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Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia
Frederick J Raal1, David Kallend1, Kausik K Ray1
1From the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.J.R.); the Medicines Company, Zurich, Switzerland (D.K.); the Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London (K.K.R.); Medpace Reference Laboratories, Cincinnati (T.T.); Deutsches Herzzentrum München, Technische Universität München, and German Center for Cardiovascular Research, Munich Heart Alliance, Munich (W.K.), and the Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm (W.K.) - all in Germany; the Division of Preventive Cardiology and the Department of Cardiology, Mayo Clinic, Rochester, MN (R.S.W.); the Medicines Company, Parsippany, NJ (P.L.J.W., D.C.); Summit Analytical, Denver (M.J.J.); Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.); and the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.).
Insights
Twice-yearly inclisiran injections significantly reduced LDL cholesterol in familial hypercholesterolemia patients. This effective treatment offers a new option for managing high cholesterol with infrequent dosing and a good safety profile.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Genetics
Background:
- Familial hypercholesterolemia (FH) elevates low-density lipoprotein (LDL) cholesterol, increasing cardiovascular disease risk.
- PCSK9 inhibitors lower LDL but require frequent administration.
- Inclisiran, a small interfering RNA, inhibits PCSK9 production, offering a novel therapeutic approach.
Purpose of the Study:
- To evaluate the efficacy and safety of twice-yearly inclisiran injections in adults with heterozygous familial hypercholesterolemia.
- To assess the long-term LDL cholesterol reduction with inclisiran compared to placebo.
Main Methods:
- Phase 3, double-blind, randomized trial (ORION-9) involving 482 adults with heterozygous FH.
- Participants received subcutaneous inclisiran (300 mg) or placebo at days 1, 90, 270, and 450.
- Primary endpoints: percent change in LDL cholesterol at day 510 and time-adjusted change from day 90 to 540.
Main Results:
- Inclisiran reduced LDL cholesterol by 39.7% at day 510 versus an 8.2% increase with placebo (P<0.001).
- Time-averaged LDL reduction was 38.1% with inclisiran compared to 6.2% increase with placebo (P<0.001).
- Robust LDL reductions were observed across all FH genotypes; adverse events were similar between groups.
Conclusions:
- Inclisiran demonstrated significant LDL cholesterol lowering in heterozygous FH patients with infrequent dosing.
- The treatment showed an acceptable safety profile, representing a promising therapeutic option.
- The study supports the use of inclisiran for managing FH and reducing cardiovascular risk.
Background:
Familial hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. Monoclonal antibodies directed against proprotein convertase subtilisin-kexin type 9 (PCSK9) have been shown to reduce LDL cholesterol levels by more than 50% but require administration every 2 to 4 weeks. In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia.
Methods:
In this phase 3, double-blind trial, we randomly assigned, in a 1:1 ratio, 482 adults who had heterozygous familial hypercholesterolemia to receive subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The two primary end points were the percent change from baseline in the LDL cholesterol level on day 510 and the time-adjusted percent change from baseline in the LDL cholesterol level between day 90 and day 540.
Results:
The median age of the patients was 56 years, and 47% were men; the mean baseline level of LDL cholesterol was 153 mg per deciliter. At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% confidence interval [CI], -43.7 to -35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of -47.9 percentage points (95% CI, -53.5 to -42.3; P<0.001). The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% (95% CI, -41.1 to -35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3 to 9.2) in the placebo group, for a between-group difference of -44.3 percentage points (95% CI, -48.5 to -40.1; P<0.001). There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia. Adverse events and serious adverse events were similar in the two groups.
Conclusions:
Among adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile. (Funded by the Medicines Company; ORION-9 ClinicalTrials.gov number, NCT03397121.).
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