Phase 3 trial does not confirm efficacy of PCSK9 siRNA in HoFH

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

Literature - Raal F, Durst R, Bi R, et al. - Circulation. 2023 Oct 18 [Online ahead of print]. doi: 10.1161/CIRCULATIONAHA.122.063460

Introduction and methods


As conventional LDL-c–lowering therapies do not sufficiently lower LDL-c levels in patients with homozygous familial hypercholesterolemia (HoFH), better therapeutic options are needed for this population. In the recent phase 2 ORION-2 trial, inclisiran—a small-interfering RNA that prevents production of the hepatic PCSK9 protein—resulted in sustained reductions in LDL-c and PCSK9 levels in HoFH patients who were simultaneously being treated with statins and ezetimibe [1].

Aim of the study

The study aim was to investigate the efficacy, safety, and tolerability of inclisiran in HoFH patients.


The ORION-5 (A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia) study was an international, multicenter, double-blind/open-label, phase 3 RCT that included 56 patients with a genetically confirmed or clinical diagnosis of HoFH and fasting LDL-c levels ≥130 mg/dL (≥3.4 mmol/L) despite maximum-tolerated doses of LDL-c–lowering therapies (statin with or with no ezetimibe) with or with no lipoprotein apheresis.

The study consisted of 2 sequential parts. In part 1 (double-blind, placebo-controlled, 6 months), patients were randomized in a 2:1 ratio to receive inclisiran sodium 300 mg (equivalent to inclisiran 284 mg) subcutaneously or placebo at day 1 and 90. In part 2 (open-label, single-arm, 18 months), placebo-treated patients from part 1 were transitioned to receive their first inclisiran dose at 180 days. All patients in part 2 received subsequent inclisiran doses at day 270, 450, 630, and 720 (end of study).


The primary endpoint was the percentage change in LDL-c level from baseline to 150 days (part 1 of the study). Key secondary endpoints were the absolute change in LDL-c level from baseline to 150 days and the percentage change in apoB, non–HDL-c, and total cholesterol levels from baseline to 150 days. Other secondary endpoints were the absolute and percentage changes in LDL-c, PCSK9, apoB, non–HDL-c, Lp(a), and total cholesterol levels from baseline to 720 days. An exploratory endpoint analysis evaluated the LDL-c reduction at 150 days by genotype.

Safety and tolerability were assessed by evaluation of adverse events, serious adverse events, and clinical laboratory values.

Main results


  • The mean baseline LDL-c level was 294.0 mg/dL in patients treated with inclisiran and 356.7 mg/dL in placebo-treated patients.
  • The mean percentage change in LDL-c level from baseline to 150 days was 0.70% (95%CI: –14.03% to 15.44%) in the inclisiran group versus 2.39% (95%CI: –19.98% to 24.75%) in the placebo group (difference: –1.68%; 95%CI: –29.19% to 25.83%; P=0.90).
  • The placebo-corrected mean absolute change in LDL-c level from baseline to 150 days was 6.47 mg/dL (P=0.87).
  • From baseline to 150 days, the placebo-corrected mean percentage changes were −4.3% for apoB (P=0.68), −2.1% for non–HDL-c (P=0.87), and −0.8% for total cholesterol (P=0.94).
  • The placebo-corrected mean percentage change in PCSK9 level from baseline to 150 days was –60.6% (95%CI: –83.5% to −37.8%; P<0.0001), which was sustained until 180 days.
  • No statistically significant differences were observed in the absolute and percentage changes from baseline to any time point for the levels of apoB, non–HDL-c, and total cholesterol between the inclisiran and placebo groups.
  • A subgroup analysis by genotype showed the placebo-corrected mean percentage change in LDL-c level from baseline to 150 days was +26.6% (P=0.18) in patients categorized as homozygous LDLR (i.e., identical LDLR pathogenic variants; n=19), −26.5% (P=0.47) in those with the compound heterozygous LDLR genotype (i.e., different LDLR pathogenic variants; n=15), and −22.5% (P=0.40) in the group with other genetic sequence variations (n=22).
  • In a post-hoc analysis excluding patients with null/null LDLR variants (who have minimal residual LDLR activity) and those with apheresis (n=30), the placebo-corrected least squares mean percentage change in LDL-c level between baseline and each visit up to 180 days ranged from −12.9% to −30.0%, compared with +4.6% to −12.1% for all patients.

Safety and tolerability

  • The frequency of adverse events and serious adverse events did not differ between the inclisiran and placebo groups throughout the entire study or between the 2 study parts.
  • The most commonly reported treatment-emergent adverse events were viral respiratory tract infection, diarrhea, and pyrexia (part 1), and coronavirus infection and increased international normalized ratio (part 2).


In the phase 3 ORION-5 trial, treatment with inclisiran, in addition to statins and ezetimibe, did not decrease LDL-c levels compared with placebo in HoFH patients despite reducing PCSK9 levels. Inclisiran also did not reduce the levels of other lipids and lipoproteins. The drug was well-tolerated, consistent with previous studies and the overall safety profile.

The authors attribute the lack of treatment effect in the overall study population to the diverse genotype sequence variations and believe “it is likely that inclisiran requires sufficient residual LDLR function to be effective in patients with HoFH.”


1. Hovingh GK, Lepor NE, Kallend D, Stoekenbroek RM, Wijngaard PLJ, Raal FJ. Inclisiran durably lowers low-density lipoprotein cholesterol and proprotein convertase subtilisin/kexin type 9 expression in homozygous familial hypercholesterolemia: the ORION-2 pilot study. Circulation. 2020;141:1829–1831. doi: 10.1161/CIRCULATIONAHA.119.044431

Find this article online at Circulation.

Facebook Comments


We’re glad to see you’re enjoying PACE-CME…
but how about a more personalized experience?

Register for free