Safety, tolerability, and pharmacokinetics of allopregnanolone as a regenerative therapeutic for Alzheimer's disease: A single and multiple ascending dose phase 1b/2a clinical trial

Abstract

Introduction: Allopregnanolone is an endogenous neurosteroid with the potential to be a novel regenerative therapeutic for Alzheimer's disease (AD). Foundations of mechanistic understanding and well-established preclinical safety efficacy make it a viable candidate.

Methods: A randomized, double-blinded, placebo-controlled, single and multiple ascending dose trial was conducted. Intravenous allopregnanolone or placebo was administered once-per-week for 12 weeks with a 1-month follow-up. Participants with early AD (mild cognitive impairment due to AD or mild AD), a Mini-Mental State Examination score of 20-26 inclusive, and age ≥55 years were randomized (6:2 to three allopregnanolone dosing cohorts or one placebo cohort). 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: A total of 24 participants completed the trial. Allopregnanolone was safe and well tolerated in all study participants. 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%]). A single non-serious AE, dizziness, was attributable to treatment. There was one serious AE not related to treatment. Pharmacokinetics indicated a predictable linear dose-response in plasma concentration of allopregnanolone after intravenous administration over 30 minutes. The maximum plasma concentrations for the 2 mg, 4 mg, 6 mg, and 10 mg dosages were 14.53 ng/mL (+/-7.31), 42.05 ng/mL (+/-14.55), 60.07 ng/mL (+/-12.8), and 137.48 ng/mL (+/-38.69), respectively. The MTD was established based on evidence of allopregnanolone-induced mild sedation at the highest doses; a sex difference in the threshold for sedation was observed (males 10 mg; females 14 mg). No adverse outcomes on cognition or magnetic resonance imaging-based imaging outcomes were evident.

Conclusions: Allopregnanolone was well tolerated and safe across all doses in persons with early AD. Safety, MTD, and PK profiles support advancement of allopregnanolone as a regenerative therapeutic for AD to a phase 2 efficacy trial.

Trial registration: ClinicalTrials.gov-NCT02221622.

Keywords: Alzheimer’s disease; allopregnanolone; maximally tolerated dose; neurogenesis; pharmacokinetics; phase 1 clinical trial; regenerative therapeutic; translational research.

Conflict of interest statement

This study was funded by the National Institute on Aging (NIA) and the Alzheimer's Drug Discovery Foundation (ADDF).Dr. Hernandez reports no disclosures. Dr. Solinsky reports no disclosures. Dr. Mack reports no disclosures. Mrs. Kono reports no disclosures. Dr. Rodgers reports no disclosures. Dr. Wu and Dr. Mollo are paid consultants and co‐founders of TOMO Pharmacometrics, which was contracted to conduct processing and pharmacokinetic analysis. Mrs. Lopez reports no disclosures. Dr. Pawluczyk reports no disclosures. Mr. Bauer reports no disclosures. Dr. Matthews is a paid consultant and CEO of ADM Diagnostics, Inc. Dr. Shi reports no competing interests. Dr. Law reports no competing interests. Dr. Rogawski is principal investigator on research grants to the University of California, Davis, from NINDS (U54NS079202, R25NS099170, U01NS112102), CURE – Citizens United for Research in Epilepsy, and Mallinckrodt Pharmaceuticals; has served as a consultant to Eisai, West Therapeutics Development, Xenon Pharmaceuticals, Supernus Pharmaceuticals, Aquestive Therapeutics, and H. Lundbeck A/S; is a member of the board of directors of Epalex; is a member of the scientific advisory boards of Zynerba Pharmaceuticals, Marinus Pharmaceuticals, and OB Pharmaceuticals; and is named as an inventor of patents and patent applications assigned to the Regents of the University of California. Dr. Schneider reports grants from Biogen, Roche/Genentech, Eli Lilly and Company, Novartis, and Biohaven; personal fees from Merck, Eli Lilly and Company, and Roche/Genentech for serving on the data and safety monitoring boards; personal fees from Takeda for serving as a consultant and on an adjudication committee; and consulting fees from AC Immune, Avraham Pharmaceuticals, Boehringer Ingelheim, Cognition Therapeutics, Cotexyme, Eisai, Neurim Pharmaceuticals, Neuronix, Tau RX, Toyama, Abbott, and vTv Therapeutics outside the submitted work. Dr. Brinton holds patent US8969329B2 for allopregnanolone for the treatment of neurodegenerative diseases.

© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.

Figures

FIGURE 1

Semilogarithmic mean plasma concentration‐time profiles of Allopregnanolone doses. Allopregnanolone 2 mg, 4 mg, and 6 mg doses shown at visit 3 and visit 14; 10 mg dose shown at visit 14 only. Measurements in all cases after 2 hours were below limit of quantitation (4 hours, 6 hours, 8 hours, and 24 hours). Error bars indicate standard error of the mean