Division of Preventive Cardiology, Department of Cardiology, Mayo Clinic, Rochester, MN 55905, USA.
Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Cardiovasc Res. 2024 Oct 14;120(12):1400-1410. doi: 10.1093/cvr/cvae109.
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.
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.
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.
ClinicalTrials.gov identifier: NCT03814187.
目前有关 inclisiran 长期疗效和耐受性的数据有限。本研究通过 ORION-8 对此进行了探索，这是先前的 2 期和 3 期安慰剂对照及开放标签扩展试验的开放标签扩展。
在完成主要试验后，患有动脉粥样硬化性心血管疾病（ASCVD）、ASCVD 风险等同物或杂合子家族性高胆固醇血症的成年患者接受开放标签 inclisiran 每年 2 次（初始剂量和 3 个月后）治疗，直至第 990 天，然后在第 1080 天或最后一次给药后≥90 天进行研究结束访视。研究终点包括达到预先指定的低密度脂蛋白胆固醇（LDL-C）目标的患者比例[ASCVD：＜1.8mmol/L（＜70mg/dL）；ASCVD 风险等同物：＜2.6mmol/L（＜100mg/dL）]、研究结束时 LDL-C 的百分比和绝对变化，以及 inclisiran 的安全性。在 3274 例患者中，2446 例（74.7%）患者随访至研究结束。平均年龄为 64.9±9.9 岁，82.7%（n=2709）患有 ASCVD，基线 LDL-C 平均为 2.9±1.2mmol/L。inclisiran 的累积暴露（包括主要试验）平均为 3.7 年；最大暴露时间为 6.8 年。用 inclisiran 治疗，78.4%[95%置信区间（CI）：76.8，80.0]的患者达到了预先指定的 LDL-C 目标，LDL-C 的平均百分比变化为-49.4%（95%CI：-50.4，-48.3）。未观察到 LDL-C 降低随时间衰减。注射部位治疗相关不良事件（均为轻度/中度）发生在 5.9%的患者中。与 inclisiran 相关的抗药物抗体发生率较低（5.5%），但对 inclisiran 的疗效或安全性没有影响。未发现新的安全性信号。
在迄今为止最大和随访时间最长的研究中，inclisiran 显示出一致且有效的 LDL-C 降低，具有良好的长期安全性和耐受性。
ClinicalTrials.gov 标识符：NCT03814187。
