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Effects of neflamapimod (p38α kinase inhibitor) on clinical progression in patients with dementia with Lewy bodies (DLB) without Alzheimer’s disease (AD) Co-Pathology

Lookup NU author(s): Professor John-Paul TaylorORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2025 The Alzheimer's Association. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. BACKGROUND: RewinD-LB phase 2b study (NCT05869669) was initiated to confirm phase 2a results in DLB in which neflamapimod demonstrated positive effects on multiple clinical endpoints, most prominently in patients without evidence of AD co-pathology (assessed by plasma ptau181). METHOD: 159 participants with DLB by consensus criteria, screening plasma ptau181<2.4 pg//mL (i.e., without AD co-pathology) were enrolled in a 16-week randomized (1:1), placebo-controlled study ("Initial Phase"), with a 32-week neflamapimod-only Extension. Unfortunately, pharmacokinetic measurements in the Initial Phase showed that expected plasma drug concentrations were not achieved. With introduction during the Extension of a new batch of capsules that achieved the targeted plasma drug concentrations, the effects of neflamapimod treatment with New Capsules (N =94; active drug arm) during the 1st 16 weeks of the Extension could be compared against outcomes in participants who continued to receive Old Capsules (N =55), which served as a lower drug level control arm. Endpoints were analyzed by linear mixed effects model for repeated measures (MMRM), except for CGIC (analyzed by Mann-Whitney). RESULT: During the initial phase, there were no discernible differences on any of the endpoints between neflamapimod and placebo. However, during the Extension phase, with New Capsules there was improvement on change in CDR-SB (p <0.001 vs. Old Capsules during Extension; p =0.003 vs. placebo utilizing all study data), improvement on ADCS-CGIC (p =0.035 vs. Old Capsules during Extension; p =0.036 in a within-participant comparison to placebo during the Initial Phase), and improvement vs. Old capsules during Extension on DCFS (fluctuations) and ISLT-Recognition (working memory). There were also positive trends vs. Old Capsules on NPI-12, TUG and UPDRS Part III (Motor); and a lower incidence of falls vs either Old Capsules or placebo. Discontinuation for adverse events was ≤ 4% in each phase. CONCLUSION: With achieving target plasma drug concentrations, there was evidence of neflamapimod having a meaningful impact on clinical progression, as assessed by the CDR-SB and CGIC, in patients with DLB who do not have AD co-pathology. The pattern of the effects across the full set of clinical endpoints evaluated are consistent with preclinical results in which neflamapimod beneficially impacts the disease process in the basal forebrain.

Publication metadata

Author(s): Honig LS, Gomperts SN, Taylor J-P, Prins ND, Gardner A, Blackburn K, Alam JJ, Galvin JE

Publication type: Article

Publication status: Published

Journal: Alzheimer's & Dementia

Year: 2025

Volume: 21

Issue: S7

Online publication date: 23/12/2025

Acceptance date: 02/04/2018

Date deposited: 08/01/2026

ISSN (print): 1552-5260

ISSN (electronic): 1552-5279

Publisher: John Wiley and Sons Inc.

URL: https://doi.org/10.1002/alz70861_108769

DOI: 10.1002/alz70861_108769

PubMed id: 41434515

Notes: Supplement: Developing Topics

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