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.

• The phase II-B trial targets early-stage DLB patients with pure cholinergic deficits, excluding those with elevated p-tau181, to maximize likelihood of clinical benefit and trial success.

• Primary endpoint is CDR sum of boxes, with 80 patients per arm, and trial simulations show high probability of success based on phase II-A data.

• Plans are in place to initiate phase III in mid-2025, pending positive results and FDA alignment, with MRI-based biomarkers to track basal forebrain atrophy.

• Compliance is expected to be high due to motivated patient population and manageable TID dosing regimen, with potential for BID dosing in phase III.

Scientific rationale and patient selection

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

• The cholinergic system, especially the basal forebrain, is central to DLB pathology and symptoms, with greater deficits than in Alzheimer's disease.

• Early-stage DLB patients with limited hippocampal neurodegeneration (low p-tau181) are most likely to benefit from cholinergic-targeted therapy, as their deficits are potentially reversible.

• GFAP is a sensitive biomarker for cholinergic degeneration and correlates with clinical outcomes in early DLB, while MRI-based atrophy measures are considered the most direct surrogate for disease progression.

• Diagnostic criteria and emerging biomarkers (e.g., SAA, FEOBV PET) are improving patient identification and trial recruitment, with consensus that clinical criteria remain robust.

Mechanistic insights and drug action

• Rab5 hyperactivation disrupts endosomal trafficking, leading to cholinergic neurodegeneration in both AD and DLB; neflamapimod inhibits p38 MAP kinase, attenuating Rab5 activation and restoring neuronal function.

• Preclinical and clinical data show that neflamapimod can reverse cholinergic dysfunction and improve clinical outcomes in early DLB, with effects observable within weeks.

• Co-pathology with Alzheimer's markers (amyloid, tau) worsens prognosis and reduces treatment responsiveness, reinforcing the focus on pure DLB patients.

• Biomarker and imaging advances (e.g., exosomal markers, PET tracers) are being explored for future trials and regulatory endpoints.

• The therapeutic approach aims for both symptomatic improvement and disease modification, with the potential for rapid clinical benefit and long-term slowing of progression.