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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.
Perspective
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Daniel J. Rader, MD
This trial was generally positive. The LDL reduction was good, and the persistence is good in terms of that, which is not surprising based on other studies with inclisiran, but it’s nice to see in heterozygous FH. It’s nice to see that the efficacy was not only on top of statins, but also in a pretty big subgroup of people on statins plus ezetimibe; this is probably the largest study in which inclisiran has been on top of both statins and ezetimibe. The safety was good. This is going to be a great addition to our armamentarium for patients with FH who really do need PCSK9 inhibition. To be able to administer the therapy once every 6 months like this is going to be a big advantage over having to inject patients every 2 weeks.
It would be interesting to see more about lipoprotein(a) because a lot of our patients with FH have high Lp(a). It’s nice to hear that there is a modest Lp(a) reduction, as the same with the antibodies.
I would really like to see this studied in children. When we think about all of our children, adolescents and young adults with FH who are less than adherent with statin therapy, not that they would come off their statins, but that lack of adherence, so to speak, could be blunted a little bit if they can get one of these injections every 6 months for inclisiran. That’s one of the big issues.
I’m increasingly comfortable with the safety. There’s been so many patients studied now and we have 18-month and 2-year data, but that’s always something we’re going to have to keep an eye on for a new platform: safety.
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