Allopregnanolone as a Regenerative Therapeutic for Early Alzheimer’s Disease: Phase 1b/2a Clinical Trial Outcomes
Gerson Hernandez 1, Claudia Lopez1, Wendy Mack2, Sonia Pawluczyk4, Dawn Matthews5, Yonggang Shi3, Meng Law6, Michael Rogawski7, Lon Schneider4, Roberta Diaz Brinton1
1Center for Innovation in Brain Science, University of Arizona, 2Preventive Medicine, 3Stevens Neuroimaging and Informatics Institute, USC School of Medicine, 4USC School of Medicine, 5ADM diagnostics, 6Neuroscience / Electrical & Computer Systems Engineering, Monash University, 7University of California - Davis
Objective:

To assess safety and tolerability of allopregnanolone (ALLO) following a 12-week once-per-week dosing regimen in persons with early Alzheimer’s disease (AD). To establish pharmacokinetic (PK) parameters and maximally tolerated dose (MTD) of ALLO.

Background:

ALLO is an endogenous neurosteroid with mechanisms of action that promote neural stem cell regeneration, neurogenesis and oligogenesis with potential as a regenerative therapeutic for Alzheimer’s disease (AD). Well-documented safety across healthy human and animal life-course served as the foundation for safety assessment in AD patients.

Design/Methods:

Randomized, double-blinded, placebo-controlled, and multiple ascending dose Phase 1b/2a clinical trial of ALLO was conducted in twenty-four sex-matched participants (n=6 placebo; n=18 ALLO. Intravenous ALLO or placebo was administered once-per-week for 12 weeks. Participants with early AD (MCI due to AD or mild AD), a Mini-Mental State Examination score of 20-26 and age ≥55 years were enrolled. Primary endpoint was safety and tolerability. Secondary endpoints included PK parameters and MTD. 

Results:

ALLO was safe and well-tolerated with all participants completing the trial. No differences were observed between treatment arms in the occurrence and severity of adverse events (AE). Most common AE were mild to moderate in severity and included rash [n=4 (22%)] and fatigue [n=3 (17%)]. Pharmacokinetics indicated predictable linear dose-response of ALLO following 30-minute infusion. Maximum plasma concentrations for 2mg, 4mg, 6mg and 10mg dosages were 14.53ng/ml (+/-7.31), 42.05ng/ml (+/-14.55), 60.07ng/ml (+/-12.8), and 137.48ng/ml (+/-38.69), respectively. MTD was established based on ALLO-induced mild sedation at the highest doses (males10mg; females 14mg). No adverse outcomes on cognition or MRI-based imaging outcomes were evident. Exploratory imaging biomarkers indicated trend of decreased hippocampal atrophy in ALLO treated APOEε4 participants.

Conclusions:

Allopregnanolone was well-tolerated and safe across all doses. Safety, MTD and PK parameters of ALLO support advancement to a Phase 2 proof-of-concept efficacy clinical trial of ALLO as a regenerative therapeutic for mild AD.