P1‐053: pharmacokinetics and safety profile of intravenous administration of allopregnanolone in patients with early alzheimer's disease

The neurosteroid Allopregnanolone (Allo) is a novel therapeutic approach to reducing the burden of Alzheimer's disease (AD) pathology by targeting the regenerative system of the brain. In this phase 1 trial we assess the safety, tolerability and pharmacokinetics of intravenous administration of Allo. A randomized double-blind, placebo-controlled, multiple ascending dose, phase 1 clinical trial was conducted in patients with mild cognitive impairment due to AD or mild AD. Men and women age ≥ 55 years, with a MMSE score ≥20 and clinical dementia rating of 0.5-1 were recruited to the study. Participants were randomly assigned to receive weekly intravenous treatment of 2, 4 and 6mg of Allo or placebo. Primary outcome was to assess safety, tolerability and maximally tolerated dose (MTD) of Allo at the three doses administered intravenously once per week over 12 weeks. A total of 24 patients were enrolled into the trial and participated in the pharmacokinetic assessment. Blood was collected at 15, 30, 45 minutes, and 1, 2, 4, 6 and 24 hours post the 30-minute infusion. Mean Tmax was 30 minutes across all cohorts. Mean Cmax at 2, 4 and 6mg was 63±21 nM, 130±26nM and 248±84nM, respectively. The Cmax closely correlated (R=0.77) with Allo delivered in mg/kg dose. MTD was established by onset of sedation at doses >6mg. Twelve-week exposure to multiple doses of Allo once per week resulted in no reportable adverse effects, serious adverse events or ARIA. Allopregnanolone administered intravenously once a week was well tolerated, appeared without adverse effects, and exhibited a favorable pharmacokinetic profile in our study population.