Introduction
The therapeutic landscape of neurodegenerative disease has been dominated for decades by attempts to remove or neutralize pathological protein aggregates—most prominently amyloid-β and tau in Alzheimer’s disease (AD). While these strategies have recently yielded modest disease-modifying effects, they have also exposed important limitations: narrow therapeutic windows, substantial safety burdens, and variable clinical relevance across non-Alzheimer dementias. Dementia with Lewy bodies (DLB), in particular, remains without an approved disease-modifying therapy despite being the second most common degenerative dementia.
Neflamapimod (VX-745), an investigational oral small molecule developed by CervoMed Inc., represents a mechanistically distinct approach. Rather than targeting aggregated proteins directly, neflamapimod is designed to stabilize synaptic and network function by inhibiting the stress-activated kinase p38α mitogen-activated protein kinase (MAPK). This strategy is grounded in the hypothesis that early neurodegenerative symptoms arise from potentially reversible synaptic dysfunction rather than irreversible neuronal loss, particularly in diseases characterized by prominent cholinergic and attentional network vulnerability.
This article reviews the molecular rationale, clinical development, biomarker evidence, safety profile, and future directions for neflamapimod, with particular emphasis on DLB and emerging applications in primary progressive aphasia (PPA) and stroke recovery.
Molecular Pharmacology and Mechanism of Action
p38α MAPK as a Therapeutic Target
p38 MAPK is a family of serine-threonine kinases involved in cellular responses to stress, inflammation, and injury. Among its isoforms, p38α plays a central role in the central nervous system. Under physiological conditions, p38α signaling is tightly regulated. In neurodegenerative disease, however, it becomes chronically overactivated in response to pathological stressors such as amyloid-β oligomers, tau aggregates, oxidative stress, and inflammatory cytokines.
Chronic p38α activation has several deleterious consequences:
Impairment of synaptic plasticity and long-term potentiation
Disruption of axonal transport
Suppression of neurotrophic signaling (e.g., BDNF–TrkB pathways)
Amplification of maladaptive neuroinflammatory cascades
Importantly, p38α sits upstream of multiple downstream processes that converge on synaptic failure, making it an attractive target for network-level intervention.
Neflamapimod: Selective p38α Inhibition
Neflamapimod is a potent, ATP-competitive, highly selective inhibitor of p38α MAPK with favorable central nervous system penetration. Unlike earlier p38 inhibitors developed for systemic inflammatory diseases, neflamapimod was repurposed specifically because its CNS penetration—initially considered a liability—proved advantageous for neurologic indications.
The therapeutic premise of neflamapimod rests on three interrelated mechanisms:
1. Synaptic Rescue
Excessive p38α signaling disrupts intracellular pathways essential for synaptic transmission and plasticity. By inhibiting p38α, neflamapimod aims to normalize intracellular signaling cascades, restore synaptic efficacy, and improve the functional integrity of large-scale cognitive networks. Clinically, this is hypothesized to translate into improvements in attention, executive function, and language—domains particularly affected in DLB and certain PPA variants.
2. Endolysosomal / Rab5 Pathway Normalization
A distinctive aspect of neflamapimod’s rationale involves its effects on Rab5-mediated early endosomal trafficking. Hyperactivation of p38α leads to overstimulation of Rab5, resulting in endosomal enlargement, impaired axonal transport, and synaptic collapse. This mechanism is strongly implicated in the degeneration of basal forebrain cholinergic neurons, which are critical for attention and cognition and are disproportionately affected in DLB.
By dampening p38α activity, neflamapimod reduces pathological Rab5 signaling, restoring endosomal trafficking and supporting synaptic maintenance.
3. Selective Anti-inflammatory Modulation
p38α acts as a master regulator of inflammatory signaling in microglia and astrocytes. Neflamapimod reduces the production of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6, while avoiding broad systemic immunosuppression. This selective modulation is particularly relevant in DLB, where neuropsychiatric destabilization and sensitivity to centrally acting medications are common clinical challenges.
Clinical Development Program
Early Development and Alzheimer’s Disease Experience
Neflamapimod was initially evaluated in Alzheimer’s disease based on the hypothesis that synaptic dysfunction could be reversed in early AD. Early Phase 2a studies demonstrated short-term improvements in episodic memory and biomarker evidence of target engagement, including reductions in cerebrospinal fluid tau and phosphorylated tau.
However, a subsequent Phase 2b trial (REVERSE-SD) failed to meet its primary cognitive endpoint despite continued biomarker effects. This divergence led to a critical insight: in diseases dominated by extensive neuronal loss and hippocampal atrophy, synaptic rescue alone may be insufficient to produce robust clinical benefit. This realization prompted a strategic pivot toward conditions characterized by prominent synaptic and cholinergic dysfunction with relatively preserved neuronal architecture.
Dementia with Lewy Bodies (DLB)
DLB emerged as the lead indication for neflamapimod based on its pathophysiology. Unlike AD, DLB is marked early by attentional fluctuations, executive dysfunction, and cholinergic network failure, often preceding severe cortical atrophy. These features align closely with neflamapimod’s mechanistic strengths.
