The Case for a Novel Therapeutic Approach to Dementia: Small Molecule Hepatocyte Growth Factor (HGF/MET) Positive Modulators

Abstract

An estimated 6.5 million Americans aged 65 years or older have Alzheimer's disease (AD), which will grow to 13.8 million Americans by 2060. Despite the growing burden of dementia, no fundamental change in drug development for AD has been seen in > 20 years. Currently approved drugs for AD produce only modest symptomatic improvements in cognition with small effect sizes. A growing mismatch exists between the urgent need to develop effective drugs for symptomatic AD and the largely failed search for disease modification. The failure rate of clinical trials in AD is high overall, and in particular for disease-modifying therapies. Research efforts in AD have focused predominantly on amyloid-β and tau pathologies, but limiting clinical research to these "classical hallmarks" of the disease does not address the most urgent patient, caregiver, or societal needs. Rather, clinical research should consider the complex pathophysiology of AD. Innovative approaches are needed that provide outside-the-box thinking, and re-imagine trial design, interventions, and outcomes as well as progress in proteomics and fluid biomarker analytics for both diagnostics and disease monitoring. A new approach offering a highly specific, yet multi-pronged intervention that exerts positive modulation on the HGF/MET neurotrophic system is currently being tested in mid-to-late-stage clinical trials in mild to moderate AD. Findings from such trials may provide data to support novel approaches for development of innovative drugs for treating AD at various disease stages, including among patients already symptomatic, and may offer benefits for other neurodegenerative diseases.

Keywords: Alzheimer’s disease; HGF/MET; hepatocyte growth factor; neurodegeneration; neurotrophic; pathogenesis; synaptogenesis.

Fig. 1

Positive Modulation of HGF/MET by Fosgonimeton. Hypothesized fast-onset effect of fosgonimeton mediated via the NMDA receptor. This mechanism of action represents a departure from drugs acting on the neurotransmitter level only, as the specific HGF/MET interaction could lead to multimodal downstream effects on processes known to be affected in various neurodegenerative conditions.

Fig. 2

Clinical Development of Fosgonimeton for Alzheimer’s Disease.