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

<title>Abstract</title> <p> <bold>Background:</bold> There is high unmet need in dementia with Lewy bodies (DLB). Neflamapimod, showed clinical activity against cognitive and motor endpoints at a dose of 40mg three-times-daily (TID) in a prior phase 2a study in DLB, most prominently in those without Alzheimer disease (AD) co-pathology, assessed by plasma ptau181. <bold>Methods:</bold> 16-week randomized, placebo-controlled clinical trial, with a 32-week open label extension, conducted at 43 centers in the US, UK and Netherlands. 159 participants with probable DLB by consensus criteria, screened to enrich for patients without AD co-pathology (plasma ptau181≥27.2 pg/mL excluded), randomized between August 2023 and June 2024 to neflamapimod 40mg (80 participants) or matching placebo (79 participants) capsules, TID. Mean age 71.4 (6.1), 85.6% male. Primary outcome measure: change in Clinical Dementia Rating Sum-of-Boxes (CDR-SB). Secondary outcome measures: Timed up and Go test, ADCS Clinical Global Impression of Change, and a study-specific cognitive test battery. Biomarker measures: plasma levels of glial fibrillary acidic protein and neurofilament light chain, and basal forebrain atrophy by structural MRI (sub-study in 18 participants). <bold>Results:</bold> There was no significant difference between neflamapimod and placebo on the primary outcome measure, change in CDR-SB. There were also no differences seen on secondary clinical outcome measures and the two plasma biomarkers, though in the sub-study, improvement relative to placebo was seen with neflamapimod on change in right basal forebrain volume from baseline to week 16. In exploratory analyses, the treatment group difference in change in CDR-SB favored neflamapimod compared to placebo among participants with low (&lt;21 pg/mL) screening plasma p-tau181. Pharmacokinetic data showed that mean trough neflamapimod plasma drug-concentrations (C _trough ) were lower than expected, and treatment effect favoring neflamapimod was seen in participants with C _trough above the study median. Discontinuation due to adverse events was 2.5% (2 of 79) with neflamapimod and 1.3% (1 of 80) with placebo <bold>Discussion:</bold> The phase 2a clinical study findings were not replicated, potentially due to the inclusion of a higher proportion of patients with AD co-pathology than targeted and the use of neflamapimod drug product that did not achieve expected plasma drug concentrations. Registered at clinicaltrials.gov on 17 May 2023 (NCT0586966) </p>