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Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial
Chadwick W Christine1, R Mark Richardson2, Amber D Van Laar2
1From 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.
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.
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