口腔 ENT-01 通过靶向肠道神经元治疗帕金森病便秘：一项随机对照试验。

Oral ENT-01 Targets Enteric Neurons to Treat Constipation in Parkinson Disease : A Randomized Controlled Trial.

机构信息

Mayo Clinic, Rochester, Minnesota (M.C.).

Penn State Hershey Medical Center, Hershey, Pennsylvania (T.S.).

出版信息

Ann Intern Med. 2022 Dec;175(12):1666-1674. doi: 10.7326/M22-1438. Epub 2022 Nov 8.

DOI:10.7326/M22-1438

PMID:36343348

Abstract

BACKGROUND

Parkinson disease (PD) is associated with α-synuclein (αS) aggregation within enteric neurons. ENT-01 inhibits the formation of αS aggregates and improved constipation in an open-label study in patients with PD.

OBJECTIVE

To evaluate the safety and efficacy of oral ENT-01 for constipation and neurologic symptoms in patients with PD and constipation.

DESIGN

Randomized, placebo-controlled phase 2b study. (ClinicalTrials.gov: NCT03781791).

SETTING

Outpatient.

PATIENTS

150 patients with PD and constipation.

INTERVENTION

ENT-01 or placebo daily for up to 25 days. After baseline assessment of constipation severity, daily dosing was escalated to the prokinetic dose, the maximum dose (250 mg), or the tolerability limit, followed by a washout period.

MEASUREMENTS

The primary efficacy end point was the number of complete spontaneous bowel movements (CSBMs) per week. Neurologic end points included dementia (assessed using the Mini-Mental State Examination [MMSE]) and psychosis (assessed using the Scale for the Assessment of Positive Symptoms adapted for PD [SAPS-PD]).

RESULTS

The weekly CSBM rate increased from 0.7 to 3.2 in the ENT-01 group versus 0.7 to 1.2 in the placebo group ( < 0.001). Improvement in secondary end points included SBMs ( = 0.002), stool consistency ( < 0.001), ease of passage ( = 0.006), and laxative use ( = 0.041). In patients with dementia, MMSE scores improved by 3.4 points 6 weeks after treatment in the ENT-01 group ( = 14) versus 2.0 points in the placebo group ( = 14). Among patients with psychosis, SAPS-PD scores improved from 6.5 to 1.7 six weeks after treatment in the ENT-01 group ( = 5) and from 6.3 to 4.4 in the placebo group ( = 6). ENT-01 was well tolerated, with no deaths or drug-related serious adverse events. Adverse events were predominantly gastrointestinal, including nausea (34.4% [ENT-01] vs. 5.3% [placebo]; < 0.001) and diarrhea (19.4% [ENT-01] vs. 5.3% [placebo]; = 0.016).

LIMITATION

Longer treatment periods need to be investigated in future studies.

CONCLUSION

ENT-01 was safe and significantly improved constipation.

PRIMARY FUNDING SOURCE

Enterin, Inc.

摘要

背景

帕金森病（PD）与肠神经元内的α-突触核蛋白（αS）聚集有关。ENT-01 可抑制 αS 聚集体的形成，并在 PD 患者的开放性研究中改善便秘。

目的

评估口服 ENT-01 治疗 PD 伴便秘患者便秘和神经症状的安全性和疗效。

设计

随机、安慰剂对照的 2b 期研究。（ClinicalTrials.gov：NCT03781791）。

地点

门诊。

患者

150 例 PD 伴便秘患者。

干预

ENT-01 或安慰剂每天最多 25 天。在便秘严重程度基线评估后，每日剂量增加至促动力剂量、最大剂量（250mg）或耐受极限，然后进行洗脱期。

测量

主要疗效终点为每周完全自发性排便次数（CSBMs）。神经学终点包括痴呆（使用简易精神状态检查[MMSE]评估）和精神病（使用改良 PD 阳性症状评定量表[SAPS-PD]评估）。

结果

ENT-01 组每周 CSBM 率从 0.7 增加到 3.2，安慰剂组从 0.7 增加到 1.2（<0.001）。次要终点的改善包括 SBM（=0.002）、粪便稠度（<0.001）、通过容易度（=0.006）和泻药使用（=0.041）。在痴呆患者中，ENT-01 组治疗 6 周后 MMSE 评分改善 3.4 分（14 例），安慰剂组改善 2.0 分（14 例）。在精神病患者中，ENT-01 组治疗 6 周后 SAPS-PD 评分从 6.5 降至 1.7（5 例），安慰剂组从 6.3 降至 4.4（6 例）。ENT-01 耐受性良好，无死亡或与药物相关的严重不良事件。不良事件主要为胃肠道，包括恶心（34.4%[ENT-01]与 5.3%[安慰剂]；<0.001）和腹泻（19.4%[ENT-01]与 5.3%[安慰剂]；=0.016）。