Phase 2b trial of neflamapimod in dementia with Lewy bodies fails to replicate earlier promise

A 16-week randomized, placebo-controlled phase 2b trial of the oral p38α inhibitor neflamapimod in dementia with Lewy bodies (DLB) found no benefit on its primary outcome, according to results published in Alzheimer’s Research & Therapy. The trial, registered at clinicaltrials.gov as NCT05869669, randomized 159 participants with probable DLB between August 2023 and June 2024 at 43 centers in the United States, the United Kingdom and the Netherlands.

The primary outcome measure was change in the Clinical Dementia Rating Sum-of-Boxes (CDR-SB) over 16 weeks. There was no difference between neflamapimod and placebo on this endpoint, with a mean difference of -0.02 (95% confidence interval: -0.41 to 0.37). No differences were seen on the secondary clinical outcome measures either, which included the Timed Up and Go test, the ADCS Clinical Global Impression of Change, and a study-specific cognitive test battery.

The drug had shown clinical activity against cognitive and motor endpoints at a dose of 40 mg three times daily in a prior phase 2a study in DLB, with the most prominent effects observed in participants without Alzheimer disease (AD) co-pathology, assessed by plasma p-tau181. The new trial was designed to build on those findings, screening participants to enrich for those without AD co-pathology: anyone with plasma p-tau181 at or above 27.2 pg/mL was excluded.

Participants received neflamapimod 40 mg (79 participants) or matching placebo (80 participants) capsules three times daily. Mean age was 71.4 years with a standard deviation of 6.1, and 85.6% of participants were male. The trial also included a 32-week open-label extension. Discontinuation due to adverse events was low in both arms: 2.5% (2 of 79) with neflamapimod and 1.3% (1 of 80) with placebo.

Biomarker measures included plasma levels of glial fibrillary acidic protein and neurofilament light chain, and basal forebrain atrophy measured by structural MRI in a sub-study of 18 participants. There were no differences between the treatment groups on the two plasma biomarkers. However, in the MRI sub-study, improvement relative to placebo was seen with neflamapimod on change in right basal forebrain volume from baseline to week 16.

Exploratory analyses suggested some signals that may inform future studies. The treatment group difference in change in CDR-SB favored neflamapimod compared to placebo among participants with low screening plasma p-tau181 levels, consistent with the idea that the drug may work best in people without Alzheimer co-pathology. Pharmacokinetic data showed that mean trough neflamapimod plasma drug concentrations (Ctrough) were lower than expected, and a treatment effect favoring neflamapimod was seen in participants whose Ctrough was above the study median.

The authors conclude that the phase 2a clinical study findings were not replicated, and they identify two potential explanations: the inclusion of a higher proportion of patients with AD co-pathology than targeted, and the use of a neflamapimod drug product that did not achieve expected plasma drug concentrations. Both factors could have diluted any true treatment effect, although the trial’s primary result remains negative as conducted.

The trial’s findings underscore the challenges of drug development in DLB, including the difficulty of excluding Alzheimer co-pathology in enrolled patients and the sensitivity of results to achieved drug exposure. The exploratory signals on basal forebrain volume and in participants with low p-tau181 or higher drug trough concentrations may help shape the design of any future studies of p38α inhibition in this population, but on the evidence of this phase 2b trial, neflamapimod did not improve the primary clinical outcome in DLB.

Subject of Research: A phase 2b randomized clinical trial testing the oral p38α inhibitor neflamapimod in dementia with Lewy bodies

Article Title: A phase 2b randomized clinical trial of the oral p38α inhibitor neflamapimod in dementia with Lewy bodies (DLB)

Article References: Taylor, J.-P., Alam, J. J., Gomperts, S. N., Honig, L. S., Prins, N. D., Koubiyr, I., Chu, H.-M., Gardner, A., Blackburn, K., Schoonheim, M. M., Teunissen, C. E., & Galvin, J. E. (2026). A phase 2b randomized clinical trial of the oral p38α inhibitor neflamapimod in dementia with Lewy bodies (DLB). Alzheimer's Research & Therapy. https://doi.org/10.1186/s13195-026-02239-6

Image Credits: AI Generated

DOI: 10.1186/s13195-026-02239-6

Keywords: dementia with Lewy bodies, neflamapimod, p38α inhibitor, phase 2b trial, CDR-SB, plasma p-tau181, basal forebrain atrophy, randomized placebo-controlled trial, pharmacokinetics, neurodegeneration, phase, randomized