Parkinson Disease Gene Therapy VY-AADC01 Proves Safe With Signs of Efficacy


Three-year data from a phase 1 study of Voyager Therapeutics’ VY-AADC01 suggest it is safe and offers potential benefits for patients with Parkinson disease.

Chadwick Christine, MD, neurologist, Parkinson's Disease and Movement Disorders Clinic, UCSF

Chadwick Christine, MD

Three-year data from 2 cohorts of patients with advanced Parkinson disease (PD) showed that treatment with VY-AADC01 resulted in the need for substantially fewer antiparkinsonian medications, and stable or improved motor function and quality of life.

All told, the gene therapy and corresponding delivery procedure were well-tolerated over the 3-year period, and when taken in context with a second phase 1 open-label assessment, support the continued clinical development of AAV2-hAADC therapy in patients with PD. A double-blind, sham-controlled, phase 2 trial, RESTORE-1 (NCT03562494) is underway.

The experimental AAV2 gene therapy encoding human aromatic L-amino acid decarboxylase (AADC) from Voyager Therapeutics was administered via bilateral, intraoperative MRI-guided putaminal infusions to 3 cohorts of 15 patients. The data, compiled by Chadwick Christine, MD, neurologist at the Parkinson's Disease and Movement Disorders Clinic at UCSF, and colleagues, were presented at the 2020 MDS Virtual Congress, September 12–16, 2020.

Christine and colleagues noted that the findings in Cohorts 2 and 3 were "consistent with those reported at earlier timepoints, demonstrating the durability of response over time," adding that these cohorts showed a greater increase in AADC enzyme activity from baseline to 6 months compared with Cohort 1.

“The absence of a clear dose response between Cohorts 2 and 3 may be due to the small number of participants per cohort and inherent variability in individual participant baseline characteristics,” Christine et al. wrote, pointing to the efficacy outcomes potentially being impacted by higher modified Hoehn and Yahr scores and Unified Dyskinesia Rating Scale scores in the third cohort.

Cohort 1 was administered ≤7.5x1011 vg, while Cohort 2 received ≤1.5x1012 vg, and Cohort 3 was given ≤4.7x1012 vg. This presentation included the mean changes from baseline to 3 years for Cohorts 2 and 3.

Patient requirements for PD medications were reduced for both Cohort 2 and Cohort 3, as measured by levodopa-equivalent dose reductions, with the groups showing reductions of 608.5 mg (±243.3) and 440.7 mg (±72.6), respectively. Parkinson’s Disease Questionnaire scores also decreased, by 5.6 (±1.9) for Cohort 2 and 2.15 (±8.1) in Cohort 3.

Meanwhile, reports of motor function and quality of life were either improved or stable. According to patient diaries, good “on” time without troublesome dyskinesia increased by 2.2 hours (±1.7) in Cohort 2 and 0.3 hours (±0.7) in Cohort 3. Likewise, “off” time decreased by 1.9 hours (±0.5) and 0.15 hours (±0.9) in Cohorts 2 and 3, respectively. At baseline, Cohorts 2 and 3 had 10.64 hours and 10.32 hours of good “on” time, respectively, and 4.28 hours and 4.66 hours of “off” time, respectively.

United Parkinson’s Disease Rating Scale-III scores improved both on and off medication for both groups. For Cohort 2, scores were reduced by 7.8 (±1.6) on medication and 12.2 (±3.3) off medication. For Cohort 3, on medication and off medication scores were reduced by 3.8 (±1.5) and 10.2 (±4.6), respectively. Baseline scores for Cohort 2 were 35.8 and for Cohort 3 were 38.2.

No serious adverse events (AEs) related to VY-AADC01 were reported. All 4 nondrug-related serious AEs—atrial fibrillation and pulmonary embolism in 1 participant, and 2 small intestinal obstructions in another (occurred 6 days apart, 29 months post-procedure)—were ultimately resolved. The most common AEs reported were headache (Cohort 1: n = 5; Cohort 2: n = 3; Cohort 3: n = 3) and hypoesthesia (Cohort 1: n = 3; Cohort 2: n = 1; Cohort 3: n = 3).

For more coverage of MDS 2020, click here.

Christine C, Richardson R, Van Laar A, et al. Three-year safety and clinical outcomes from the PD-1101 trial of AADC gene therapy for advanced Parkinson’s disease. Presented at: MDS Virtual Congress; September 12–16, 2020. Abstract 879.
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