Dataset Information

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.

SUBMITTER: Hernandez GD

PROVIDER: S-EPMC7744018 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

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.

Hernandez Gerson D GD Solinsky Christine M CM Mack Wendy J WJ Kono Naoko N Rodgers Kathleen E KE Wu Chun-Yi CY Mollo Ana R AR Lopez Claudia M CM Pawluczyk Sonia S Bauer Gerhard G Matthews Dawn D Shi Yonggang Y Law Meng M Rogawski Michael A MA Schneider Lon S LS Brinton Roberta D RD

Alzheimer's & dementia (New York, N. Y.) 20201216 1

<h4>Introduction</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 33344752

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Project description:IntroductionAllopregnanolone (ALLO), an endogenous neurosteroid, promoted neurogenesis and oligogenesis and restored cognitive function in animal models of Alzheimer's disease (AD). Based on these discovery research findings, we conducted a randomized-controlled phase 1b/2a multiple ascending dose trial of ALLO in persons with early AD (NCT02221622) to assess safety, tolerability, and pharmacokinetics. Exploratory imaging outcomes to determine whether ALLO impacted hippocampal structure, white matter integrity, and functional connectivity are reported.MethodsTwenty-four individuals participated in the trial (n = 6 placebo; n = 18 ALLO) and underwent brain magnetic resonance imaging (MRI) before and after 12 weeks of treatment. Hippocampal atrophy rate was determined from volumetric MRI, computed as rate of change, and qualitatively assessed between ALLO and placebo sex, apolipoprotein E (APOE) ε4 allele, and ALLO dose subgroups. White matter microstructural integrity was compared between placebo and ALLO using fractional and quantitative anisotropy (QA). Changes in local, inter-regional, and network-level functional connectivity were also compared between groups using resting-state functional MRI.ResultsRate of decline in hippocampal volume was slowed, and in some cases reversed, in the ALLO group compared to placebo. Gain of hippocampal volume was evident in APOE ε4 carriers (range: 0.6% to 7.8% increased hippocampal volume). Multiple measures of white matter integrity indicated evidence of preserved or improved integrity. ALLO significantly increased fractional anisotropy (FA) in 690 of 690 and QA in 1416 of 1888 fiber tracts, located primarily in the corpus callosum, bilateral thalamic radiations, and bilateral corticospinal tracts. Consistent with structural changes, ALLO strengthened local, inter-regional, and network level functional connectivity in AD-vulnerable regions, including the precuneus and posterior cingulate, and network connections between the default mode network and limbic system.DiscussionIndicators of regeneration from previous preclinical studies and these exploratory MRI-based outcomes from this phase 1b/2a clinical cohort support advancement to a phase 2 proof-of-concept efficacy clinical trial of ALLO as a regenerative therapeutic for mild AD (REGEN-BRAIN study; NCT04838301).

Project description:BackgroundAmyloid beta protein (Aβ) is a treatment target in Alzheimer's Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen, an orally administered small molecule, binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aβ. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aβ metabolism using Stable Isotope Labeling Kinetic (SILK) analysis.MethodsDouble-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) confirmed by low CSF Aβ42/40 were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21-23 days, then underwent CSF catheter placement, intravenous infusion of 13C6-leucine, and CSF sampling for 36 h. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aβ40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aβ and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21.ResultsFrom June 2017 to December 2021, 19 participants were enrolled, randomized within dose cohorts (5 active: 3 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aβ40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs. placebo groups.ConclusionsPosiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects.Trial registrationNCT02925650 on clinicaltrials.gov (registered on 10-24-2016).

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Dataset Information

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.

Introduction

Methods

Results

Conclusions

Trial registration

Publications

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.

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