Phase 2a: AscenD-LB
The AscenD-LB trial was a 16-week, randomized, placebo-controlled Phase 2a study involving approximately 90 patients with DLB. The study employed a cognitive battery emphasizing attention and executive function, along with functional mobility assessments.
Key findings included:
Significant improvement in attention and executive performance
Improvements in functional mobility (Timed Up and Go test)
Dose-response signal, with greatest benefit at 40 mg three times daily
This trial provided proof-of-concept that p38α inhibition could yield clinically meaningful effects in DLB.
Phase 2b: RewinD-LB
The RewinD-LB study was designed as a larger, more definitive evaluation of neflamapimod in DLB, using the Clinical Dementia Rating–Sum of Boxes (CDR-SB) as the primary endpoint.
Initial Double-Blind Phase
The first 16-week double-blind phase did not meet its primary endpoint. Subsequent investigation revealed a critical confound: the capsule formulation used (Batch A) failed to achieve target plasma drug concentrations due to stability and bioavailability issues related to capsule age.
Open-Label Extension and Reformulated Capsules
During the 32-week extension phase, patients received a reformulated, more bioavailable capsule (Batch B). With adequate systemic exposure achieved, the clinical signal changed substantially:
In patients without Alzheimer’s co-pathology (“pure” DLB), neflamapimod reduced clinical worsening by approximately 80–90% compared with placebo trajectories.
Mean improvement of ~1.1 points on CDR-SB was observed.
Risk of clinically meaningful progression (≥1.5-point increase in CDR-SB) was reduced by ~75%.
These findings reframed RewinD-LB not as a negative study, but as a pharmacokinetically compromised trial that nonetheless yielded compelling efficacy signals when adequate exposure was achieved.
Biomarker-Driven Patient Enrichment
A critical advance arising from the RewinD-LB program was the recognition that treatment response was strongly modulated by Alzheimer’s co-pathology. Plasma p-tau181 emerged as a practical biomarker to distinguish “pure” DLB from mixed AD/DLB cases.
Patients with low plasma p-tau181 levels demonstrated:
Greater clinical benefit
Stronger biomarker responses
More consistent slowing of progression
This finding supports a biologically coherent principle: neflamapimod is most effective when neurons are functionally impaired but not yet irreversibly lost.
Planned Phase 3 Development
Based on these data, CervoMed has aligned with regulatory authorities on a pivotal Phase 3 program in DLB. The planned trial is expected to:
Enroll approximately 300 patients globally
Use strict biomarker enrichment to exclude AD co-pathology
Employ CDR-SB as the primary endpoint
Initiate in the second half of 2026
If successful, this program would represent the first disease-modifying therapy specifically developed for DLB.
Expansion into Other Indications
Frontotemporal Dementia and Primary Progressive Aphasia
Neflamapimod has received FDA Orphan Drug Designation for frontotemporal dementia. An ongoing Phase 2a trial is evaluating its effects in the nonfluent/agrammatic variant of primary progressive aphasia. The rationale mirrors that of DLB: language networks may fail due to synaptic and endolysosomal dysfunction before extensive neuronal loss occurs, creating a window for network stabilization.
Ischemic Stroke Recovery
Separate Phase 2a studies are investigating neflamapimod in post-ischemic stroke recovery. Preclinical and early clinical data suggest that p38α inhibition may enhance synaptic plasticity and functional recovery during the subacute phase after stroke, extending the drug’s potential utility beyond classical neurodegeneration.
Biomarker Evidence
Across studies, neflamapimod treatment has been associated with favorable biomarker changes consistent with its proposed mechanism:
Plasma GFAP: Significant reductions correlated with improvements in CDR-SB, suggesting reduced astrocytic reactivity and neurodegenerative stress.
Amyloid Aβ42/40 ratio: Increases consistent with reduced neuroinflammatory burden or altered amyloid processing.
Neurofilament light chain (NfL): Exploratory trends toward reduced axonal injury.
These biomarker effects provide objective support for disease-process engagement rather than purely symptomatic benefit.
Safety and Tolerability
Across more than 800 participants exposed to neflamapimod:
Common adverse events: Mild to moderate headache, gastrointestinal symptoms, fatigue, and somnolence.
Hepatic effects: Reversible transaminase elevations in approximately 1–2.5% of participants, without bilirubin elevation or serious liver injury.
Neurologic safety: No consistent worsening of parkinsonism, hallucinations, or cognition—an important distinction from many centrally acting agents in DLB.
No ARIA, differentiating neflamapimod from anti-amyloid monoclonal antibodies.
Overall, the safety profile appears well suited for older patients with cognitive and neuropsychiatric vulnerability.
Conceptual Implications and Conclusion
Neflamapimod exemplifies a shift in neurodegenerative therapeutics from protein clearance to network and synaptic stabilization. Its development underscores a broader conceptual lesson: not all neurodegenerative diseases are best treated by targeting aggregated proteins, particularly when synaptic dysfunction precedes irreversible neuronal loss.
If ongoing and future trials confirm its efficacy, neflamapimod could redefine therapeutic strategy in DLB and related disorders—offering a disease-modifying approach that repairs the functional infrastructure of the brain rather than removing its pathological debris
