Objective:

To obtain definitive clinical proof-of-concept for, i.e. demonstrate the efficacy of, the oral p38α kinase inhibitor neflamapimod as a treatment for dementia with Lewy bodies (DLB).

Background:

The RewinD-LB phase 2b clinical study (NCT05869669) of neflamapimod, targeting cholinergic degeneration, was initiated to confirm phase 2a results, in which neflamapimod demonstrated positive effects in mild-to-moderate DLB on multiple clinical endpoints measuring cognition and/or function, most prominently in patients without elevation in plasma levels of the neurodegeneration biomarker ptau181.

Design/Methods:

16-week, double-blind, placebo-controlled clinical trial, with 32-week open-label-extension. Patients: DLB by 2017 consensus clinical criteria, with very mild or mild dementia (global CDR=0.5 or 1.0) and plasma ptau181 at screening < 2.4 pg/mL. Treatment: neflamapimod 40mg or matching placebo capsules, three-times-per-day, randomized 1:1, stratified by background therapy (none, acetylcholinesterase inhibitor (AChEI), or memantine). Primary endpoint: change in CDR-SB vs. placebo during the placebo-controlled phase of the study.  Secondary endpoints: Timed up and go (TUG) test, a cognitive-test battery, and ADCS-CGIC. Additional endpoints include NPI-10, UPDRS Part III (Motor), EEG, and plasma biomarkers (GFAP, NfL); as well, in a sub-set of patients, basal forebrain atrophy by MRI. 43 investigational sites (32 USA, 8 UK, 3 Netherlands). Primary funding: US National Institute of Aging Grant R01AG080536.

Results:

159 participants randomized between August’23 and June’24.  Baseline characteristics of the sample were males 85%, age (mean (SD) =71.4(6.1), clinical disease severity (CDR-SB) = 4.4(2.0), MMSE=23.3(4.4), movement (TUG=14.2(15.1) seconds) psychiatric symptoms (NPI-10=11.5(13.8). prevalence of core clinical features: fluctuations=73%, visual hallucinations=57%, REM sleep disorder=78%, parkinsonism=87%; 75% were receiving AChEI therapy (of which 15% were also receiving memantine) and 3% were receiving memantine without AChEI.

Conclusions:

Analysis of all clinical, EEG, plasma biomarker and MRI endpoints as well safety, from the 16-week placebo-controlled portion of the study will be completed in the first quarter of 2025, and presented at the meeting.