Cooper Medical School at Rowan University, Camden, NJ, USA; Clintrex Research Corporation, Sarasota, FL, USA.
Rho, Hillsborough, NJ, USA.
Lancet Neurol. 2024 Jan;23(1):37-45. doi: 10.1016/S1474-4422(23)00378-2.
Converging lines of evidence suggest that microglia are relevant to Parkinson's disease pathogenesis, justifying exploration of therapeutic agents thought to attenuate pathogenic microglial function. We sought to test the safety and efficacy of NLY01-a brain-penetrant, pegylated, longer-lasting version of exenatide (a glucagon-like peptide-1 receptor agonist) that is believed to be anti-inflammatory via reduction of microglia activation-in Parkinson's disease.
We report a 36-week, randomised, double-blind, placebo-controlled study of NLY01 in participants with early untreated Parkinson's disease conducted at 58 movement disorder clinics in the USA. Participants meeting UK Brain Bank or Movement Disorder Society research criteria for Parkinson's disease were randomly allocated (1:1:1) to one of two active treatment groups (2·5 mg or 5·0 mg NLY01) or matching placebo, based on a central computer-generated randomisation scheme using permuted block randomisation with varying block sizes. All participants, investigators, coordinators, study staff, and sponsor personnel were masked to treatment assignments throughout the study. The primary efficacy endpoint for the primary analysis population (defined as all randomly assigned participants who received at least one dose of study drug) was change from baseline to week 36 in the sum of Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III. Safety was assessed in the safety population (all randomly allocated participants who received at least one dose of the study drug) with documentation of adverse events, vital signs, electrocardiograms, clinical laboratory assessments, physical examination, and scales for suicidality, sleepiness, impulsivity, and depression. This trial is complete and registered at ClinicalTrials.gov, NCT04154072.
The study took place between Jan 28, 2020, and Feb 16, 2023. 447 individuals were screened, of whom 255 eligible participants were randomly assigned (85 to each study group). One patient assigned to placebo did not receive study treatment and was not included in the primary analysis. At 36 weeks, 2·5 mg and 5·0 mg NLY01 did not differ from placebo with respect to change in sum scores on MDS-UPDRS parts II and III: difference versus placebo -0·39 (95% CI -2·96 to 2·18; p=0·77) for 2·5 mg and 0·36 (-2·28 to 3·00; p=0·79) for 5·0 mg. Treatment-emergent adverse events were similar across groups (reported in 71 [84%] of 85 patients on 2·5 mg NLY01, 79 [93%] of 85 on 5·0 mg, and 73 [87%] of 84 on placebo), with gastrointestinal disorders the most commonly observed class in active groups (52 [61%] for 2·5 mg, 64 [75%] for 5·0 mg, and 30 [36%] for placebo) and nausea the most common event overall (33 [39%] for 2·5 mg, 49 [58%] for 5·0 mg, and 16 [19%] for placebo). No deaths occurred during the study.
NLY01 at 2·5 and 5·0 mg was not associated with any improvement in Parkinson's disease motor or non-motor features compared with placebo. A subgroup analysis raised the possibility of motor benefit in younger participants. Further study is needed to determine whether these exploratory observations are replicable.
D&D Pharmatech-Neuraly.
越来越多的证据表明，小胶质细胞与帕金森病的发病机制有关，这证明了探索被认为可以通过减轻致病小胶质细胞功能来治疗疾病的治疗药物是合理的。我们试图测试 NLY01（一种穿透大脑的、聚乙二醇化的、作用时间更长的 exenatide（一种胰高血糖素样肽-1 受体激动剂）的安全性和有效性，据信通过减少小胶质细胞的激活可以起到抗炎作用）在帕金森病患者中的作用。
我们报告了一项在美国 58 个运动障碍诊所进行的为期 36 周、随机、双盲、安慰剂对照的 NLY01 研究，该研究纳入了早期未经治疗的帕金森病患者。符合英国脑库或运动障碍学会帕金森病研究标准的参与者，按照中央计算机生成的随机化方案，使用随机区组随机化和不同的区组大小，以 1:1:1 的比例随机分配到两个活性治疗组（2.5 mg 或 5.0 mg NLY01）或匹配的安慰剂。所有参与者、研究者、协调员、研究人员和赞助商人员在整个研究过程中均对治疗分配进行了屏蔽。主要分析人群（定义为所有接受至少一剂研究药物的随机分配参与者）的主要疗效终点是从基线到第 36 周的运动障碍学会统一帕金森病评定量表（MDS-UPDRS）第二部分和第三部分的总和变化。安全性评估的人群是安全性人群（所有接受至少一剂研究药物的随机分配参与者），记录不良事件、生命体征、心电图、临床实验室评估、体检以及自杀意念、嗜睡、冲动和抑郁量表。这项试验已经完成并在 ClinicalTrials.gov 上注册，NCT04154072。
该研究于 2020 年 1 月 28 日至 2023 年 2 月 16 日进行。共有 447 人接受了筛查，其中 255 名符合条件的参与者被随机分配（每组 85 人）。一名被分配到安慰剂的患者未接受研究治疗，未纳入主要分析。在 36 周时，2.5 mg 和 5.0 mg NLY01 与安慰剂相比，MDS-UPDRS 第二部分和第三部分的总和评分没有差异：与安慰剂相比，差值分别为 -0.39（95%CI -2.96 至 2.18；p=0.77）和 0.36（95%CI -2.28 至 3.00；p=0.79）。各组的治疗相关不良事件相似（85 名接受 2.5 mg NLY01 的患者中有 71 例[84%]、85 名接受 5.0 mg NLY01 的患者中有 79 例[93%]和 84 名接受安慰剂的患者中有 73 例[87%]报告），胃肠道疾病是最常见的治疗组（52 例[61%]接受 2.5 mg，64 例[75%]接受 5.0 mg，30 例[36%]接受安慰剂），恶心是最常见的总体事件（33 例[39%]接受 2.5 mg，49 例[58%]接受 5.0 mg，16 例[19%]接受安慰剂）。研究期间无死亡发生。
与安慰剂相比，2.5 mg 和 5.0 mg 的 NLY01 与帕金森病的运动或非运动特征的任何改善无关。一项亚组分析提出了年轻参与者可能受益于运动的可能性。需要进一步的研究来确定这些探索性观察结果是否具有可重复性。
D&D Pharmatech-Neuraly。
