300 mg Inclirisan.
ORION-9 aimed to assess the efficacy and safety of Inclirisan 300 mg as subcutaneous injections on day 1, day 90, and then every 6 months over an 18 month period in subjects with HeFH. ORION-9 met all primary and secondary efficacy endpoints. There was a 50% observed LDL-C lowering at Day 510 with a 45% time adjusted LDL-C lowering between days 90 and 540. This was on top of maximally tolerated statin therapy and ezetimibe. The reduction in LDL-C was independent of underlying FH genotype. In addition, Inclirisan’s safety profile was similar to placebo except adverse events at the site of injection which were mostly mild and transient. There was no evidence of liver, kidney, muscle or platelet toxicity. There was no difference in serious adverse events. Inclirisan shows potential to address the unmet need to reduce the high burden of risk in HeFH patients.
Primary Endpoints Results:
Co-primary endpoints were the percent change from baseline in LDL-C at Day 510 and the time-adjusted average percentage change from baseline in LDL-C between Day 90 up to Day 540.
Secondary Endpoints Results:
The mean absolute change at Day 510, the time averaged absolute reduction from baseline between Day 90 up to Day 540, and changes in other lipids and lipoproteins.
Trial Design: An 18-month, Phase III, placebo-controlled, double-blind, randomized study in participants with HeFH and elevated LDL-C to evaluate the efficacy, safety, and tolerability of subcutaneous (SC) injection(s) of inclisiran.
Trial Population: 482 patients with heterozygous familial hypercholesterolemia (based on genetic confirmation or established phenotypic criteria)
- Percentage Change In LDL-C from Baseline To Day 510 [Time Frame: Baseline, Day 510]
- [Time-adjusted Percentage Change in LDL-C from Baseline After Day 90 and up to Day 540 Levels [Time Frame: Baseline, Day 90 to Day 540]
- Absolute Change in LDL-C from Baseline to Day 510
- Time-adjusted Absolute Change in LDL-C from Baseline After Day 90 and up to Day 540
- Percentage Change in Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) from Baseline to Day 510
- Percentage Change in Total Cholesterol from Baseline to Day 510
- Percentage Change in Apolipoprotein B (ApoB) from Baseline To Day 510
- Percentage Change in Non-high-density Lipoprotein (HDL)-C from Baseline To Day 510
Sponsor: The Medicines Company
References and Sources:
- Presented by: Frederick J Raal at AHA Scientific Sessions 2019, Philadelphia, PA
- ClinicalTrials.gov Identifier: NCT03397121 (opens in new window)(link opens in new window)
- Fitzgerald K, White S, Borodovsky A, et al. A Highly Durable RNAi Therapeutic Inhibitor of PCSK9. The New England Journal of Medicine. 2016;376(1):41-51.
- Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. The New England Journal of Medicine. 2017;376(15):1430-1440.
- Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. British Medical Journal. 1991;303(6807):893-896.
- Chora JR, Medeiros AM, Alves AC, Bourbon M. Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: Application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis. Genetics in medicine: Official journal of the American College of Medical Genetics. 2018;20(6):591-598.
- ORION clinical development program (opens in new window)(link opens in new window). Updated 01 Oct 2019. Accessed 11/17/19, 2019.