Randomized phase 2a trial assessing a novel septin molecular glue in Alzheimer's disease.

INTRODUCTION

Pharmacological restoration of septin filament integrity has the potential to provide symptomatic benefit and disease modification in Alzheimer's disease (AD).

METHODS

REM127, a septin modulator, was assessed in mild-to-moderate AD (EudraCT: 2022-000080-43) in a phase 2a trial (n = 14).

PRIMARY ENDPOINTS: safety and tolerability; exploratory endpoints: pharmacokinetics, cerebrospinal fluid (CSF) biomarkers, electroencephalography (EEG), and functional outcomes.

RESULTS

In participants on active therapy, dose-dependent increases in serum aminotransferase were observed, leading to study discontinuation. CSF hyperphosphorylated tau (P-tau181), endpoints reflecting synaptic function and cognitive outcomes, were changed significantly (p < 0.05) to normal compared to placebo.

DISCUSSION: REM127 triggers off-target liver adverse effects. Anticipated on-target outcomes suggest septin modulation has symptomatic benefit and modifies processes underlying AD. Results are considered exploratory as statistical power is constrained due to the small sample size caused by early termination. Further investigation of the therapeutic concept using an optimized septin molecular glue with an improved safety profile is warranted.

HIGHLIGHTS: Septin 6/7 molecular glue REM127 was assessed in symptomatic participants with Alzheimer's disease (AD). REM127 triggers off-target effects suggesting liver adverse effects. REM127 brain exposure was consistent with saturated target engagement. Biomarker and cognitive outcomes were changed consistent with therapeutic benefit. Septin modulation may restore synaptic function and mitigate pathology in AD.