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Cited by 89Parkinson's Disease Mechanisms and TreatmentsVirus-based gene therapy researchDeep Brain Stimulation and Movement Disorders

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

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Christine, Chadwick W., Richardson, R. Mark, Van Laar, Amber D., Thompson, Marin E., Fine, Elisabeth M., Khwaja, Omar S., Li, Chunming, Liang, Grace S., Meier, Andreas, Roberts, Eiry W., Pfau, Madeline L., Rodman, Josh R., Bankiewicz, Krystof S., Larson, Paul S.·2022·Neurology
DOI 10.1212/wnl.0000000000012952PMC PMC8726573
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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 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. 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.

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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 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.CC BY-NC-ND · PubMed Central
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 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.CC BY-NC-ND · PubMed Central
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 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.CC BY-NC-ND · PubMed Central
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 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.CC BY-NC-ND · PubMed Central
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.
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.CC BY-NC-ND · PubMed Central

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  1. Factor S, Van Laar A, Richardson R, et al. AADC gene therapy administered via a posterior approach: 18-month results from the PD-1102 trial in advanced Parkinson's disease. Mov Disord. 2020;35(suppl 1); Abstract 889.

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Authors
Christine, C. W., Richardson, R. M., Van Laar, A. D., Thompson, M. E., Fine, E. M., Khwaja, O. S., Li, C., Liang, G. S., Meier, A., Roberts, E. W., Pfau, M. L., Rodman, J. R., Bankiewicz, K. S., & Larson, P. S.
Affiliations
  • Harvard University (US)
  • From the Departments of Neurology (C.W.C.) and Neurological Surgery (M.E.T., K.S.B., P.S.L.), University of California, San Francisco; Department of Neurosurgery (R.M.R.), Massachusetts General Hospital; Harvard Medical School (R.M.R.), Boston, MA; Department of Neurology (A.D.V.L.), University of Pittsburgh Medical Center, PA; Brain Neurotherapy Bio (A.D.V.L.), Inc., Columbus, OH; Voyager Therapeutics, Inc. (E.M.F., O.S.K., C.L., A.M.), Cambridge, MA; Neurocrine Biosciences, Inc. (G.S.L., E.W.R.),...
Corresponding author
Christine, Chadwick W.
ORCID
Venue
Neurology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2022-01-04
Volume
98
Issue
1
Pages
e40-e50
ISSN
  • 0028-3878 (ISSN-L)
  • 1526-632X
DOI
10.1212/wnl.0000000000012952
PMC
PMC8726573
OpenAlex
W3206548941
Cited by
89
References
27
Citations by year
2026: 15 · 2025: 18 · 2024: 28 · 2023: 14 · 2022: 14
FWCI
6.70
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Neurology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Health Sciences › Medicine › Clinical Neurology › Deep Brain Stimulation and Movement Disorders
Keywords
Parkinson's disease, gene therapy, AAV2 vector, motor fluctuations, dose escalation, safety, motor function, quality of life
MeSH terms
Amino Acids, Antiparkinson Agents, Carboxy-Lyases, Humans, Parkinson Disease, Quality of Life, Genetic Therapy, Treatment Outcome

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