CVN424, a GPR6 inverse agonist, for Parkinson's disease and motor fluctuations: a double-blind, randomized, phase 2 trial.

IF 9.6 1区医学 Q1 MEDICINE, GENERAL & INTERNAL

EClinicalMedicine Pub Date : 2024-10-18 eCollection Date: 2024-11-01 DOI:10.1016/j.eclinm.2024.102882

Nicola L Brice, Mark Carlton, David H Margolin, Martin Bexon, Kim L Matthews, Lee A Dawson, Aaron L Ellenbogen, C Warren Olanow, Jordan Dubow, Karl Kieburtz

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引用次数: 0

Abstract

Background: CVN424 is a GPR6 inverse agonist that provides selective pharmacological control of the indirect striatopallidal pathway. We assessed the safety and efficacy of CVN424 as an adjunctive treatment to levodopa for reducing OFF-time in individuals with Parkinson's disease (PD) experiencing motor-fluctuations.

Methods: This was a randomised, double-blind, placebo-controlled study conducted at 21 sites across the United States to evaluate two doses of CVN424 (NCT04191577). Patients with PD (Hoehn and Yahr stages 2-4) who were on a stable dose of levodopa and experiencing ≥2 h of daily OFF-time were randomised (1:1:1) to receive either once-daily CVN424 (50 mg or 150 mg) or placebo for a 28-day treatment period. The primary endpoints were safety and tolerability. The key secondary endpoint was the change from baseline to Day 27 in OFF-time.

Findings: The study was conducted from December 23, 2019, to October 14, 2021. Out of 198 participants screened, 141 eligible participants were randomised to one of the three treatment groups (n = 47 per group), and 127 participants completed the 28-day treatment period. The most common treatment emergent adverse events (TEAEs) were headache (2% with CVN424 50 mg, 9% with CVN424 150 mg, and 2% with placebo) and nausea (4% with CVN424 50 mg, 6% with CVN424 150 mg and 2% with placebo). No serious treatment-related adverse events were reported. On Day 27, the mean ± standard deviation (SD) change from baseline in daily OFF-time was -1.3 ± 3.0 h in the CVN424 50 mg group, -1.6 ± 2.5 h in the CVN424 150 mg group, and -0.5 ± 2.9 h in the placebo group. The placebo-adjusted LS mean ± standard error (SE) treatment difference was significant for the CVN424 150 mg dose (1.3 ± 0.56 h, [95 CI% -2.41 to -0.19], nominal p = 0.02).

Interpretation: Treatment with CVN424 was safe and well-tolerated. Despite the short study duration and small sample size, the 150 mg CVN424 dose provided a clinically meaningful reduction in daily OFF-time. This study supports the development of CVN424 for the treatment of PD.

Funding: Cerevance.

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CVN424是一种GPR6反向激动剂，用于治疗帕金森病和运动波动：一项双盲、随机、2期试验。

背景CVN424 是一种 GPR6 反向激动剂，可对间接纹状体通路进行选择性药理控制。我们评估了 CVN424 作为左旋多巴的辅助治疗药物在减少帕金森病（PD）患者运动波动的关机时间方面的安全性和有效性：这是一项随机、双盲、安慰剂对照研究，在全美 21 个地点进行，评估两种剂量的 CVN424（NCT04191577）。研究人员随机（1:1:1）安排服用稳定剂量左旋多巴且每日关机时间≥2小时的帕金森病患者（Hoehn和Yahr分期2-4）在28天的治疗期内接受每日一次的CVN424（50毫克或150毫克）或安慰剂治疗。主要终点是安全性和耐受性。关键的次要终点是关机时间从基线到第27天的变化：研究于 2019 年 12 月 23 日至 2021 年 10 月 14 日进行。在筛选出的 198 名参与者中，141 名符合条件的参与者被随机分配到三个治疗组中的一组（每组 n = 47），127 名参与者完成了 28 天的治疗。最常见的治疗突发不良事件（TEAEs）是头痛（CVN424 50 mg为2%，CVN424 150 mg为9%，安慰剂为2%）和恶心（CVN424 50 mg为4%，CVN424 150 mg为6%，安慰剂为2%）。未报告与治疗相关的严重不良事件。第27天，CVN424 50毫克组每日关机时间与基线相比的平均±标准差（SD）变化为-1.3±3.0小时，CVN424 150毫克组为-1.6±2.5小时，安慰剂组为-0.5±2.9小时。安慰剂调整后的LS平均值±标准误差（SE）治疗差异在CVN424 150毫克剂量组显著（1.3±0.56小时，[95 CI% -2.41至-0.19]，标称P = 0.02）：CVN424治疗安全且耐受性良好。尽管研究持续时间短、样本量小，但150毫克CVN424剂量可减少每日OFF时间，具有临床意义。这项研究为开发CVN424治疗帕金森病提供了支持：Cerevance.

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来源期刊

EClinicalMedicine Medicine-Medicine (all)

CiteScore

18.90

自引率

1.30%

发文量

506

审稿时长

22 days

期刊介绍： eClinicalMedicine is a gold open-access clinical journal designed to support frontline health professionals in addressing the complex and rapid health transitions affecting societies globally. The journal aims to assist practitioners in overcoming healthcare challenges across diverse communities, spanning diagnosis, treatment, prevention, and health promotion. Integrating disciplines from various specialties and life stages, it seeks to enhance health systems as fundamental institutions within societies. With a forward-thinking approach, eClinicalMedicine aims to redefine the future of healthcare.