The authors cited 2 unanticipated problems, though. A pTau181 assay change meant the exclusion cutoff left an estimated 60% to 65% of participants free of substantive co-pathology, short of the 80% or more expected. Mean trough plasma concentration was 4.15 ng/mL, below the expected 5.0 ng/mL and near the 3.7 ng/mL seen with a 40 mg twice-daily dose that failed in phase 2a. In the subset with pTau181 below 21 pg/mL, CDR-SB worsening lessened progressively across placebo, below-median trough, and above-median trough (3.64 ng/mL) groups (P = .038). In the extension, a second capsule batch yielded a mean trough of 5.2 ng/mL and less worsening than the original batch (mean difference, −0.57; 95% CI, −0.98 to −0.16).
Discontinuations due to adverse events were 2.5% (2 of 79) with neflamapimod and 1.3% (1 of 80) with placebo. The single related event was an abnormal liver function test, with aminotransferases up to 5 times the upper limit of normal, that normalized after discontinuation. Two deaths were reported in the placebo group, marked unrelated to the medication.
Biomarker and Mechanistic Findings
Further research tested whether neflamapimod blocks IL-1β signaling, which depends on p38α.² In human peripheral blood mononuclear cells, it inhibited IL-1β–induced IL-6 and IL-8 production, with half-maximal effective concentrations of 6.3 nM and 7.1 nM, respectively.
In a 6-week study of patients with early Alzheimer disease, 40 mg twice daily lowered cerebrospinal fluid IL-6 and IL-8 in a concentration-dependent manner, plateauing at trough plasma concentrations near 4 ng/mL; only 7 patients had complete paired samples. In RewinD-LB, plasma Aβ42/40 ratio rose and plasma glial fibrillary acidic protein fell, but only during the open-label extension among participants originally assigned to placebo. Neither changed in the randomized phase.
The authors acknowledge that the analyses were exploratory and post hoc, involved small samples, and drew cytokine data from patients with Alzheimer disease rather than DLB. They describe the link to clinical effects as indirect.
Next Steps
The RewinD-LB authors call the subgroup findings “hypothesis generating” and conclude that further evaluation in a more stringently defined DLB population, using a formulation that reaches target concentrations, is warranted. CervoMed plans a phase 3 trial of a 100 mg twice-daily regimen using a 50 mg tablet.
References
1. CervoMed Announces Publication of Two Peer-Reviewed Research Articles Supporting Neflamapimod as a Potential Treatment for Dementia with Lewy Bodies (DLB). Press release. October 29, 2026. Accessed October 29, 2026. https://www.biospace.com/press-releases/cervomed-announces-publication-of-two-peer-reviewed-research-articles-supporting-neflamapimod-as-a-potential-treatment-for-dementia-with-lewy-bodies-dlb
2. Taylor J-P, Alam JJ, Gomperts SN, et al. A phase 2b randomized clinical trial of the oral p38α inhibitor neflamapimod in dementia with Lewy bodies (DLB). Alzheimers Res Ther. Online ahead of print October 20, 2026.
3. Alam JJ, Germann UA, Maruff P. Targeting pro-inflammatory interleukin-1 beta signaling to modulate neuroinflammatory processes associated with cognitive decline in dementia with Lewy bodies. Cells. 2026;15(19):1803.