Two important approaches for disease modifying AD therapies include targeting the accumulation of pathological forms of amyloid beta (Aβ) or tau. A limitation of these strategies is that they each target a narrow set of AD-related pathophysiological processes. AD is a complex and heterogeneous disease in which multiple mechanisms underly synaptic failure and degeneration. PharmatrophiX is a clinical-stage company developing a small molecule, LM11A-31-BHS, targeting a cell surface receptor and signaling networks that regulate cellular pathways and pathological processes underlying AD, particularly those relevant to synaptic resilience and degeneration. This approach can be applied to either pre-symptomatic or symptomatic phases of AD.

An extensive series of preclinical studies involving LM11A-31 in amyloid- and tau-based models has been published. In addition, three double-blind clinical trials have been completed. Phase 1 and phase 1b studies in normal subjects demonstrated a favorable safety profile and verified that with oral dosing, LM11A-31 achieves brain exposure. A phase 2a safety and exploratory endpoint randomized controlled trial in mild-moderate AD subjects with 242 randomized to three groups of placebo, low dose, and high dose, with treatment administered twice daily over a 26-week period, demonstrated a favorable safety profile. Measures in three out of three exploratory outcome domains demonstrated statistically significant drug versus placebo evidence of slowing of disease progression. Outcome areas included CSF markers of synaptic degeneration and glial activation, structural MRI, and FDG-PET brain scans. A trend of slowing cognitive loss was found and a trial of greater size and longer duration is planned for formal cognitive assessment. ADDF grant funding will support chemistry, manufacturing, and control (CMC) related activities in support of a Phase 2b/3 randomized controlled trial enrolling AD subjects with mild cognitive impairment and mild dementia. This study will address the hypothesis that LM11A-31-BHS slows progression of cognitive loss in AD subjects.