New data from a phase IIb trial extension study suggested that investigational neflamapimod led to significant improvements on key outcomes in people with dementia with Lewy bodies (DLB).
In the RewinD-LB extension study, neflamapimod reduced plasma glial fibrillary acidic protein (GFAP) levels, which correlated with improved Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores in DLB patients, reported John-Paul Taylor, MBBS, of Newcastle University in England, at the Clinical Trials on Alzheimer's Disease annual meeting.
In topline data released in 2024, neflamapimod did not demonstrate significant effects versus placebo in RewinD-LB. An initial analysis suggested that target plasma drug concentrations were not reached during the double-blind phase of the trial.
The extension phase of RewinD-LB tested a second batch of neflamapimod capsules (Batch B) after it was determined that participants in the double-blind phase did not achieve expected drug concentration levels with Batch A, likely because the capsules were too old, Taylor noted. In the extension phase, Batch A served as a control arm.
In the initial 16-week double-blind period, there was no significant difference in plasma GFAP between neflamapimod (Batch A) and placebo.
At week 16 of the extension phase, participants who received Batch B capsules had a significant drop in plasma GFAP (median change -16.0 pg/mL, P<0.0001). This reduction correlated with improvement in CDR-SB scores (r=o.35, P=0.036), Taylor said.
DLB, an alpha-synucleinopathy characterized by widespread cortical and subcortical Lewy bodies, has no approved disease-modifying treatment. It progresses more rapidly than Alzheimer's disease, and Alzheimer's co-pathology is common in up to 50% of DLB patients.
"In early stages, a major driver of disease expression and progression is dysfunction and degeneration of basal forebrain cholinergic neurons," Taylor said.
Neflamapimod is an oral p38 alpha kinase inhibitor that targets dysfunction and degeneration of acetylcholine-producing neurons. The drug is in clinical development to treat DLB, recovery after ischemic stroke, and frontotemporal dementia.
Data from early research supported advancing neflamapimod to a phase IIb study in DLB, Taylor pointed out. In the phase IIa AscenD-LB study, the drug improved CDR-SB scores and reduced GFAP levels compared with placebo.
The phase IIb RewinD-LB trial evaluated DLB patients with a baseline Clinical Dementia Rating global score of 0.5 (very mild dementia) or 1.0 (mild dementia). Participants had a plasma phosphorylated tau 181 (p-tau181) level under 27.2 pg/mL to minimize the risk of Alzheimer's co-pathology.
When RewinD-LB started, 27.2 pg/ml was estimated to be the optimal p-tau181 cutoff for Alzheimer's co-pathology in DLB patients, Taylor noted. Research now supports a more stringent cutoff of 21.0 pg/mL.
RewinD-LB had two parts: a 16-week placebo-controlled phase and a 32-week open-label phase. The first phase randomized 159 DLB patients to 40 mg of oral neflamapimod three times a day or placebo. In the second phase, all participants received 40 mg of oral neflamapimod three times a day.
CDR-SB score changes were 52% lower in patients who received Batch B compared with those who received Batch A, and 82% lower in patients with plasma p-tau181 under 21.0 pg/mL at baseline, Taylor noted.
This indicates a "significant effect on clinical progression when target plasma concentrations were achieved, most prominently in patients with low likelihood of having Alzheimer's disease co-pathology," he said. The clinical effect was durable to 32 weeks of treatment, he added.
Few participants dropped out of the study due to adverse events. During the placebo-controlled phase, 2.5% of neflamapimod recipients discontinued the study due liver enzyme elevations; in the extension phase, 1.3% did. All liver enzyme elevations were reversible, and none were associated with bilirubin elevation. The only adverse event with more than 10% incidence was falls.
Drug developer CervoMed plans to start a phase III trial of 300 DLB patients in the second half of 2026, Taylor said. The study will focus on DLB patients with plasma p-tau 181 levels under 21.0 pg/ml, he added.
Disclosures
The study was funded primarily by the National Institutes on Aging.
Taylor disclosed a relationship with CervoMed. Some co-authors are CervoMed employees.
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