PD-1102: A Phase 1 study of VY-AADC01 Administered Using a Posterior Approach in Patients with Parkinson’s Disease and Motor Fluctuations (P1.8-017)

Objective: Evaluate safety, putaminal coverage, aromatic L-amino acid decarboxylase (AADC) activity, and clinical outcomes at 12 months in patients with Parkinson’s disease and motor fluctuations treated with VY-AADC01, an AAV2-AADC vector-based therapy administered to bilateral putamen. Background: The phase 1 study (PD-1101) showed improved putaminal coverage, AADC activity, and clinical outcomes with dose escalation and improved administration of VY-AADC. This study (PD-1102) changed to a single administration trajectory per putamen targeting the posterior tail, with a goal of increasing coverage and improving clinical outcomes. Design/Methods: Eight subjects with similar baseline characteristics to those in PD-1101 were administered up to 2.6×1012 vg/mL in up to 1.8 mL per putamen (total dose up to 9.4×1012 vg) using a single parietal-occipital trajectory per putamen, optimizing vector delivery to motor areas in postcommisural putamen. VY-AADC01 was admixed with gadoteridol, allowing real-time MR imaging of the location and volume of infusate; AADC activity was assessed by (18)F-DOPA PET at baseline and Results: At baseline, mean age was 56.8 years and mean PD duration 9.2 years; subjects reported a mean 6.8 hours of diary OFF time and 9.1 hours of diary ON time. There were no vector-related serious adverse events; two subjects experienced mild surgical intra-cerebral hemorrhage, which resolved without residual deficits. Mean VY-AADC01 coverage of the putamen was 53.5%. AADC activity by (18)F-DOPA PET increased to levels similar to healthy adults (Feigin, 2002) and there was a 33% reduction in the need for antiparkinsonian medications. Diary ON and OFF times, and UPDRS at 12 months will be reported. Conclusions: Modifying the neurosurgical administration of VY-AADC01 resulted in increased putaminal coverage and associated AADC activity. Together with the reductions in antiparkinsonian medications, these findings suggest potential clinical benefit. Disclosure: Dr. Van Laar has received research support from Biogen, The Michael J. Fox Foundation and Voyager Therapeutics, Inc. Dr. Richardson has received research support from Voyager Therapeutics, Inc. Dr. Christine has received research support from The Michael J. Fox Foundation and Voyager Therapeutics, Inc. Dr. Factor has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Neurocrine, Lundbeck, Teva, Avanir, Sunovion, Adamas, Prexton, Biogen. Dr. Factor has received research support from Ipsen, Medtronics, Teva, US World Meds, Sunovion, Solstice, Vaccinex, Voyager, CHDI Foundation, Michael J. Fox Foundation, NIH. Dr. Gross has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Medtronic, Boston Scientific, Neuropace, Biomet Zimmer, and Abbott. Dr. Gross has received research support from Medtronic, Boston Scientific, Neuropace, and Voyager. Dr. Kostyk has nothing to disclose. Dr. Lonser has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Voyager and GE Healthcare. Dr. Lonser has received personal compensation in an editorial capacity for Elsevier. Dr. Lonser has received royalty, license fees, or contractual rights payments from NIH. Dr. de Somer has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Voyager Therapeutics. Dr. Sedkov has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Voyager Therapeutics and Acorda Therapeutics. Dr. Sedkov has received compensation for serving on the Board of Directors of Accorda Therapeutics. Dr. Ravina has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Voyager therapeutics. Dr. Kells has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Voyager Therapeutics. Dr. Bankiewicz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Voyager, Medicenna. Dr. Bankiewicz has received royalty, license fees, or contractual rights payments from UCSF. Dr. Bankiewicz holds stock and/or stock options in Voyager which sponsored research in which Dr. Bankiewicz was involved as an investigator. Dr. Bankiewicz has received research support from Voyager. Dr. Larson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with St Jude Medical, Medtronic, Inc.. Dr. Larson has received research support from Voyager and MRI Interventions.