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

Article · Wright RS, Raal FJ, Koenig W, Landmesser U, Leiter LA, Vikarunnessa S, Lesogor A, Maheux P, Talloczy Z, Zang X, Schwartz GG, Ray KK

- Archive id: doi:10.1093/cvr/cvae109
- Published: 2024-10-01
- Venue: Cardiovascular research
- DOI: https://doi.org/10.1093/cvr/cvae109
- PMID: 38753448
- PMCID: PMC11481169
- Citations: 78
- Source URL: https://doi.org/10.1093/cvr/cvae109
- PDF: https://europepmc.org/articles/PMC11481169/pdf
- Provenance: europepmc

## Abstract

Aims Data describing the long-term efficacy and tolerability of inclisiran are limited. This was explored in ORION-8, an open-label extension of preceding Phase 2 and Phase 3 placebo-controlled and open-label extension trials. Methods and results Following completion of the parent trial, adult patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalent, or heterozygous familial hypercholesterolaemia received open-label inclisiran twice yearly (after initial and 3-month doses) until Day 990, followed by an end-of-study visit at Day 1080 or ≥ 90 days after the last dose. The study endpoints included the proportion of patients achieving pre-specified low-density lipoprotein cholesterol (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 end-of-study, and safety of inclisiran. Of 3274 patients, 2446 (74.7%) were followed until end-of-study. 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% \[95% confidence interval (CI): 76.8, 80.0\] of patients achieved pre-specified LDL-C goals and mean percentage change in LDL-C was -49.4% (95% CI: -50.4, -48.3). No attenuation of LDL-C lowering over time was observed. Treatment-emergent adverse events at injection site (all mild/moderate) occurred in 5.9% of the 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. Conclusion In the largest and longest follow-up to date with \>12 000 patient-years exposure, inclisiran demonstrated consistent and effective LDL-C lowering with a favourable long-term safety and tolerability profile. Trial registration number ClinicalTrials.gov identifier: NCT03814187.

_Abstract reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [Cardiovascular Therapeutics](https://space-kitty.com/topics/cardiovascular-innovation)

Cited in dossiers:
- [Cardiovascular Therapeutics: State of the Field (October 2026)](https://space-kitty.com/dossiers/cardiovascular-innovation)

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