CervoMed (CRVO) Status Update summary

Clinical program and trial design

• Lead program focuses on neflamapimod, an oral drug for dementia with Lewy bodies (DLB), with positive phase II-A data and a confirmatory phase II-B REWIND-LB trial fully enrolled and reading out in December 2024.

• Phase II-B trial targets early-stage DLB patients with pure cholinergic deficits, excluding those with advanced disease or elevated p-tau181, aiming for higher efficacy and clearer clinical signals.

• Primary endpoint is CDR sum of boxes, with trial simulations showing high probability of success based on phase II-A data.

• Plans for phase III trial in 2025, with MRI-based biomarkers for basal forebrain atrophy to track cholinergic degeneration.

• Compliance expected to be high due to motivated patient population and manageable TID dosing regimen.

Scientific rationale and patient selection

• DLB is a major health challenge with high morbidity, mortality, and economic burden, lacking disease-modifying therapies.

• Cholinergic system dysfunction is central to DLB symptoms, with greater deficits than in Alzheimer's disease.

• Early-stage DLB patients, identified by low p-tau181 and absence of significant hippocampal atrophy, are most likely to benefit from neflamapimod due to reversible cholinergic dysfunction.

• GFAP is a sensitive biomarker for cholinergic degeneration and correlates with clinical outcomes in early DLB.

• MRI and PET imaging, as well as emerging biomarkers like SAA, are being explored for diagnosis and tracking disease progression.

Mechanism of action and preclinical insights

• Neflamapimod targets p38 MAP kinase, inhibiting Rab5 hyperactivation, which is implicated in cholinergic neurodegeneration in DLB and Alzheimer's.

• Preclinical models show neflamapimod reverses cholinergic neuron dysfunction and tauopathy, restoring function in stressed but viable neurons.

• Rab5 and associated pathways are central to the convergence of pathologies in DLB and Alzheimer's, with co-pathology increasing neurotoxicity.

• Early intervention in the window before significant neuronal loss is critical for therapeutic efficacy.