390 Efficacy of gene therapy with eladocagene exuparvovec in patients with AADC deficiency compared with natural history controls

Abstract

<h3></h3> Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder resulting in marked or complete loss of dopamine, impeding normal motor development. Eladocagene exuparvovec, a recombinant adeno-associated virus containing the human cDNA encoding the AADC enzyme, is in clinical development for treatment of AADC deficiency. Eladocagene exuparvovec was administered via bilateral infusion into the putamen of 28 children with AADC deficiency in 3 clinical trials (AADC-CU/1601 [8 patients, completed], AADC-010 [10 patients, ongoing], and AADC-011 [10 patients at data cutoff of 26 February 2020; ongoing]). Patients received a total dose of 1.8 × 1011 vg (n=21) or 2.4 × 1011 vg (n=7; AADC-011). Motor milestone achievement was assessed using the Peabody Developmental Motor Scales, 2nd Edition. Improvements in motor function from treated patients in the full analysis set were compared to 49 subjects from a comprehensive Natural History Database (NHDB). This database was derived from a systematic review of literature reporting data from patients with AADC deficiency. From an original pool of 237 patients, 49 were chosen as matched natural history controls. These natural history controls were chosen because they met the criteria of unique patients with confirmed AADC deficiency who had not participated in clinical trials of eladocagene exuparvovec, had documented lack of motor milestone achievement, and had a similar disease phenotype to patients in clinical trials. As early as 12 months after receiving eladocagene exuparvovec, 44% of patients achieved head control and 20% of subjects could sit unassisted. At 24 months after gene therapy, 64% of subjects achieved head control, 50% could sit unassisted, and 18% could stand with support. At 60 months after gene therapy, 75% of subjects achieved head control, 67% of subjects could sit unassisted, 25% of subjects could stand with support, and 8% subjects could walk with support. In contrast, only 4% of the subjects in the NHDB control group achieved key motor milestones (P&lt;0.0001 ). These results demonstrate that the attainment of milestones is sequential in nature and that the percentage of patients achieving more advanced milestones (eg, standing with support, walking with assistance) increases over time. The number of patients achieving full head control and sitting unassisted was significantly higher in patients treated with eladocagene exuparvovec compared to the NHDB control group. The results indicate that patients with AADC deficiency treated with eladocagene exuparvovec show significant improvements in achieving motor milestones, impacting the natural history of disease.