Inclisiran administration potently and durably lowers LDL-C over an extended-term follow-up: the ORION-8 trial

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

doi:10.1093/cvr/cvae109

Inclisiran administration potently and durably lowers LDL-C over an extended-term follow-up: the ORION-8 trial

Cardiovasc Res. 2024 May 16:cvae109. doi: 10.1093/cvr/cvae109. Online ahead of print.

Authors

Affiliations

¹ Division of Preventive Cardiology and Department of Cardiology, Mayo Clinic, Rochester, Minnesota, USA.
² Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
³ German Heart Centre, Technical University of Munich, DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany and Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany.
⁴ Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité; Charité-Universitätsmedizin Berlin; Berlin Institute of Health, DZHK, Partner Site Berlin, Friede Springer Cardiovascular Prevention Center at Charité, Berlin, Germany.
⁵ Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
⁶ Novartis Pharmaceuticals Corp, East Hanover, New Jersey, USA.
⁷ Novartis Pharma AG, Basel, Switzerland.
⁸ Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
⁹ Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, United Kingdom.

PMID: 38753448
DOI: 10.1093/cvr/cvae109

Abstract

Background and aims: Data describing the long-term efficacy, safety, and tolerability of inclisiran are limited. This was explored in ORION-8, an open-label extension study of preceding Phase 2 and Phase 3 placebo-controlled and open-label extension trials.

Methods: Adults with ASCVD, ASCVD risk equivalent, or HeFH received open-label inclisiran every 180 days (after completion of the parent trial) until Day 990, followed by an end-of-study (EOS) visit at Day 1080 or ≥90 days after last dose. Study endpoints included proportion of patients achieving pre-specified LDL-C goals (ASCVD: <1.8 mmol/L [<70 mg/dL]; ASCVD risk equivalent: <2.6 mmol/L [<100 mg/dL]), percentage and absolute changes in LDL-C at EOS, and safety of inclisiran.

Results: Of 3274 patients included in the analysis, 2446 (74.7%) were followed until EOS. Mean age was 64.9±9.9 years, 82.7% (n=2709) had ASCVD, and mean baseline LDL-C was 2.9±1.2 mmol/L. Mean cumulative exposure to inclisiran (including parent trials) was 3.7 years; maximum exposure was 6.8 years. With inclisiran, 78.4% (95% CI: 76.8, 80.0) of patients achieved pre-specified LDL-C goals and mean percentage LDL-C reduction was -49.4% (95% CI: -50.4, -48.3). No attenuation of LDL-C lowering over time was observed. Treatment-emergent adverse events at the injection site (all mild or moderate) occurred in 5.9% of inclisiran-treated patients. Inclisiran-associated anti-drug antibodies were infrequent (5.5%) and had no impact on the efficacy or safety of inclisiran. No new safety signals were identified.

Conclusions: In the largest and longest follow-up to date, inclisiran demonstrated sustained and substantial LDL-C lowering with a favourable long-term safety and tolerability profile. ClinicalTrials.gov identifier: NCT03814187.

Keywords: Inclisiran; atherosclerotic cardiovascular disease; exposure; long-term; low-density lipoprotein cholesterol; proprotein convertase subtilisin/kexin type 9.

Associated data

ClinicalTrials.gov/NCT03814187