ORION-9: Inclisiran safely lowers LDL up to 50% in familial hypercholesterolemia
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PHILADELPHIA — Patients with heterozygous familial hypercholesterolemia who were treated with inclisiran had reductions in LDL at 510 days and at an average of the period between 90 days and 540 days independent of their underlying genotype, according to results of the ORION-9 trial presented at the American Heart Association Scientific Sessions.
The aims and objectives of this trial were to assess the safety and efficacy of inclisiran (The Medicines Company) in 482 patients with heterozygous familial hypercholesterolemia (FH) over an 18-month period.
“Inclisiran is a small interfering double-stranded RNA which harnesses natural process of RNA interferences in the liver,” Frederick J. Raal, MBBCh, PhD, FCP(SA), FRCPC, MRCP, professor at University of the Witwatersrand, Johannesburg, said during the presentation. “Phase 1 and phase 2 studies have shown that a dose of 300 mg administered every 6 months results in a sustained and potent reduction in LDL cholesterol of over 50%.”
To do so, researchers analyzed data from patients with heterozygous FH who were diagnosed by phenotype or genotype with an LDL greater than 100 mg/dL on a low-fat diet and maximally tolerated statin doses.
Patients were assigned 300 mg of inclisiran subcutaneously every 6 months (n = 242; median age, 56 years; 46% men; baseline LDL, 155 mg/dL) or placebo (n = 240; median age, 56 years; 48% men; baseline LDL, 151 mg/dL), both of which were on top of maximally tolerated statins. Treatment was administered for 18 months.
Some patients also participated in a genetic subanalysis (n = 432), during which next-generation sequencing was performed. LDL receptor variants were identified and classified as pathogenic, likely pathogenic and of uncertain significance.
The primary effectiveness endpoint was the percent of LDL change compared with placebo at 510 days and an average between 90 days and 540 days. Secondary effectiveness endpoints included LDL change over time and changes in PCSK9 and other lipids. Safety and tolerability endpoints were defined as treatment-emergent adverse events and laboratory parameters.
Patients assigned inclisiran had highly significant reductions in LDL compared with placebo at 510 days (difference = –50%; P < .0001) and in a time-averaged analysis between 90 days and 540 days (difference = –45%; P < .0001). Robust responses were seen in all genotypes.
“The reduction in those that were found to have an LDL variant was very similar to those with an ApoB variant,” Raal said during the presentation. “Interestingly, the patients that had two variants also had a robust reduction in LDL cholesterol. The single patients with a PCSK9 gain-of-function mutation had a greater than 90% reduction in LDL cholesterol, which is in keeping with the mechanism of action of inclisiran.”
The safety profile of inclisiran was similar to placebo except for adverse events at the injection site, which occurred in 13.3% of patients assigned inclisiran vs. 0% in those assigned placebo. Injection-site reactions were often minor or moderate. There was no evidence of liver, kidney, muscle or platelet toxicity and no difference in serious adverse events in the inclisiran group vs. the placebo group.
“Inclisiran shows potential to address the unmet need of high-risk FH patients,” Raal said during the presentation. – by Darlene Dobkowski
Reference:
Raal FJ, et al. Late Breaking Science VI: New Frontiers in Lipid Therapy. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.
Disclosures: The trial is sponsored by The Medicines Company. Raal reports he received honoraria from Amgen, Sanofi/Regeneron and The Medicines Company. Please see the abstract for all other authors’ relevant financial disclosures.
Editor’s Note: This article was modified on Nov. 21, 2019 to update the data.