Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial

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.

Figure 1. Participant Flow Diagram for the PD-1101 Trial

PD-1101 was a phase 1b, open-label, dose escalation trial of VY-AADC01 in participants with moderately advanced Parkinson disease. Of the 2 participants excluded from enrollment, 1 participant had an elevated anti-AAV2 antibody titer and the other participant had a modified Hoehn & Yahr score below the inclusion criteria. Participants were screened for eligibility within 60 days of VY-AADC01 administration and followed for 36 months after administration. All participants were included in analyses.

Figure 2. AADC Enzyme Activity, VY-AADC01 Putaminal Coverage, and LED Change From Baseline by Cohort in PD-1101

(A) Coverage and l-amino acid decarboxylase (AADC) enzyme activity data shown are mean percent coverage (total putamen coverage and posterior putamen coverage) and percent AADC increase from baseline. Error bars represent SEM. Change from baseline in AADC enzyme activity was measured using ¹⁸F-DOPA PET 5–6 months after VY-AADC01 administration. The change in AADC enzyme activity as measured by ¹⁸F-DOPA PET correlated with total putamen coverage. (B) Levodopa equivalent dose (LED) changes from baseline at months 12, 24, and 36 are shown as mean change in mg/day ± SEM. Daily PD medication requirements were decreased from baseline in cohorts 2 and 3 throughout the trial. A sensitivity analysis that excluded the participant in cohort 1 who underwent deep brain stimulation resulted in a mean ± SEM change from baseline of 531 ± 465 mg/day at month 36.

Figure 3. PD Diary “Off” Time and “On” Times at Baseline and Months 12, 24, and 36

Data shown are mean hours normalized to a 16-hour waking day. Change from baseline (CFB) at 36 months is reported to the right of each panel. PD diary “off” time and good “on” time (sum of “on” time with no dyskinesia and “on” time with nontroublesome dyskinesia [NTD]) were stable or improved from baseline throughout the trial. In a sensitivity analysis that excluded the participant in cohort 1 who underwent deep brain stimulation, “off” time and good “on” time (mean ± SEM) at month 36 were 3.4 ± 1.5 hours and 12.3 ± 1.6 hours, respectively. TD = troublesome dyskinesia.

Figure 4. Changes From Baseline in UPDRS III Scores

(A) “Off” medication. (B) “On” medication. Data shown are mean change in points ± SEM. Unified Parkinson's Disease Rating Scale (UPDRS) III “off”-medication scores improved in all cohorts throughout the trial, and “on”-medication scores improved in cohorts 2 and 3 throughout the trial. A sensitivity analysis that excluded the participant in cohort 1 who underwent deep brain stimulation resulted in a mean ± SEM change from baseline of −17.3 ± 4.5 points (“off” medication) and 0.8 ± 2.4 points (“on” medication) at month 36.

Figure 5. Changes From Baseline in PDQ-39 Summary Index Score at Months 12, 24, and 36

Data shown are mean change in points ± SEM. Quality of life (39-item Parkinson's Disease Questionnaire [PDQ-39]) scores were improved throughout the trial in cohort 2, and at months 12 and 24 in cohort 3. A sensitivity analysis that excluded the participant in cohort 1 who underwent deep brain stimulation resulted in a mean ± SEM change from baseline of −0.6 ± 4.6 points at month 36.