A Phase 2b Clinical Study of the P38 Alpha Kinase Inhibitor Neflamapimod in Patients with Mild-to-Moderate Dementia with Lewy Bodies (DLB)

P38 α激酶抑制剂 Neflamapimod 治疗轻至中度路易体痴呆 (DLB) 患者的 2b 期临床研究

• 批准号: 10582488
• 负责人: John Alam
• 金额: $ 668.21万
• 依托单位: EIP PHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582488
• 关键词: Admission activity; Adverse event; Affect; Aggressive behavior; Agitation; Alzheimer' s Disease; American; Attention; Behavioral Symptoms; Biological Availability; Brain; Cessation of life; Cholinesterase Inhibitors; Clinical; Clinical Research; Clinical Trials; Clinical dementia rating scale; Cognition; Cognitive; Collection; Data; Dementia; Dementia with Lewy Bodies; Dependence; Diagnosis; Disease; Dose; Double-Blind Method; Down Syndrome; Drug usage; Effectiveness; Electroencephalography; Enzymes; Equilibrium; Equipment and supply inventories; Eye; Family; Family Caregiver; Functional disorder; Future; Grief reaction; Hallucinations; Laboratories; Measures; Medical; Mental Depression; Mental disorders; Modeling; Monitor; Motor; Movement Disorder Society Unified Parkinson' s Disease Rating Scale; Nerve Degeneration; Neurobehavioral Manifestations; Neuropsychological Tests; Nursing Homes; Oral; Outcome; Outcome Measure; Parkinson Disease; Pathogenicity; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Placebo Control; Placebos; Population; Process; Progressive Disease; Quality of life; Randomized; Research; Rest; Risk; Safety; Sleep; Sum; System; Testing; Thinness; Time; Transgenic Mice; Visual; basal forebrain; basal forebrain cholinergic neurons; cholinergic; clinical development; clinical efficacy; clinically relevant; cognitive testing; cooperative study; design; efficacy evaluation; executive function; fall risk; family burden; impression; improved; inhibitor; inhibitor therapy; investigator-initiated trial; kinase inhibitor; motor symptom; neurodegenerative dementia; neuropsychiatry; off-label use; p38 Mitogen Activated Protein Kinase; patient population; phase 2 study; phase III trial; pre-clinical; preclinical study; primary endpoint; primary outcome; prospective; reduce symptoms; research clinical testing; secondary endpoint; therapeutic target; treatment effect; visual learning

Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer’s disease (AD). DLB is a more rapidly progressive disease than AD, with a median time from diagnosis to death or nursing home admission that is half that seen in AD and is associated with extensive burden on both patients and family caregivers. There is a great unmet medical need, with no approved treatments, only AD and Parkinson’s disease (PD) drugs used off-label to partially or temporarily relieve some of its severe cognitive and motor symptoms. The proposed treatment, neflamapimod, an orally bioavailable, highly specific inhibitor of the intracellular enzyme p38 mitogen activated protein kinase alpha (p38α), is in clinical development by EIP Pharma with a phase 2a study in DLB and phase 2 studies in early AD already completed. Preclinical data indicate that neflamapimod, through inhibiting p38α, therapeutically targets specific pathogenic mechanisms underlying dysfunction and degeneration of neurons in a part of the brain called the basal forebrain, abnormalities in which are considered to be the major pathogenic drivers of the dementia in DLB. For example, neflamapimod increased the number of functioning basal forebrain cholinergic neurons in Ts2 transgenic mice that, along with modeling Down syndrome, develop neurodegeneration in the basal forebrain cholinergic system. Together, such evidence provides a strong scientific rationale for neflamapimod as a disease modifying treatment for DLB. In accordance with this, neflamapimod received Fast-Track designation by the FDA for DLB. A recently completed phase 2a exploratory (i.e., hypothesis-generating) clinical trial (NCT04001517) in 91 patients with mild-to-moderate DLB, also receiving cholinesterase inhibitor therapy, provided preliminary evidence of clinical efficacy of neflamapimod on various cognitive, motor, and functional aspects of the disease. The proposed phase 2b trial will confirm and expand upon these results. The Specific Aims are to, in the context of performing a phase 2b randomized, double- blind, placebo-controlled, 16-week treatment study of neflamapimod (40mg TID) in 160 subjects with mild-to-moderate DLB: (Aim 1). Demonstrate that neflamapimod improves cognition and function, based on primary (Neuropsychological Test Battery) and secondary (Clinical Dementia Rating Scale sum of boxes, Timed Up and Go test, The Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change) efficacy measures in patients with mild-to-moderate DLB receiving cholinesterase inhibitors; (Aim 2). Assess neuropsychiatric outcomes and safety/tolerability during treatment with neflamapimod in patients with DLB; and (Aim 3). Assess effects of neflamapimod on electroencephalographic (EEG) measures of DLB, specifically beta functional connectivity and alpha-reactivity; both markers of basal forebrain cholinergic dysfunction. Successful completion of this phase 2b trial will inform our pivotal phase 3 trial, advancing neflamapimod as a disease- modifying treatment for DLB and providing hope for these patients and their families.

