ORION-9, a phase 3 randomized clinical trial, shows that inclisiran effectively reduces low-density lipoprotein cholesterol (LDL-C) by 50% at 18 months in patients with heterozygous familial hypercholesterolemia, according to results presented Monday at the American Heart Association Scientific Sessions 2019 in Philadelphia.
Frederick Raal, MD, PhD, of University of the Witwatersrand, Johannesburg, presented the study on behalf of the ORION-9 investigators.
Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder affecting 30 million people worldwide. LDL receptor gene mutations account for >90% of cases. The primary management of this disorder is through LDL-C lowering therapy by statins, ezetimibe and PCSK9 inhibitors. Inclisiran is in the small-interfering double-stranded RNA class, and it inhibits PCSK9 synthesis by harnessing the natural mechanism of RNAi. Phase I and II study data show that inclisiran lowers LDL-C levels effectively by twice-yearly dose (300 mg).
In the ORION-9 trial, 482 patients were randomized to either inclisiran or placebo. About 97% of patients completed the study. Major inclusion criteria were patients with HeFH diagnosed by genetic testing and/or Simon Broome criteria and LDL-C level >100 mg/dL. Exclusion criteria were patients who had a prior or recent use of PCSK9 inhibitors or major adverse cardiovascular events within 3 months of randomization, left ventricular ejection fraction <30% and fasting triglyceride levels >400 mg/mL (4.5 mmol/L).
Baseline characteristics were well-balanced between the groups. Median age in the inclisiran group was 56 years; 90% were already receiving statins and 56% were taking ezetimibe. Baseline LDL-C level was 151±50 mg/dl in the inclisiran arm. At 18 months, inclisiran effectively reduced LDL-C by 50%. Similar effects were noticed on sensitivity and time averaged analysis (45% reduction). Reduction in LDL-C was independent of underlying HeFH genotype. No differences in serious adverse events were noted. Raal also stated that though injection-site-related adverse events were higher in the inclisiran group, the majority were mild and all were transient.
Raal concluded that inclisiran on top of statins and ezetimibe safely lowered LDL-C by 50% in HeFH patients and that this reduction was independent of the underlying FH genotype. The safety profile of inclisiran was similar to that of placebo, with higher injection-site-related adverse events, which were mostly mild and all transient, in the inclisiran arm.
Inclisiran is still awaiting FDA approval. The ORION-9 study was funded by The Medicines Company.