Allopregnanolone as Regenerative Therapeutic for Alzheimer's: Phase 2 Clinical Trial

PROJECT SUMMARY/ABSTRACT
Therapeutics to prevent, delay and treat Alzheimer’s disease (AD) remain an unmet need. Proposed herein is a
regenerative medicine, systems biology approach that targets the regenerative system of the brain while
simultaneously activating systems to reduce burden of AD pathology. Allopregnanolone (Allo) is a pleiotropic
neurosteroid that in preclinical discovery models of AD and aging promotes neurogenesis, restores cognitive
function and reduces burden of AD pathology. Mechanisms by which Allo promotes neural stem cell regeneration
and restoration of cognitive function are extensively characterized with a large margin of safety. Importantly, Allo
promotes regeneration of human neural stem cells in vitro. Allo is a low molecular weight neurosteroid
endogenous to the brain that is blood brain barrier penetrant with abundant existing safety data in animals and
humans. Completed National Institute on Aging (NIA) Phase 1 clinical trial of Allo in persons diagnosed with MCI
due to AD or mild AD, indicates that the regenerative treatment regimen of once per week via intravenous
infusion is well tolerated with no indications of Allo-related adverse events. MRI brain imaging for regenerative
surrogate markers and cognitive testing were well tolerated and feasible in this early AD cohort. Safety and
tolerability findings in women and men are consistent with outcomes of IND-enabling chronic toxicology in two
species indicating no adverse outcomes following 24 weeks of once per week Allo exposure at doses exceeding
those to be tested in humans by 10-fold. Based on a foundation of discovery and mechanistic preclinical
research, IND-enabling studies and Phase 1 clinical development in women and men, we propose a delayed
start Phase 2 clinical trial of Allo administered in a regenerative treatment regimen for 18 months, which includes
a placebo-controlled period of 12 months followed by a delayed-start (open label) period of 6 months. To advance
clinical development, three specific aims are proposed. Aim 1 is designed to conduct a Phase 2, randomized,
placebo-controlled, delayed start group, proof of concept clinical trial of Allo in APOEe4 positive participants
diagnosed with mild AD. The primary outcome measure will be rate of change in ADAS-cog14 score after 12
months. Secondary analyses will assess change from baseline to 12 months on activities of daily living
assessed by ADCS-iADL, MRI volumetric outcomes, and on cognitive function as determined by CANTAB
AD battery, MMSE, and CDR-SB. Aim 1 exploratory analyses will assess cognitive clinical and functional
outcomes during the delayed-start period (12-18 months). Aim 2 is exploratory and designed to develop
surrogate MRI-based biomarkers of hippocampal regeneration and connectivity. Aim 3 is exploratory and is
designed to establish a blood-based predictive biomarker of regenerative responders and non-responders.
To be explored are Allo-induced regeneration of iPSC-derived neural stem cells and mitochondrial
respiration. Secondary objective is to determine the cellular population with greatest predictive accuracy
using participant derived iPSCs / neural stem cells, peripheral blood mononuclear cells and CD34+ cells.

Grant Number: 5R01AG063826-05
NIH Institute/Center: NIH
Principal Investigator: ROBERTA BRINTON