[P3–025]: ALLOPREGNANOLONE, REGENERATIVE THERAPEUTIC FOR ALZHEIMER's DISEASE: PHASE 1B/2A UPDATE
Year: 2017
Type: article
Abstract: Allopregnanolone (Allo) is a regenerative therapeutic that promotes neurogenesis, regeneration of human neural stem cells, restores cognitive function in a preclinical AD model and wild type aged mice and reduces AD pathology. Allo, a neurosteroid, has abundant existing safety data in animals and humans. Its mechanisms of neural stem cell proliferation, restoration of cognitive function and AD pathology reduction are well characterized and unlikely to induce amyloid related imaging abnormalities (ARIA). Phase 1b/ 2a clinical trial to establish safety and maximally tolerated Dose: Allopregnanolone for Mild Cognitive Impairment Due to Alzheimer's Disease or Mild AD. ClinicalTrials.gov Identifier: NCT02221622. Secondary objectives are to: assess potential short-term effects of Allo dosing on cognition and MRI indicators of AD; inform subsequent phase 2 proof of concept trial with MRI-based biomarkers of regenerative efficacy. Allopregnanolone at two doses, 2mg and 4mg, was intravenously infused once per week for 12 weeks to 8 participants / dose cohort (6 allopregnanolone + 2 placebo / dose cohort). Within 15 minutes of start of infusion, peak plasma level was reached Cma = 46.34 +/- 23 nanomolar. No sedation was observed in any participant during or after infusion indicating a tolerable dose. The Cmax closely correlated (r=0.77) with Allo delivered in mg/kg dose. Twelve-week exposure to 2mg or 4mg of Allopregnanolone once per week had no detectable adverse effects. Dose cohort 3 is underway. Primary safety outcomes and secondary exploratory outcomes of MRI based biomarkers, metabolomics, cognition and iPSC derived neural stem cell response to Allo will be presented. Allopregnanolone is a first in class regenerative therapeutic for MCI and AD that targets endogenous neural stem cells and disease modifying mechanisms. Trial outcomes will provide: 1) an estimated safe and well-tolerated dose of Allo; 2) parameter estimates for MRI based markers of regeneration, cognitive efficacy and iPSC / neural stem cell based indicator of responders and foundation to advance to a Phase 2 proof of concept trial of Allo in persons diagnosed with early AD. Supported by NIA U01AG03111 & U01AG047222 to RDB; UF1AG046148 to RDB & LS; ADDF to RDB
Source: Alzheimer s & Dementia
Institutions: University of Arizona, University of Southern California
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2766099593