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

路易体痴呆（DLB）是神经退行性痴呆的第二大常见原因， 阿尔茨海默病（AD）。DLB是一种比AD进展更快的疾病，从诊断开始的中位时间 死亡或入住疗养院的风险是AD的一半，并且与两者的广泛负担相关。 患者和家庭护理人员。有一个巨大的未满足的医疗需求，没有批准的治疗，只有AD和 帕金森病（PD）药物标签外使用，部分或暂时缓解其严重的认知和 运动症状所提出的治疗，neflamapimod，一种口服生物可利用的，高度特异性的抑制剂， 细胞内酶p38丝裂原活化蛋白激酶α（p38α），正在由EIP Pharma进行临床开发 DLB的2a期研究和早期AD的2期研究已经完成。临床前数据表明， neflamapimod通过抑制p38α，治疗靶向特定的致病机制， 在大脑的一部分称为基底前脑的神经元功能障碍和退化，异常，其中 被认为是DLB中痴呆的主要致病驱动因素。例如，neflamapimod增加 Ts 2转基因小鼠中功能正常的基底前脑胆碱能神经元的数量，沿着建模 唐氏综合症，基底前脑胆碱能系统发生神经变性。这些证据加在一起 为奈夫拉莫德作为DLB的疾病改善治疗提供了强有力的科学依据。根据 因此，neflamapimod被FDA指定为DLB的快速通道药物。最近完成的第2a阶段 探索性的（即，在91例轻度至中度DLB患者中进行的临床试验（NCT 04001517）， 也接受胆碱酯酶抑制剂治疗，提供了neflamapimod临床疗效的初步证据 对疾病的各种认知运动和功能方面的影响。拟议的2b期试验将证实， 扩大这些成果。具体目的是，在进行2b期随机化的背景下， 在160名患有糖尿病的受试者中进行的奈夫拉莫德（40 mg TID）的双盲、安慰剂对照、16周治疗研究 轻度至中度DLB：（目标1）。证明neflamapimod改善认知和功能，基于 主要（神经心理测试组合）和次要（临床痴呆评定量表，方框总和，计时 阿尔茨海默病合作研究-临床总体印象变化）疗效 在接受胆碱酯酶抑制剂治疗的轻度至中度DLB患者中的措施;（目的2）。评估 在DLB患者中用奈弗拉莫德治疗期间的神经精神结局和安全性/耐受性;以及 (Aim 3）。评估奈夫拉莫德对DLB的脑电图（EEG）测量的影响，特别是β 功能连接和α反应性;基底前脑胆碱能功能障碍的两个标志物。成功 这项2b期试验的完成将为我们关键的3期试验提供信息，推进奈弗拉莫德作为一种疾病- 改变DLB的治疗方法，为这些患者及其家属带来希望。

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.