Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial
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Résumé
INTRODUCTION: Whether long-term treatment with the twice-yearly, siRNA therapeutic inclisiran, which reduces hepatic production of proprotein convertase subtilisin/kexin type 9 (PCSK9), results in sustained reductions in LDL cholesterol with an acceptable safety profile is not known. The aim of this study was to assess the effect of long-term dosing of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol. METHODS: ORION-3 was a 4-year open-label extension study of the placebo-controlled, phase 2 ORION-1 trial, conducted at 52 sites across five countries. Patients with prevalent atherosclerotic cardiovascular disease or high-risk primary prevention and elevated LDL cholesterol despite maximally tolerated statins or other LDL-lowering treatments, or with documented statin intolerance, who had completed the ORION-1 trial were eligible. Patients receiving inclisiran in ORION-1 received twice-yearly 300 mg subcutaneous inclisiran sodium throughout ORION-3 (inclisiran-only arm), whereas patients receiving placebo in ORION-1 first received subcutaneous evolocumab 140 mg every 2 weeks until day 360 thereafter transitioning to inclisiran twice-yearly for the remainder of ORION-3 study (switching arm). The primary efficacy endpoint was the percentage change in LDL cholesterol with inclisiran from the start of ORION-1 through to day 210 of the open label extension phase in the inclisiran-only arm (approximately 570 days of total inclisiran exposure in the modified intention-to-treat population). Secondary and exploratory endpoints included changes in LDL-C cholesterol and PCSK9 concentrations levels up to day 1440 (4 years) in each arm, and safety. ORION-3 is registered with ClinicalTrials.gov, NCT03060577. FINDINGS: Of the original ORION-1 cohort of 497 patients, 290 of 370 patients allocated to drug continued into the inclisiran-only arm and 92 of 127 patients allocated to placebo entered the switching-arm in the ORION-3 extension study conducted between March 24, 2017, and Dec 17, 2021. In the inclisiran-only arm, LDL cholesterol was reduced by 47·5% (95% CI 50·7-44·3) at day 210 and sustained over 1440 days. The 4-year averaged mean reduction of LDL-C cholesterol was 44·2% (95% CI: 47·1-41·4), with reductions in PCSK9 ranging from 62·2% to 77·8%. Adverse events at the injection site were reported in 39 (14%) of 284 patients in the inclisiran-only arm and 12 (14%) of 87 patients in the switching arm. The incidence of treatment-emergent serious adverse events possibly related to the study drug was 1% (three of 284) in the inclisiran-only arm and 1% (one of 87) in the switching arm. INTERPRETATION: Twice-yearly inclisiran provided sustained reductions in LDL cholesterol and PCSK9 concentrations and was well tolerated over 4 years in the extension study. This is the first prospective long-term study to assess repeat hepatic exposure to inclisiran. FUNDING: Novartis Pharma.
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Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,001 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découle