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

Chadwick W Christine; R Mark Richardson; Amber D Van Laar; Marin E Thompson; Elisabeth M Fine; Omar S Khwaja; Chunming Li; Grace S Liang; Andreas Meier; Eiry W Roberts; Madeline L Pfau; Josh R Rodman; Krystof S Bankiewicz; Paul S Larson

doi:10.1212/WNL.0000000000012952

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

Neurology. 2022 Jan 4;98(1):e40-e50. doi: 10.1212/WNL.0000000000012952. Epub 2021 Oct 14.

Affiliations

¹ 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.), San Diego, CA; ApotheCom (M.L.P., J.R.R.), New York, NY; and Department of Neurological Surgery (K.S.B.), Ohio State University, Columbus. chad.christine@ucsf.edu.
² 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.), San Diego, CA; ApotheCom (M.L.P., J.R.R.), New York, NY; and Department of Neurological Surgery (K.S.B.), Ohio State University, Columbus.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids / genetics
Amino Acids / therapeutic use
Antiparkinson Agents / adverse effects
Carboxy-Lyases* / therapeutic use
Genetic Therapy / methods
Humans
Parkinson Disease* / drug therapy
Quality of Life
Treatment Outcome

Substances

Amino Acids
Antiparkinson Agents
Carboxy-Lyases

Associated data

ClinicalTrials.gov/NCT01973543