Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease

Abstract

Background and Objectives 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.Methods 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 × 1011 vector genomes (vg); cohort 2, ≤1.5 × 1012 vg; cohort 3, ≤4.7 × 1012 vg.Results 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 Parkinson's 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 Parkinson's Disease Questionnaire) were stable or improved compared with baseline at 12, 24, and 36 months following VY-AADC01 administration across cohorts.Discussions 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.Trial Registration Information NCT01973543.Classification of Evidence 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.AADC=L-amino acid decarboxylase; AAV2=adeno-associated virus serotype 2; AE=adverse event; CED=convection-enhanced delivery; CGI-I=Clinical Global Impression–Improvement; DBS=deep brain stimulation; DVT=deep vein thrombosis; 18F-DOPA=(18)F-fluoro-l-dihydroxyphenylalanine; FDA=Food and Drug Administration; GPi=globus pallidus interna; hAADC=human amino acid decarboxylase; ITT=intent-to-treat; LED=levodopa equivalent dose; mH&Y=modified Hoehn & Yahr; MR=magnetic resonance; NHP=nonhuman primate; PD=Parkinson disease; PDQ-39=39-item Parkinson's Disease Questionnaire; PGI-I=Patient Global Impression of Improvement; SAE=serious adverse event; SEM=standard error of the mean; TEAE=treatment-emergent adverse event; UCSF=University of California, San Francisco; UDysRS=Unified Dyskinesia Rating Scale; UPDRS=Unified Parkinson's Disease Rating Scale; UPMC=University of Pittsburgh Medical Center; vg=vector genome