Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease
Chadwick W. Christine, R. Mark Richardson, Amber D. Van Laar, Marin E. Thompson, Elisabeth M. Fine, Omar Khwaja, Chunming Li, Grace Liang, Andreas Meier, Eiry W. Roberts, Madeline L. Pfau, Josh R. Rodman, Krystof S. Bankiewicz, Paul Larson
Abstract
<h3>Background and Objectives</h3> To report final, 36-month safety and clinical outcomes from the PD-1101 trial of NBIb-1817 (VY-AADC01) in participants with moderately advanced Parkinson disease (PD) and motor fluctuations. <h3>Methods</h3> PD-1101 was a phase 1b, open-label, dose escalation trial of VY-AADC01, an experimental AAV2 gene therapy encoding the human aromatic l-amino acid decarboxylase (AADC) enzyme. VY-AADC01 was delivered via bilateral, intraoperative MRI-guided putaminal infusions to 3 cohorts (n = 5 participants per cohort): cohort 1, ≤7.5 × 10<sup>11</sup> vector genomes (vg); cohort 2, ≤1.5 × 10<sup>12</sup> vg; cohort 3, ≤4.7 × 10<sup>12</sup> vg. <h3>Results</h3> No serious adverse events (SAEs) attributed to VY-AADC01 were reported. All 4 non-vector–related SAEs (atrial fibrillation and pulmonary embolism in 1 participant and 2 events of small bowel obstruction in another participant) resolved. Requirements for PD medications were reduced by 21%–30% in the 2 highest dose cohorts at 36 months. Standard measures of motor function (PD diary, Unified Parkinson9s Disease Rating Scale III “off”-medication and “on”-medication scores), global impressions of improvement (Clinical Global Impression of Improvement, Patient Global Impression of Improvement), and quality of life (39-item Parkinson9s Disease Questionnaire) were stable or improved compared with baseline at 12, 24, and 36 months following VY-AADC01 administration across cohorts. <h3>Discussions</h3> VY-AADC01 and the surgical administration procedure were well-tolerated and resulted in stable or improved motor function and quality of life across cohorts, as well as reduced PD medication requirements in cohorts 2 and 3 over 3 years. <h3>Trial Registration Information</h3> NCT01973543. <h3>Classification of Evidence</h3> This study provides Class IV evidence that, in patients with moderately advanced PD and motor fluctuations, putaminal infusion of VY-AADC01 is well tolerated and may improve motor function.