P1‐072: Comparative Pharmacokinetic Assessment of Allopregnanolone to Develop a Regenerative Therapeutic for Mild Cognitive Impairment and Early Alzheimer’s Disease

Currently in Phase 1b, Allopregnanolone (Allo) is in development as the first regenerative therapeutic for Alzheimer’s disease (AD). Pharmacokinetic (PK) outcomes in animals estimate the maximally tolerated dose (MTD) and no observed adverse effect level (NOAEL). Dose-escalating clinical PK studies (placebo-controlled) are underway to evaluate safe doses of Allo in men and women age 55+ with MCI/earlyAD (NCT02221622). Allo plasma concentrations (LC-MS/MS) were compared in: 1) 5-month 3xTgAD or 15-month nonTg male mice treated acutely via s.c., i.m., t.d., i.n., i.v. 2) Adult male and female Sprague Dawley rats at doses from 1-8 mg/kg i.m. 3) Adult New Zealand White female rabbits at 3mg/kg t.d. and 5mg/kg i.v. 4) Adult male and female Beagles at doses from 2.4-6 mg/kg i.m. and i.v 5) Men and women age >55years with MMSE >20 diagnosed with MCI/earlyAD dosed by 30min. i.v. infusion. PK profiles from multiple species were compared across MTD, NOAEL, Cmax, Tmax, AUC and half-life. Across species, Allo plasma levels ∼1000ng/ml elicited gait ataxia; above ∼1500ng/ml elicited moderate to deep sedation within 5-15minutes. We estimate 3-fold brain/plasma ratios across multiple routes and formulations, useful for understanding MTD limits. Sedation effects at high-doses were more enhanced in males than females (mg/kg) despite similar plasma concentrations. Cmax and AUClast increased with ascending dose levels, approximately proportional to dose. Cmaxplasma 33ng/ml; brain 160ng/g elicited efficacy in AD mouse models indicating that, relative to MTD, moderate plasma Allo is sufficient. Half-life values were <1hr for most routes and formulations. Acute administration of Allo in several species allowed us to compare PK parameters to assess safety and establish a scalable dose range predicted to be efficacious. Previously we showed that Allo transiently and robustly phosphorylated CREB within 5min and increased levels of NeuroD within 4h (Irwin et al., 2015) at mild to moderate doses. Allo as a regenerative therapeutic is based on well-defined mechanistic targets for neurogenesis and disease modification, dosing, formulation, route of administration, and the appropriate treatment regimen necessary to advance to Phase2 for MCI/earlyAD. Research supported by NIA U01 AG031115; NIA U01 AG047222; UF1 AG046148 and ADDF to RDB.