Investigating the Effects of Brain Cholesterol Metabolism Using CYP46A1 Gene Therapy in Subjects with Huntington’s Disease (P1-11.016)

Abstract

<h3>Objective:</h3> To report the clinical trial study design evaluating the safety, tolerability, and preliminary efficacy of investigational gene therapy rAAVrh10.CYP46A1wt (AB-1001) in subjects with Huntington’s disease (HD). <h3>Background:</h3> HD is a progressive, genetic neurodegenerative disorder linked to cholesterol dysregulation and subsequent protein aggregation in the brain. A neuron-specific enzyme, cholesterol-24-hydroxylase (CYP46A1), assists in regulating brain cholesterol synthesis and metabolism, and is deficient in subjects with HD. CYP46A1 restoration in striatal neurons using the adeno-associated virus (AAV) therapy AB-1001 led to reduced mutant Huntingtin protein aggregation and improved pathology hallmarks in two mouse models. <h3>Design/Methods:</h3> This first in-human, Phase 1/2, open-label, dose-finding study will consist of one-time intracerebral bilateral injections of AB-1001, an investigational AAV gene therapy comprising an AAVrh10 vector carrying gene encoded CYP46A1, within the striatum. To be eligible for enrollment, subjects will be 18–65 years old, possess a CAG expansion in the huntingtin gene ≥40, have early manifest HD, and have striatal MRI volumes per hemisphere compatible with local delivery of study drug. The trial will include screening (8 weeks), treatment and initial follow-up (52 weeks), and long-term follow-up (4 years). The treatment phase includes dose-finding (Cohort 1: n=3–6, single dose of 4.0E8 vg/μL; Cohort 2: n=3–6, single dose of 1.1E9 vg/μL) and dose-expansion (n=6, nonsequential dosing with selected dose). The primary endpoint will be the incidence of dose-limiting toxicities, treatment-emergent adverse events, and serious adverse events. Secondary endpoints include change from baseline to week 52 in MRI-assessed measures of HD-impacted brain regions, composite Unified Huntington’s Disease Rating Scale (cUHDRS), and MRS metabolic profile. Other endpoints include additional HD biomarkers and quality-of-life measures. <h3>Results:</h3> N/A <h3>Conclusions:</h3> Preclinical results show the potential for CYP46A1 gene therapy with AB-1001 to demonstrate therapeutic benefits in subjects with HD and rationalize progression to the first in-human Phase I/II clinical trial. <b>Disclosure:</b> Dr. Schultz has received personal compensation for serving as an employee of AskBio. The institution of Dr. Durr has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. The institution of Dr. Durr has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology Genetics. The institution of Dr. Durr has received research support from NIH. The institution of Dr. Durr has received research support from BIOGEN. The institution of Dr. Durr has received research support from MINORYX. The institution of Dr. Durr has received research support from TRIPLETS THERAPEUTICS. The institution of Dr. Durr has received research support from Servier. The institution of Dr. Durr has received research support from ANR. The institution of Dr. Durr has received research support from PTC. Prof. Karachi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Boston scientific / Medtronic / Neurotrials. Dr. O’Callaghan has received personal compensation for serving as an employee of Asklepios Biopharmaceuticals. Dr. O’Callaghan has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Asklepios Biopharmaceuticals. Dr. O’Callaghan has stock in Asklepios Biopharmaceuticals. Dr. O’Callaghan has received intellectual property interests from a discovery or technology relating to health care. Dr. ALVES has nothing to disclose. Dr. Lamontagne has received personal compensation for serving as an employee of Asklepios Biopharmaceutical Inc. Mrs. HURMIC has nothing to disclose. Dr. Cartier has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for askbio. Dr. Cartier has stock in brainvectis.