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Abstract Details

Exploratory Imaging Outcomes of a Phase 1b/2a Clinical Trial of Allopreganolone as a Regenerative Therapeutic for Alzheimer’s Disease: Structural and Functional Connectivity Outcomes
Aging, Dementia, Cognitive, and Behavioral Neurology
P9 - Poster Session 9 (5:30 PM-6:30 PM)
3-001

Imaging biomarkers are well-documented indicators of neurodegeneration and AD severity. Based on ALLO-induced neurogenesis, oligogenesis, and restoration of cognitive function in animal models of AD, exploratory MRI imaging was conducted to explore impact of Allo on hippocampal structure, white matter integrity, and functional connectivity.

Determine feasibility of MRI-based imaging outcomes to detect regenerative indicators in randomized-controlled, Phase 1b/2a multiple ascending dose trial of allopregnanolone (ALLO), an endogenous neurosteroid, in persons with early Alzheimer's disease (AD).

Twenty-four individuals participated in a Phase 1b/2a clinical trial of ALLO (n=6 placebo; n=18 ALLO) and underwent brain-MRI at baseline and following 12-week treatment. Hippocampal atrophy rate was determined from volumetric MRI, computed as rate of change, and qualitatively assessed between ALLO and placebo sex, APOEε4 allele, and dose subgroups. White matter integrity was assessed by fractional and quantitative anisotropy. Changes in local, inter-regional, and network-level functional connectivity were assessed using resting-state functional MRI.

ALLO slowed, and in some cases reversed, rate of decline in hippocampal volume (HV) compared to placebo. Gain of HV was evident specifically in APOEε4 carriers (range: 0.6-7.8% increased HV). Multiple measures of white matter integrity indicated evidence of preserved or improved integrity. ALLO significantly increased fractional anisotropy in 690/690 and quantitative anisotropy in 1416/1888 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.

Indicators of regeneration from previous preclinical studies coupled with exploratory MRI-based outcomes from Phase 1b/2a clinical trial of ALLO 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).

Authors/Disclosures
Roberta Diaz Brinton, PhD (University of Arizona)
PRESENTER
Roberta Diaz Brinton, PhD has nothing to disclose.
Adam Raikes, PhD Dr. Raikes has nothing to disclose.
Gerson David Hernandez Rivera, MD, MPH (Center for Innovation in Brain Science / University of Arizona) Dr. Hernandez Rivera has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NeuTherapeutics. The institution of Dr. Hernandez Rivera has received research support from National Institute on Aging. The institution of Dr. Hernandez Rivera has received research support from National Institute on Aging.
Dawn Matthews Dawn Matthews has received personal compensation for serving as an employee of ADM Diagnostics, Inc. Dawn Matthews has received stock or an ownership interest from ADM Diagnostics Inc. The institution of Dawn Matthews has received research support from National Institutes of Health.
Ana Lukic, PhD (ADM DIAGNOSTICS INC) Dr. Lukic has received personal compensation for serving as an employee of ADM Diagnostics. The institution of Dr. Lukic has received research support from NIH.
Yonggang Shi Yonggang Shi has nothing to disclose.
Meng Law No disclosure on file
Lon Schneider, MD (USC School of Medicine) Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AC Immue. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biovie. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Athira. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alpha-cognition. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Corium. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cortexyme. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurim Ltd. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novo Nordisk. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lundbeck. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Otsuka. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. The institution of Dr. Schneider has received research support from NIH. The institution of Dr. Schneider has received research support from Eli Lilly. The institution of Dr. Schneider has received research support from Biogen. The institution of Dr. Schneider has received research support from Biohaven.