Efficacy, Safety, and Tolerability of Inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial

Abstract

BACKGROUND: Homozygous familial hypercholesterolemia is a genetic disease characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C) and a high risk of premature cardiovascular events. Phase 2 of ORION (A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia) showed that inclisiran, a small interfering RNA that prevents production of the hepatic PCSK9 protein (proprotein convertase subtilisin/kexin type 9), could lead to durable reductions in LDL-C levels when added to statins and ezetimibe in patients with homozygous familial hypercholesterolemia. METHODS: ORION-5 was a phase 3, 2-part, multicenter study in 56 patients with homozygous familial hypercholesterolemia and elevated LDL-C levels despite maximum tolerated doses of LDL-C–lowering therapies with or without lipoprotein apheresis. Patients eligible for part 1 (double-blind, 6 months) were randomized 2:1 to receive either 300 mg of inclisiran sodium (equivalent to 284 mg of inclisiran) or placebo. Placebo-treated patients from part 1 were transitioned to inclisiran in part 2 (open-label, 18 months). The primary end point was the percentage change in LDL-C levels from baseline to day 150. RESULTS: The mean age of the patients was 42.7 years, and 60.7% were women. The mean baseline LDL-C levels were 294.0 mg/dL and 356.7 mg/dL in the inclisiran and placebo groups, respectively. The placebo-corrected percentage change in LDL-C level from baseline to day 150 was −1.68% (95% CI, −29.19% to 25.83%; P =0.90), and the difference was not statistically significant between the inclisiran and placebo groups. The placebo-corrected percentage change in PCSK9 levels from baseline to day 150 was −60.6% with inclisiran treatment ( P <0.0001); this was sustained throughout the study, confirming the effect of inclisiran on its biological target of PCSK9. No statistically significant differences between the inclisiran and placebo groups were observed in the levels of other lipids and lipoproteins (apolipoprotein B, total cholesterol, and non−high-density lipoprotein cholesterol). Adverse events and serious adverse events did not differ between the inclisiran and placebo groups throughout the study. CONCLUSIONS: Inclisiran treatment did not reduce LDL-C levels in patients with homozygous familial hypercholesterolemia despite substantial lowering of PCSK9 levels. Inclisiran was well-tolerated, and the safety findings were consistent with previously reported studies and the overall safety profile. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03851705.

Dyslipidemia: A Narrative Review on Pharmacotherapy

“…On the other hand, the phase 3 ORION-5 trial showed that inclisiran treatment did not reduce LDL-C levels in patients with HoFH despite substantial lowering of PCSK9 levels [ 126 ].…”

PCSK9-directed therapies: an update

“…Inclisiran has been tested in patients with HoFH in the ORION-5 study [23 ▪ ] (Table 2). The 56 patients were randomized 2 : 1 and had a mean LDL-C of 294.0 mg/dl and 356.7 mg/dl in the inclisiran and placebo group, respectively.…”

LDL-C–Lowering Therapies for Adults and Children With Homozygous Familial Hypercholesterolemia: Challenges and Successes

“…In this issue of Circulation , Raal et al 4 and Wiegman et al 5 present contrasting data on the impact of novel LDL-C–lowering therapies in HoFH. In ORION 5 (A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia), Raal et al 4 studied the effects of inclisiran, an siRNA molecule that reduces PCSK9 synthesis in hepatocytes, in 56 adults on stable concomitant lipid-lowering treatment (age, 42.7±12.9 years; 60.7% women; 67.9% with previous atherosclerotic cardiovascular disease and 35.7% undergoing lipoprotein apheresis).…”

“…In this issue of Circulation , Raal et al 4 and Wiegman et al 5 present contrasting data on the impact of novel LDL-C–lowering therapies in HoFH. In ORION 5 (A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia), Raal et al 4 studied the effects of inclisiran, an siRNA molecule that reduces PCSK9 synthesis in hepatocytes, in 56 adults on stable concomitant lipid-lowering treatment (age, 42.7±12.9 years; 60.7% women; 67.9% with previous atherosclerotic cardiovascular disease and 35.7% undergoing lipoprotein apheresis). The study was divided into 2 parts: Part 1 was a double-blind randomized study in which patients received 2:1 subcutaneous injection of inclisiran 300 mg (n=37) or placebo (n=19) at days 1 and 90 and after 6 months; part 2 was an open-label single-arm extension in which all participants received the therapy at day 180 and every 6 months until end of study at day 720.…”

“…Data from the study of Wiegman et al 5 in children and the ELIPSE study (Efficacy and Safety of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia) in adults 11 clearly show a more constant and robust effect of ANGPTL3 inhibition in contrast to PCSK9 inhibitors in HoFH. 4,8,9 The mechanism of action of evinacumab is still not well understood but may be mediated by suppression of the inhibitory effect of ANGPTL3 on endothelial lipase activity. 12 This in turn increases clearance of LDL and its precursors, for example, very-low-density lipoprotein and intermediate-density lipoprotein, by still unknown LDLR-independent pathways.…”