Faculty of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France; INSERM UMR_S 999 (HPPIT), Le Kremlin-Bicêtre, France; Department of Respiratory and Intensive Care Medicine, Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, ERN-LUNG, Le Kremlin-Bicêtre, France.
Rare Diseases Unit VSIA Pauls Stradins Clinical University Hospital, Riga Stradiņš University, Riga, Latvia.
Lancet Respir Med. 2024 Nov;12(11):865-876. doi: 10.1016/S2213-2600(24)00226-1. Epub 2024 Sep 19.
The role of serotonin in pulmonary arterial hypertension has been extensively studied in recent decades, with preclinical data strongly indicating involvement in disease pathogenesis; however, clinical studies have yielded mixed results.
ELEVATE-2 was a phase 2b dose-ranging, randomised, double-blind, placebo-controlled, multicentre trial investigating rodatristat ethyl as a treatment for patients with pulmonary arterial hypertension. The study was conducted at 64 sites across 16 countries in Europe and North America. Eligible participants were aged 18 years or older, had pulmonary arterial hypertension with WHO functional class II or III symptom severity, and had received a stable dose and regimen of one or more pulmonary arterial hypertension treatments for at least 12 weeks. Participants were randomly assigned 1:1:1 to receive two placebo tablets, one placebo and one rodatristat ethyl 300 mg tablet, or two rodatristat ethyl 300 mg tablets twice daily using an interactive response system. Participants, investigators, site personnel, and sponsors were masked to treatment allocation. Participants who completed the 24 week treatment period were invited to continue in an open-label extension. The primary endpoint was percent change in pulmonary vascular resistance (PVR) from baseline to week 24. Primary efficacy analyses were conducted on the intention-to-treat population and analyses of harms were conducted in the safety population, which included all patients who received any amount of the study drug. This trial is registered with ClinicalTrials.gov, NCT04712669, and is now complete.
Between March 18, 2021 and Dec 13, 2022, 108 participants were enrolled and randomly assigned. 36 participants received placebo, 36 received rodatristat ethyl 300 mg, and 36 received rodatristat ethyl 600 mg twice daily. Overall, 85 (79%) of participants were female and 23 (21%) were male. The mean age was 52·8 years (SD 14·7) in the full analysis set. In the open-label extension phase, 62 (82%) of participants were female and 14 (18%) were male, and the mean age was 52·8 years (SD 14·7); this phase was terminated following sponsor review of unmasked main study results. Least-squares mean percent change in PVR from baseline to week 24 favoured placebo and was 5·8% (SE 18·1) for the placebo group, 63·1% (18·5) for the rodatristat ethyl 300 mg group, and 64·2% (18·0) for the rodatristat ethyl 600 mg group. Treatment-emergent adverse events (TEAE) were reported for 29 (81%) patients in the placebo group, 33 (92%) patients in the rodatristat ethyl 300 mg group, and all 36 (100%) patients in the rodatristat ethyl 600 mg group. TEAE leading to study discontinuation were reported for three (8%) patients in the placebo group, four (11%) patients in the rodatristat ethyl 300 mg group, and four (11%) in the rodatristat ethyl 600 mg group. There was one (3%) TEAE leading to death in the rodatristat ethyl 300 mg group.
Our results indicate that reducing peripheral serotonin concentrations via rodatristat ethyl has a negative effect on pulmonary haemodynamics and cardiac function in patients with pulmonary arterial hypertension. This finding suggests that manipulating this pathway might not be a suitable option for pulmonary arterial hypertension therapy.
Enzyvant Therapeutics (now Sumitomo Pharma America).
几十年来，人们对血清素在肺动脉高压中的作用进行了广泛研究，临床前数据强烈表明其参与了疾病的发病机制；然而，临床研究的结果却喜忧参半。
ELEVATE-2 是一项 2b 期剂量递增、随机、双盲、安慰剂对照、多中心试验，旨在研究罗曲司特乙酯治疗肺动脉高压患者的疗效。该研究在欧洲和北美 16 个国家的 64 个地点进行。符合条件的参与者年龄在 18 岁及以上，患有世界卫生组织（WHO）功能分类 II 或 III 级症状严重程度的肺动脉高压，并且接受了一种或多种肺动脉高压治疗药物的稳定剂量和方案至少 12 周。参与者以 1:1:1 的比例随机分配接受两片安慰剂、一片安慰剂和一片罗曲司特乙酯 300mg 片或每天两次两片罗曲司特乙酯 300mg 片，使用交互式反应系统。参与者、研究者、现场工作人员和赞助商对治疗分配情况不知情。完成 24 周治疗期的参与者被邀请继续参加开放标签扩展。主要终点是从基线到第 24 周时肺血管阻力（PVR）的百分比变化。主要疗效分析在意向治疗人群中进行，安全性人群中进行了危害分析，安全性人群包括接受任何剂量研究药物的所有患者。这项试验在 ClinicalTrials.gov 注册，编号为 NCT04712669，现已完成。
2021 年 3 月 18 日至 2022 年 12 月 13 日期间，共纳入 108 名参与者并进行了随机分组。36 名参与者接受安慰剂，36 名参与者接受罗曲司特乙酯 300mg，36 名参与者接受罗曲司特乙酯 600mg，每日两次。总体而言，85 名（79%）参与者为女性，23 名（21%）为男性。全分析集的平均年龄为 52.8 岁（SD 14.7）。在开放标签扩展阶段，62 名（82%）参与者为女性，14 名（18%）为男性，平均年龄为 52.8 岁（SD 14.7）；在赞助商审查未蒙面的主要研究结果后，该阶段终止。从基线到第 24 周时，PVR 的最小二乘平均百分比变化对安慰剂有利，安慰剂组为 5.8%（SE 18.1），罗曲司特乙酯 300mg 组为 63.1%（18.5），罗曲司特乙酯 600mg 组为 64.2%（18.0）。报告了 29 名（81%）安慰剂组患者、33 名（92%）罗曲司特乙酯 300mg 组患者和 36 名（100%）罗曲司特乙酯 600mg 组患者出现治疗后不良事件（TEAE）。安慰剂组有 3 名（8%）患者、罗曲司特乙酯 300mg 组有 4 名（11%）患者和罗曲司特乙酯 600mg 组有 4 名（11%）患者因 TEAE 而停止研究。罗曲司特乙酯 300mg 组有 1 名（3%）患者因 TEAE 导致死亡。
我们的结果表明，通过罗曲司特乙酯降低外周血清素浓度对肺动脉高压患者的肺血流动力学和心脏功能产生负面影响。这一发现表明，操纵这一途径可能不是肺动脉高压治疗的合适选择。
Enzyvant Therapeutics（现为 Sumitomo Pharma America）。
