LM11A-31 SMALL MOLECULE P75 RECEPTOR MODULATOR –PRECLINICAL ASSESSMENT AND BIOMARKERS RELEVANT TO A PHASE 2A EXPLORATORY TRIAL IN ALZHEIMER’S DISEASE
- Frank Longo, United States of America
Abstract
Aims
In the context of outcome measures in APP- and tauopathy-based mouse models, assess exploratory endpoint measures to be applied in a phase 2a trial in mild-moderate Alzheimer’s disease (AD) for LM11A-31, a first-in-class small molecule modulating p75 neurotrophin receptor signaling.
Methods
Studies incorporating APP-L/S, Tg-2576 and P301S (PS19) mice included oral gavage for three-month treatment periods commencing after establishment of amyloid- and tau-related pathology. Outcome measures included p75 receptor-linked downstream signaling; accumulation of pathological tau species and tau seeding activity; neurite, synaptic and spine degeneration; measures of microglia and astrocyte status; and behavioral assessment. A phase 2a exploratory endpoint trial in mild-moderate AD contains three study arms: placebo, low-dose and high-dose administered by oral capsules for 6 months. Baseline and post-treatment assessments include: ADAS-Cog-13, a Neurological Testing Battery and other cognitive tests; CSF biomarkers; volumetric MRI and statistical region of interest FDG-PET.
Results
Mouse model studies suggest relevant biomarkers available in the context of a clinical trial. A total of 242 from a target 240 subjects were enrolled. Randomization resulted in similar populations across the three study arms. Within-subject baseline and post-treatment FDG-PET imaging, MRI imaging and CSF was obtained from approximately 65%. Data assessment is underway.
Conclusions
Consideration of preclinical studies guides the application of imaging and CSF biomarkers in this exploratory endpoint trial. The treatment phase of the 2a trial has been completed. Formal analyses following data lock will assess primary safety as well as exploratory imaging, CSF biomarker and cognitive endpoints.