Objective: To describe changes over the first year in disease severity and activities of daily living using modified Hoehn and Yahr (mH&Y) stage and UPDRS II in PD-1101, an open-label study of VY-AADC01 for advanced Parkinson’s disease (PD) with motor fluctuations despite optimal medical management.

Background: VY-AADC01 is an experimental AAV2 gene therapy encoding human aromatic L-amino acid decarboxylase (AADC). In PD-1101, 3 cohorts (n=5 patients/cohort) received intraoperative MRI-guided infusions of VY-AADC01 into bilateral putamen with escalating doses of ≤7.5×10^11 vector genomes (vg), ≤1.5×10^12 vg, and ≤4.7×10^12 vg for cohorts 1, 2, and 3, respectively. Administration of VY-AADC01 was well tolerated, and improvements were seen in measures of motor function relative to baseline, particularly in cohorts 2 and 3 [1]. This report presents data on additional efficacy outcomes assessed in the study.

Method: Outcomes measured at 6 and 12 months included mH&Y stage off medication and UPDRS II.

Results: All patients had lower mH&Y stage at 6 and 12 months compared to baseline. Of 13 patients with stage 3 mH&Y at baseline, 2 decreased to stage 2.5, 10 to stage 2, and 1 to stage 1 at 12 months. Of 2 patients with stage 4 mH&Y at baseline, 1 decreased to stage 2.5 and 1 to stage 2 at 12 months post-administration. Decreases in mH&Y scores were consistent with previously-reported improvements in motor function off medication [1] and paralleled improvements on the Clinical Global Impression of Change [1], an assessment of overall function. Changes in clinician-assessed measures of disease severity were accompanied by improvements in patient-reported outcomes in cohorts 2 and 3. Mean±SE UPDRS II off medication scores decreased from baseline by 3.4±1.2 points in cohort 2 and by 4.4±1.4 points in cohort 3 at 12 months, with minimal change in cohort 1. Decreases in cohorts 2 and 3 exceeded 3 points, the minimal clinically important change in UPDRS II for patients with mH&Y of 2.5 and 3 [2]. These changes paralleled previously-reported improvements in patient-reported quality of life (PDQ-39 score) [1].

Conclusion: These findings from this phase 1b study at 12 months show the potential of the experimental VY-AADC01 gene therapy to improve clinician- and patient-reported outcomes in PD with motor fluctuations despite optimal medical management.

References: 1. Christine CW, Bankiewicz KS, Van Laar AD, et al. MRI-guided phase 1 trial of putaminal AADC gene therapy for Parkinson’s disease. Ann Neurol. Published online: February 25, 2019 (doi: 10.1002/ana.25450). 2. Schrag A, Sampaio C, Counsell N, Poewe W. Minimal clinically important change on the unified Parkinson’s disease rating scale. Mov Disord 2006; 21: 1200-1207.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/longitudinal-analysis-of-the-modified-hoehn-and-yahr-disease-stage-in-pd-1101-a-phase-1b-clinical-study-of-vy-aadc01/