Abstract Details

Title Phase 1b Safety and Preliminary Efficacy of Bilateral Intraputaminal Delivery of AAV2 GDNF (AB-1005) in Participants With Mild or Moderate Parkinson’s Disease

Topic Movement Disorders

Presentation(s) N2 - Neuroscience in the Clinic: Neuromodulation: From Bench to Bedside (2:18 PM-2:30 PM)

Poster/Presentation
Number 001

Background

GDNF is required for development and survival of dopaminergic neurons. GDNF putaminal transduction via gene therapy is a promising approach to durably restore dopaminergic network function.

Objective To assess safety and preliminary efficacy of adeno-associated virus vector serotype 2 containing glial cell?derived neurotrophic factor (AAV2-GDNF), AB-1005, in participants with mild or moderate Parkinson’s disease (PD) administered using magnetic resonance imaging (MRI)-monitored, one-time bilateral, convection-enhanced delivery (CED).

Design/Methods This phase 1b trial (NCT04167540) enrolled participants with mild (<5 years post-diagnosis, Movement Disorder Society Unified Parkinson’s Disease Rating Scale [MDS-UPDRS] III OFF score ≤32) and moderate (≥4 years; MDS-UPDRS III 33?60) PD. Participants received up to 1.8 mL AAV2-GDNF (3.3e12 vg/mL/gadoteridol 2mM co-infusion) per putamen via MRI-monitored CED and optimized neurosurgical technique. The primary outcome was safety (adverse events [AE]). Outcomes were assessed using PD clinical-rating scales.

Results Of 11 participants enrolled (n=5, Mild Cohort; n=6, Moderate Cohort), 10 are 18-months post-treatment. Mean (SE) putaminal coverage was 63% (2%). Asymptomatic, small, unilateral T1 hypointensities were observed in 3 participations at 6 months. All participants experienced treatment-emergent AE; most were transient and perioperative. Serious AEs (n=5) were unrelated to AAV2-GDNF. The Mild Cohort exhibited stable MDS-UPDRS, motor diary, unified dyskinesia rating scale (UDysRS) scores, and levodopa equivalent daily dose (LEDD). One Mild Cohort participant had heterozygous tyrosine hydroxylase mutation of unknown significance. At 18 months post-treatment, the Moderate Cohort demonstrated improvements from baseline in mean±SE MDS-UPDRS Part III OFF scores (–18.8±6.6), motor diary OFF time (−2.20±1.26 h), UDysRS (−2.75±2.29), and LEDD (−321.9±192.15 mg).

Conclusions Analysis of this phase 1b trial is ongoing; topline 18-month data will be presented. These preliminary findings suggest AAV2-GDNF is well tolerated in participants with PD, demonstrating general stability of the Mild Cohort and possible clinical benefit in the Moderate Cohort. A phase 2 randomized controlled study is planned to confirm these findings.

Authors/Disclosures
Amber D. Van Laar, MD (Asklepios BioPharmaceutical Inc) PRESENTER	Dr. Van Laar has received personal compensation for serving as an employee of Asklepios Biopharmaceutical. The institution of an immediate family member of Dr. Van Laar has received research support from Asklepios BioPharmaceutical Inc.
Chadwick W. Christine, MD, FAAN	The institution of Dr. Christine has received research support from Neurocrine Biosciences. The institution of Dr. Christine has received research support from Brain Neurotherapy Bio, Inc. The institution of Dr. Christine has received research support from Michael J Fox Foundation for Parkinson's Research. The institution of Dr. Christine has received research support from Annovis Bio. The institution of Dr. Christine has received research support from Aspen Neurosciences.
Aristide Merola, MD, PhD (The Ohio State University)	Dr. Merola has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Abbvie. Dr. Merola has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Abbott. Dr. Merola has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Frontiers in Neurology.
Nicolás Phielipp, MD (UCI Health, WEN center)	No disclosure on file
Bradley Elder	No disclosure on file
Paul Larson	No disclosure on file
Waldy San Sebastian	No disclosure on file
Massimo Fiandaca	No disclosure on file
Adrian Kells	No disclosure on file
Krystof Bankiewicz (The Ohio State University)	No disclosure on file