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

Allopregnanolone: An overview on its synthesis and effects

“…Treatment with this neuroactive steroid shows: (A) beneficial effects on spinal cord trauma, (B) prevention of neuronal death, (C) reduction of cholesterol accumulation and stroke, (D) decrease in epileptic events, (E) beneficial effects in nervous damage induced by diabetes mellitus, (F) protective effects on neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis), (G) anxiolytic and anti-stress actions, (H) effects against the neurotoxicity exerted by human immunodeficiency virus (HIV), (I) protective effects in an experimental model of Niemann-Pick type C and in (J) neuroinflammatory conditions (eg, multiple sclerosis and experimental autoimmune encephalomyelitis), and (K) analgesic effects against neuropathic pain regimen appears to be crucial. 237,238,240 By contrast, intranasal delivery of this neuroactive steroid has been proposed as an excellent therapeutic strategy against seizures. 241 In this context, it is important to highlight that neuroactive steroids represent an important target for the treatment of focal epileptic disorders.…”

Evaluation of mild cognitive impairment genetic susceptibility risks in a Chinese population

“…New research suggests that neurosteroids such as diethylstilbestrol may be a new treatment for AD, indicating that lipid metabolism occupied a significant position in AD [ 41 , 42 ]. Some studies have found that the behavior of STARD6 is similar to the steroidogenic acute regulatory protein (StAR), which controls the rate-limiting step of neurosteroid synthesis [ 35 , 43 ].…”

Development of neuroactive steroids for the treatment of postpartum depression

“…Furthermore, in children with Fragile X syndrome, ganaxolone treatment did not result in a statistically significant improvement in CGI‐I score and most scales of anxiety and aberrant behaviour compared to placebo (although it did lead to a significant improvement in the depression subscale of the Anxiety, Depression and Mood Scale) 89 . ALLO has also been tested in a phase 1b/2a clinical trial in 24 patients with early Alzheimer's disease; an exploratory efficacy analysis demonstrated that there were no differences between the ALLO and placebo groups at 12 weeks with respect to cognition scores and hippocampal volume 90 . Additional clinical trials of ALLO in patients with early or mild Alzheimer's disease are currently planned or underway 91,92…”

“…89 ALLO has also been tested in a phase 1b/2a clinical trial in 24 patients with early Alzheimer's disease; an exploratory efficacy analysis demonstrated that there were no differences between the ALLO and placebo groups at 12 weeks with respect to cognition scores and hippocampal volume. 90 Additional clinical trials of ALLO in patients with early or mild Alzheimer's disease are currently planned or underway. 91,92…”