Lewy Bodies（DLB）的痴呆症是神经退行性痴呆症的第二大最常见原因 阿尔茨海默氏病（AD）。 DLB比AD更快地进行性疾病，诊断为中位时间 死亡或护士住院，这是AD中看到的一半，并且都与两者的广泛燃烧有关 患者和家庭护理人员。有很大的未满足医疗需求，没有批准的治疗，只有广告和 帕金森氏病（PD）药物使用标签外的药物部分或暂时营救其某些严重的认知和 运动症状。拟议的治疗Neflamapimod是一种口服的生物利用，高度特异的抑制剂 细胞内酶p38有丝分裂激活的蛋白激酶α（p38α）在EIP Pharma中正在临床发育中 在DLB和第二阶段研究中，AD早期的研究已经完成。临床前数据表明 Neflamapimod，通过抑制p38α，治疗靶向基础的特定致病机制 神经元的功能障碍和变性，在大脑的一部分中称为基本前脑，异常，其中 被认为是DLB痴呆症的主要致病驱动因素。例如，Neflamapimod增加了 TS2转基因小鼠中功能的基本前脑胆碱能神经元的数量，以及建模 唐氏综合症，在基本前脑胆碱能系统中发展神经退行性。在一起，这样的证据 为Neflamapimod作为DLB的疾病治疗提供了强烈的科学原理。根据 这样，Neflamapimod接受了FDA的快速轨道指定DLB。最近完成的2A期 探索性（即假设生成）临床试验（NCT04001517）在91例轻度至中度DLB的患者中 还接受胆碱酯酶抑制剂疗法，提供了Neflamapimod临床效率的初步证据 在疾病的各种认知，运动和功能方面。拟议的2B期试验将确认并 扩展这些结果。具体目的是在执行2B阶段随机的情况下 双盲，安慰剂对照，16周的Neflamapimod（40mg TID）的160名受试者的治疗研究 轻度至中度DLB ：（ AIM 1）。证明Neflamapimod基于 初级（神经心理测试电池）和次级（临床痴呆率评级量表盒子的总和，时机 向上并进行测试，阿尔茨海默氏病合作研究 - 临床全球变化印象）效率 接受胆碱酯酶抑制剂的轻度至中度DLB患者的措施； （目标2）。评估 DLB患者的Neflamapimod治疗期间的神经精神疗法和安全性/易学性；和 （目标3）。评估Neflamapimod对DLB脑电图（EEG）测量的影响，特别是Beta 功能连通性和α反应性；基本前脑胆碱能功能障碍的两个标记。成功的 该阶段2B试验的完成将为我们的关键第三阶段试验提供信息，将Neflamapimod作为一种疾病前进 - 修改DLB的治疗方法，并为这些患者及其家人提供希望。