Neflamapimod Delivers Clinical and Biomarker Benefits in Dementia with Lewy Bodies: Key Findings from the Phase 2b RewinD-LB Trial

Dementia with Lewy bodies (DLB) is a common type of neurodegenerative dementia. It is marked by fluctuating cognition, visual hallucinations, Parkinsonian movement symptoms, and early problems with attention. Current therapies provide only partial relief, showing the need for treatments that can modify disease progression. DLB develops due to the accumulation of abnormal alpha-synuclein protein in the brain, which causes progressive cognitive decline and neuropsychiatric symptoms that differ from those seen in Alzheimer’s disease. Recent studies identify neuroinflammation and synaptic damage as major targets for new therapeutic strategies.

Neflamapimod is a novel oral small molecule which plays a key role in the disease mechanisms of DLB. It has shown clinical benefit in both exploratory (AscenD-LB) and confirmatory (RewinD-LB) trials, particularly in patients with DLB who do not have co-existing Alzheimer’s disease pathology. CervoMed Inc., the main sponsor and marketing authorization holder, has led its development and clinical evaluation. The company has advanced Neflamapimod through well-designed, multi-center trials in collaboration with research and regulatory partners.

About the Investigational Drug: Neflamapimod

Neflamapimod is a once-daily oral inhibitor of p38 alpha mitogen-activated protein kinase (p38 MAPK), an intracellular signaling pathway involved in stress-related synaptic dysfunction, neuroinflammation, and neuronal injury in several neurodegenerative diseases. By blocking p38 MAPK, neflamapimod may help restore synaptic function, reduce inflammation in the brain, and potentially slow or stop disease progression. Its pharmacokinetic profile, safety data, and optimal dosing for phase 2 and 3 trials have been refined through earlier studies and ongoing formulation improvements.

Understanding Dementia with Lewy Bodies

Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disease that accounts for up to 20% of dementia cases worldwide. Its symptoms go beyond cognitive decline and include motor difficulties, fluctuating attention, REM sleep behavior disorder, and repeated visual hallucinations. DLB shares some pathological and clinical features with both Parkinson’s and Alzheimer’s diseases but requires a distinct approach to diagnosis and management. The absence of approved disease-modifying treatments makes DLB a major unmet need in neurology and geriatric care.

Clinical Trial Information: The RewinD-LB Phase 2b Study

Study Design

RewinD-LB (NCT05869669) was a multicenter, randomized, double-blind, placebo-controlled phase 2b clinical trial. The study included a 16-week double-blind treatment phase, followed by a 32-week open-label extension in which all participants received neflamapimod. A distinctive feature of this trial was the use of plasma p-tau181 thresholding at enrollment to select patients with DLB who did not have significant Alzheimer’s disease co-pathology, a factor that has often confounded results in earlier DLB studies.

Participant Criteria

Adults who met the diagnostic criteria for probable DLB were enrolled from multiple study centers. Plasma p-tau181 screening was used to identify participants with a low likelihood of Alzheimer’s disease co-pathology, allowing a more accurate evaluation of neflamapimod disease-specific efficacy.

Intervention and Dosing

During the double-blind phase, participants received either oral neflamapimod or a matching placebo. A protocol amendment introduced a new capsule formulation with higher drug exposure following a manufacturing batch change. This allowed researchers to evaluate dose and exposure–response relationships more effectively.

Study Endpoints and Results

Primary and Secondary Endpoints

The primary endpoint of the study was the change from baseline in the Clinical Dementia Rating Sum of Boxes (CDR-SB) at prespecified time points. Key secondary endpoints included assessments of functional mobility using the Timed Up and Go (TUG) test, neuropsychological evaluations of attention and executive function, and the Clinician’s Global Impression of Change (CGIC). Biomarker endpoints measured plasma levels of glial fibrillary acidic protein (GFAP), phosphorylated tau (p-tau181), and neurofilament light chain (NfL) to monitor neurodegeneration and evaluate the response to treatment.

 Results

Disposition and Demographics: Enrollment, baseline demographics, and clinical characteristics were well balanced between the treatment and placebo groups, according to sponsor data.

Efficacy: Neflamapimod showed a statistically significant improvement over placebo on the primary endpoint (CDR-SB) in the overall study population. Greater benefits were seen in participants who received the higher-exposure capsule formulation during the extension phase.

Secondary Outcomes: Participants demonstrated improvements in functional mobility (TUG) and in cognitive measures of attention and executive function, especially among those with low plasma p-tau181, indicating minimal Alzheimer’s co-pathology.

Biomarkers: Treatment with neflamapimod led to reductions in plasma GFAP and other markers of neurodegeneration, supporting its potential as a disease-modifying therapy rather than one offering only symptomatic relief.

Safety Profile

The RewinD-LB trial confirmed that neflamapimod is generally safe and well tolerated, consistent with earlier studies. No new safety concerns emerged, and reported adverse events were consistent with expectations and manageable in the context of DLB research. These findings support moving neflamapimod into larger and longer-term clinical trials.

Expert Opinions and Future Significance

John Alam, M.D., Chief Executive Officer of CervoMed and Co-Principal Investigator of the RewinD-LB trial, expressed strong confidence in neflamapimod’s potential as a treatment for dementia with Lewy bodies, highlighting that the significant clinical improvements observed in CDR-SB scores compared to placebo together with correlated reductions in a key neurodegeneration biomarker reinforce optimism for the drug’s disease-modifying effects. He emphasized that insights and learning from the Phase 2b results have been essential in refining and optimizing the planned Phase 3 trial design, as the team now looks forward to forthcoming feedback from the FDA later this quarter.

Study Significance and Future Implications

The RewinD-LB trial results support advancing neflamapimod into pivotal, registration-focused studies that prioritize precise patient selection and optimized pharmacokinetics. Enriching for DLB-specific pathology and using clinically relevant and biomarker-based endpoints provides a framework for future neurodegenerative drug development. Longer-term independent validation and early regulatory engagement will be important next steps in developing the first potential disease-modifying therapy for DLB.