Drug Development

Background: We have previously reported the neuroprotective effects of fosgonimeton in amyloid-β (Aβ)-driven preclinical models of Alzheimer's disease (AD). Fosgonimeton is an investigational small-molecule positive modulator of the neurotrophic hepatocyte growth factor (HGF) system, currently under investigation for mild-to-moderate AD (LIFT-AD; NCT04488419). Given the recent approvals of Aβ-targeting monoclonal antibodies (Aβ-mAbs) for the treatment of AD, and growing recognition that combination therapies may improve treatment outcomes, we sought to investigate the preclinical activity of fosgonimeton in the presence of Aβ-mAbs. Here, we report the neuroprotective effects of fosgonimeton against Aβ toxicity in primary cortical neurons in the presence and absence of lecanemab, an Aβ-targeting mAb that has received full approval for early AD.

Method: Primary rat cortical neurons were pre-treated with the active metabolite of fosgonimeton (fosgo-AM; 100 nM), lecanemab (25 nM), or fosgo-AM + lecanemab for 15 minutes, and subsequently challenged with Aβ1-42 (15 µM). In another condition, the drug treatments were co-applied with Aβ1-42. Following 24- or 48-hour Aβ exposure, cultures were immunoassayed for microtubule-associated protein-2 (neuronal marker) to determine neuronal survival and neurite network length.

Result: Cortical neurons pre-treated with fosgo-AM and/or lecanemab exhibited a significant increase in neuronal survival and neurite network length following 24h or 48h Aβ challenge. In the Aβ1-42 co-application conditions, following 24h Aβ exposure, all treatments significantly promoted neuronal survival, but only the combination of fosgo-AM + lecanemab significantly preserved neurite networks. In the Aβ1-42 co-application conditions, following 48h Aβ exposure, only the combination of fosgo-AM + lecanemab significantly promoted neuronal survival, and none of the treatments had a significant effect on neurite network.

Conclusion: This study provides preliminary evidence that, on a cellular level, the neuroprotective ability of fosgonimeton against Aβ-mediated toxicity in primary neurons is maintained in the presence of lecanemab. Furthermore, in some conditions, only the combination of fosgo-AM and lecanemab demonstrated a significant increase in neuronal survival. While additional experiments are required to characterize these effects, these initial observations may have important implications regarding the potential of fosgonimeton as a treatment for AD, with or without Aβ-targeting antibodies.