From the CervoMed (formerly EIP Pharma) (J.J.A., S.R.D., J.C.), Inc., Boston, MA; CogState Ltd London (P.M.), United Kingdom; Anoixis Corporation (H.-M.C.), Natick; Massachusetts Alzheimer's Disease Research Center (S.N.G.), Department of Neurology, Massachusetts General Hospital, Charlestown; and Neurochemistry Lab (C.T.), Department of Laboratory Medicine, Amsterdam Neuroscience, Neurodegeneration, Amsterdam UMC, Vrije Universiteit Amsterdam, the Netherlands.
Neurology. 2023 Oct 24;101(17):e1708-e1717. doi: 10.1212/WNL.0000000000207755. Epub 2023 Sep 1.
In a proportion of patients, dementia with Lewy bodies (DLB) is associated with Alzheimer disease (AD) copathology, which is linked to accelerated cognitive decline and more extensive cortical atrophy. The objective was to evaluate the relationship between a biomarker of AD copathology, plasma tau phosphorylated at residue 181 (ptau181), and the treatment effects of the p38α kinase inhibitor neflamapimod, which targets the cholinergic degenerative process in DLB.
The AscenD-LB study was a phase 2a, randomized (1:1), 16-week, placebo-controlled clinical trial of neflamapimod in DLB, the main results of which have been published. After the study was completed (i.e., post hoc), pretreatment plasma ptau181 levels were determined and participants were grouped based on a cutoff for AD pathology of 2.2 pg/mL (established in a separate cohort to identify AD from healthy controls). Clinical outcomes for the comparison of placebo with neflamapimod 40 mg three times daily (TID; the higher and more clinically active of 2 doses studied) were analyzed using mixed models for repeated measures within each subgroup (baseline plasma ptau181 < and ≥2.2 pg/mL).
Pretreatment plasma ptau181 levels were determined in eighty-five participants with mild-to-moderate DLB receiving cholinesterase inhibitors, with 45 participants below and 40 above the 2.2 pg/mL cutoff at baseline. In the 16-week treatment period, in the comparison of placebo with neflamapimod 40 mg TID, for all end points evaluated, improvements with neflamapimod treatment were greater in participants below the cutoff, compared with those above the cutoff. In addition, participants below the ptau181 cutoff at baseline showed significant improvement over placebo in an attention composite measure (+0.42, 95% CI 0.07-0.78, = 0.023, = 0.78), the Clinical Dementia Rating Scale Sum of Boxes (-0.60, 95% CI -1.04 to -0.06, = 0.031, = 0.70), the Timed Up and Go test (-3.1 seconds, 95% CI -4.7 to -1.6, < 0.001, = 0.74), and International Shopping List Test-Recognition (+1.4, 95% CI 0.2-2.5, = 0.024, = 1.00).
Exclusion of patients with elevated plasma ptau181, potentially through excluding patients with extensive cortical neurodegeneration, enriches for a patient with DLB population that is more responsive to neflamapimod. More generally, plasma biomarkers of AD copathology at study entry should be considered as stratification variables in DLB clinical trials.
NCT04001517 at ClinicalTrials.gov.
在一部分患者中，路易体痴呆（DLB）与阿尔茨海默病（AD）共病相关，这与认知能力下降加速和更广泛的皮质萎缩有关。目的是评估 AD 共病生物标志物——血浆中磷酸化 tau 181 位（ptau181）——与 p38α 激酶抑制剂 neflamapimod 治疗效果之间的关系，后者靶向 DLB 中的胆碱能退行性过程。
AscenD-LB 研究是一项针对 DLB 的 2a 期、随机（1:1）、16 周、安慰剂对照的 neflamapimod 临床研究，其主要结果已发表。研究完成后（即事后），测定了预处理血浆 ptau181 水平，并根据 AD 病理学的 2.2 pg/mL 截断值（在另一队列中确定，用于将 AD 与健康对照区分开）将参与者分组。使用混合模型对每个亚组（基线血浆 ptau181 < 2.2 pg/mL 和基线血浆 ptau181 ≥ 2.2 pg/mL）内的安慰剂与 neflamapimod 40 mg 每日 3 次（TID；研究中使用的两种剂量中的较高和更有效剂量）的临床结局进行分析。
对接受胆碱酯酶抑制剂治疗的 85 名轻度至中度 DLB 患者进行了预处理血浆 ptau181 水平测定，其中 45 名患者在基线时低于，40 名患者高于 2.2 pg/mL 截断值。在 16 周的治疗期间，在安慰剂与 neflamapimod 40 mg TID 的比较中，对于评估的所有终点，与高于截断值的参与者相比，低于截断值的参与者接受 neflamapimod 治疗的改善更大。此外，基线时低于 ptau181 截断值的参与者在注意力复合测量方面（+0.42，95%CI 0.07-0.78， = 0.023， = 0.78）、临床痴呆评定量表总分（-0.60，95%CI -1.04 至 -0.06， = 0.031， = 0.70）、计时起立行走测试（-3.1 秒，95%CI -4.7 至 -1.6， < 0.001， = 0.74）和国际购物清单测试-识别（+1.4，95%CI 0.2-2.5， = 0.024， = 1.00）方面，与安慰剂相比有显著改善。
排除血浆 ptau181 水平升高的患者（可能通过排除皮质神经退行性病变广泛的患者），使 DLB 患者更易对 neflamapimod 产生反应。更普遍地说，在研究入组时，AD 共病的血浆生物标志物应被视为 DLB 临床试验的分层变量。
NCT04001517 在 ClinicalTrials.gov 注册。
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