双重5-HT6/5-HT2A拮抗剂SYN120治疗帕金森病痴呆的安全性、耐受性及初步疗效：一项随机对照概念验证试验

Safety, tolerability, and preliminary efficacy of SYN120, a dual 5-HT6/5-HT2A antagonist, for the treatment of Parkinson disease dementia: A randomized, controlled, proof-of-concept trial.

作者信息

Fernandez Hubert H, Weintraub Daniel, Macklin Eric, Litvan Irene, Schwarzschild Michael A, Eberling Jamie, Videnovic Aleksandar, Kenney Christopher J

机构信息

Cleveland Clinic Neurological Institute, USA.

University of Pennsylvania School of Medicine, Departments of Neurology and Psychiatry, USA.

出版信息

Parkinsonism Relat Disord. 2023 Sep;114:105511. doi: 10.1016/j.parkreldis.2023.105511. Epub 2023 Jul 13.

DOI:10.1016/j.parkreldis.2023.105511

PMID:37532622

Abstract

BACKGROUND

SYN120 is a dual serotonin receptor (5-HT6/5-HT2A) antagonist hypothesized to improve cognition and psychiatric symptoms.

OBJECTIVES

We evaluated the safety, tolerability, and efficacy of SYN120 in patients with Parkinson disease dementia (PDD).

METHODS

In a multicenter, double-blind, parallel-group, 16-week phase 2a proof-of-concept trial in PDD with concomitant cholinesterase inhibitor use, eligible patients were randomized to oral SYN120 (100 mg/day) or placebo. Adverse events (AEs), Unified Parkinson's Disease Rating Scale (UPDRS) scores, and discontinuations assessed safety and tolerability. The primary and key secondary efficacy measures were the Cognitive Drug Research (CDR) computerized assessment system Continuity of Attention and Quality of Episodic Memory scores. Other efficacy measures were: Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC), Brief Penn Parkinson's Daily Activity Questionnaire-15 (PDAQ-15), Scales for Outcomes in Parkinson's Disease-Sleep Scale (SCOPA-Sleep), and Neuropsychiatric Inventory (NPI).

RESULTS

Eighty-two patients were randomized to SYN120 (N = 38) or placebo (N = 44), AEs occurred in 74% and 77% of patients, and treatment discontinuation in both groups was 16%. Nausea and vomiting were more frequent, and motor symptoms (UPDRS) worsened in the SYN120 group. At week 16, the SYN120 and placebo groups did not differ significantly for any cognitive assessment. Cognitive activities of daily living (PDAQ-15) and the NPI-Apathy/Indifference scores improved nominally in the SYN120 group compared with placebo (unadjusted p = 0.029 and 0.028).

CONCLUSIONS

SYN120 was adequately tolerated, mild worsening of motor symptoms was noted and it did not improve cognition in PDD patients. Its potential benefits for cognitive activities of daily living and apathy warrant further study.

REGISTRATION

Clinicaltrials.gov as NCT02258152.

摘要

背景

SYN120是一种双重血清素受体（5-HT6/5-HT2A）拮抗剂，据推测可改善认知和精神症状。

目的

我们评估了SYN120在帕金森病痴呆（PDD）患者中的安全性、耐受性和疗效。

方法

在一项多中心、双盲、平行组、为期16周的2a期概念验证试验中，PDD患者同时使用胆碱酯酶抑制剂，符合条件的患者被随机分为口服SYN120（100毫克/天）或安慰剂组。不良事件（AE）、统一帕金森病评定量表（UPDRS）评分和停药情况评估安全性和耐受性。主要和关键的次要疗效指标是认知药物研究（CDR）计算机评估系统的注意力连续性和情景记忆质量评分。其他疗效指标包括：阿尔茨海默病评估量表-认知分量表（ADAS-Cog）、阿尔茨海默病协作研究-临床医生对变化的整体印象（ADCS-CGIC）、简短的宾夕法尼亚帕金森病日常活动问卷-15（PDAQ-15）、帕金森病结局量表-睡眠量表（SCOPA-睡眠）和神经精神科问卷（NPI）。

结果

82名患者被随机分为SYN120组（N = 38）或安慰剂组（N = 44），74%和77%的患者发生了AE，两组的治疗停药率均为16%。SYN120组恶心和呕吐更为频繁，运动症状（UPDRS）恶化。在第16周时，SYN120组和安慰剂组在任何认知评估中均无显著差异。与安慰剂相比，SYN120组的日常生活认知活动（PDAQ-15）和NPI-情感淡漠/无动于衷评分名义上有所改善（未调整p = 0.029和0.028）。