Phase 3 ORION-5 Study Results: Inclisiran’s PCSK9 reduction not enough to lower LDL-C in HoFH

Despite its effectiveness in substantially lowering PCSK9 levels, inclisiran, a small interfering RNA, did not lead to significant reductions in low-density lipoprotein cholesterol (LDL-C) levels in patients with homozygous familial hypercholesterolemia (HeFH), according to a study.

The study, involving 56 patients with HeFH and elevated LDL-C levels despite maximum tolerated doses of LDL-C-lowering therapies, focused on inclisiran—a small interfering RNA inhibiting the production of the hepatic PCSK9 protein. PCSK9 plays a crucial role in cholesterol regulation, and inhibiting its production is expected to lead to reduced LDL-C levels.

During the double-blind, 6-month phase of ORION-5, patients were randomized to receive either 300 mg of inclisiran sodium or a placebo. Results indicated that the placebo-corrected percentage change in LDL-C levels from baseline to day 150 was -1.68%, and this difference was not statistically significant between the inclisiran and placebo groups.

Despite the lack of notable impact on LDL-C levels, inclisiran did demonstrate a substantial reduction in PCSK9 levels, with a placebo-corrected percentage change of -60.6% (P<0.0001). This reduction was sustained throughout the study.

No statistically significant differences were observed in the levels of other lipids and lipoproteins (apolipoprotein B, total cholesterol, and non-high-density lipoprotein cholesterol) between the inclisiran and placebo groups. Adverse events and serious adverse events did not differ between the groups, and inclisiran was well-tolerated, aligning with safety findings from prior studies.

Reference
Raal F, Durst R, Bi R, et al. Efficacy, Safety, and Tolerability of Inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial. Circulation. 2023;doi: 10.1161/CIRCULATIONAHA.122.063460. Epub ahead of print. PMID: 37850379.