ORION-8: Inclisiran Displays Sustained LDL-C Lowering Over Long-Term

R. Scott Wright, MD

Credit: Mayo Clinic

Twice-yearly administration of inclisiran demonstrated consistent and effective lowering of low-density lipoprotein cholesterol (LDL-C), with a favorable safety profile, in patients at high cardiovascular risk, according to new research.¹

ORION-8 was an open-label extension study of previous Phase 2 and Phase 3 trials in the ORION program, with this data report focused on the consistent efficacy of inclisiran across >12,000 patient-years of patients with atherosclerotic cardiovascular disease (ASCVD) or risk equivalent.

“Our findings from ORION-8 demonstrate that inclisiran is an effective lipid-lowering therapy (LLT) with sustained and substantial efficacy as an LDL-C lowering therapy, extending the prior, shorter-term observations from ORION-3, ORION-9, ORION-10, and ORION-11 that comprised 4113 patient-years of inclisiran exposure,” wrote the investigative team, led by R. Scott Wright, MD, a professor in the division of preventive cardiology and the department of cardiology, at the Mayo Clinic.

Inclisiran is a first-in-class, small interfering ribonucleic acid (siRNA) targeting the hepatic proprotein convertase subtilisin/kexin type (PCSK9) mRNA to suppress protein translation in the liver and leading to a notable reduction in the levels of LDL-C.² Pooled analyses of pivotal data from 3 placebo-controlled Phase 3 ORION trials showed inclisiran reduced LDL-C by approximately 50% compared with placebo over an 18-month treatment period, with a similar frequency of treatment-emergent adverse events.³

Long-term data on the durability of LDL-C lowering was assessed in ORION-8, which evaluated 3274 participants from the 4 previous inclisiran trials, with up to 6.8 years of follow-up.¹ Based on this analysis, Wright and colleagues pointed to the clinical relevance of determining whether the observed effect of LDL-C lowering with inclisiran was sustained over a longer follow-up period.

Patients with ASCVD, or the risk equivalent, received open-label inclisiran every 180 days, after completion of the parent trial, until day 990. This was followed by an end-of-study visit on Day 1080 or ≥90 days after the last dose. The proportion of patients achieving pre-specified LDL-C goals (ASCVD: <1.8 mmol/L and risk equivalent: <2.6 mmol/L), percentage, and absolute changes in LDL-C at the end of the study, and the safety of inclisiran, were measured by the investigators.

Among the full analysis set, 2446 patients (74.7%) completed the full 3-year study period, after 828 (25.3%) discontinued treatment. Patients had a mean age of 64.9 years, approximately 83% (n = 2709) had ASCVD, and the mean baseline LDL-C was 2.9 ± 1.2 mmol/L. The population exhibited an average cumulative exposure to inclisiran of 3.7 years, with the maximum exposure being 6.8 years.

Upon analysis, 78.4% (95% CI, 76.8 - 80.0) of patients achieved the pre-specified LDL-C goals. This included 79.4% of 2205 patients and 74.3% of 526 patients achieving their prespecified LDL-C goals at the end of the study in the ASCVD and ASCVD risk equivalent populations, respectively.

Moreover, the analysis identified the mean percentage and mean absolute change in LDL as –49.4% (95% CI, –50.4 to –48.3) and –1.5 mmol/L at the end of the study. Wright and colleagues observed no evidence that the long-term lipid-lowering effect of inclisiran was attenuated by the formation of inclisiran-associated anti-drug antibodies in 5.5% of patients.

Treatment-emergent adverse events at the injection site occurred in 5.9% of inclisiran-treated patients. An exploratory analysis was performed in patients who rolled over into ORION-8 from previous ORION trials after inclisiran treatment—14.4% of this population experienced major adverse cardiovascular event (MACE)-related safety events, compared with 16.3% of patients switched from placebo, suggesting some benefit to earlier initiation of inclisiran.

“With these caveats, it appeared that earlier initiation of inclisiran (assignment to inclisiran versus placebo in the double-blind treatment period of the parent trials) was associated with a numerically lower incidence of MACE-related safety events,” they wrote. “The long-term effect of inclisiran on cardiovascular events is currently under further investigation in large, placebo-controlled trials, ORION-4, VICTORION-1 Prevent, and VICTORION-2 Prevent.”

References

1. _{R Scott Wright, Frederick J Raal, Wolfgang Koenig, Ulf Landmesser, Lawrence A Leiter, Sheikh Vikarunnessa, Anastasia Lesogor, Pierre Maheux, Zsolt Talloczy, Xiao Zang, Gregory G Schwartz, Kausik K Ray, Inclisiran administration potently and durably lowers LDL-C over an extended-term follow-up: the ORION-8 trial, Cardiovascular Research, 2024;, cvae109, https://doi.org/10.1093/cvr/cvae109}
2. _{Khvorova A. Oligonucleotide Therapeutics - A New Class of Cholesterol-Lowering Drugs. N Engl J Med. 2017;376(1):4-7. doi:10.1056/NEJMp1614154}
3. _{Wright RS, Ray KK, Raal FJ, et al. Pooled Patient-Level Analysis of Inclisiran Trials in Patients With Familial Hypercholesterolemia or Atherosclerosis. J Am Coll Cardiol. 2021;77(9):1182-1193. doi:10.1016/j.jacc.2020.12.058}