Aims

To assess safety, tolerability and pharmacokinetics of allopregnanolone following a single-dose administration and after chronic exposure over a 12-week period of once-per-week dosing in persons with early Alzheimer’s disease (AD).

Methods

Randomized, double-blinded, placebo-controlled, single and multiple ascending dose study (ClinicalTrials.gov-NCT02221622). Intravenous allopregnanolone or placebo was administered once-per-week for 12 weeks with a 1-month follow-up. 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 randomized. Primary endpoint was safety and tolerability. Secondary endpoints included pharmacokinetic (PK) parameters and maximally tolerated dose (MTD). Exploratory endpoints included cognitive and imaging biomarkers.

Results

Twenty-four participants completed the trial. Allopregnanolone was safe and well-tolerated. No

differences between treatment arms in the occurrence and severity of adverse events (AE). Most

common AEs were mild to moderate in severity and included rash [n=4 (22%)] and fatigue [n=3 (17%)].

A single non-serious AE, dizziness, was attributable to treatment. Pharmacokinetics indicated

predictable linear dose-response in plasma allopregnanolone following 30-minute infusion. The

maximum plasma concentrations for the 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 evidence of allopregnanolone-induced mild sedation at the highest

doses (males10mg; females 14mg). No adverse outcomes on cognition or MRI-based imaging outcomes

were evident. Exploratory imaging analyses were indicative of responders and non-responders on

outcomes relevant to regeneration.

Conclusions

Allopregnanolone was well-tolerated and safe across all doses in this cohort. Safety, MTD and PK profiles support advancement to a phase 2 efficacy trial.