Investigational Oral Therapy Shows Promise as Treatment for People with Dementia with Lewy Bodies

Results from the open-label extension (OLE) portion of the phase 2b RewinD-LB clinical trial (NCT05869669) demonstrate that oral neflamapimod (CervoMed, Boston, MA) treatment significantly reduced the risk of clinical worsening in people with dementia with Lewy bodies (DLB), particularly in those without Alzheimer disease (AD) copathology. In data presented at the 2025 meeting of the Alzheimer’s Association International Conference (AAIC), people with DLB treated with neflamapimod capsules showed an over 50% reduction in the risk of clinically significant worsening on the Clinical Dementia Rating Sum of Boxes (CDR-SB) scale compared with controls. The reduction in risk was even higher for participants with p-tau181 levels above 2.2 pg/mL, which is a proposed threshold for the exclusion of AD copathology.

RewinD-LB was a randomized, 16-week, double-blind, placebo-controlled trial in which 159 people with DLB received treatment with neflamapimod 40 mg twice daily or placebo. The clinical trial was followed by a 32-week OLE. In the double-blind portion of the study and part of the OLE, an older batch of neflamapimod was used, which did not achieve the expected and targeted range of plasma exposure. A newer batch of neflamapimod was used during the remaining portion of the OLE, which did achieve expected plasma exposure. The primary end point of the study was change in CDR-SB; secondary outcomes included change in Alzheimer’s Disease Cooperative Study—Clinical Global Impression of Change (ADCS-CGIC) score and plasma biomarkers such as glial fibrillary acidic protein (GFAP).

At week 32, in terms of the primary end point, there was a reduction of ≥1.5 points in worsening on the CDR-SB scale for:

• 54% of participants with p-tau181 <2.4 pg/mL (hazard ratio [HR], .46; 95% CI, .31 to .70; P=0.0037)
• 64% of participants with p-tau181 <2.2 pg/mL (HR, .36; 95% CI, .23 to .56; P=.0001)
• 65% of participants with p-tau181 <1.8 pg/mL (HR, .35; 95% CI, .20 to .61; P=.0002)

At week 32 of the OLE, there was a mean reduction from baseline of 18.4 ± 4.0 pg/mL in plasma GFAP levels for all participants (P<0.0001), and a reduction of 21.2 ± 4.4 pg/mL for those with p-tau181 <2.2 pg/mL. During the initial double-blind period of the study, placebo-treated participants showed an increase in plasma GFAP of 1.1 ± 3.0 pg/mL.

Commenting on the results, Lawrence S. Honig, MD, PhD, Professor of Neurology at the Columbia University Irving Medical Center, stated: “This level of effect, if confirmed in a Phase 3 pivotal trial, would be an important advance in the unmet treatment needs of patients with DLB, the second most common dementia, which is a challenging disease, due to its involvement of both movement and cognition, and due to the lack of effective current treatments.” Dr. Honig presented these data at AAIC 2025.