Pharmacodynamics, Efficacy, and Safety of Intraputaminal Eladocagene Exuparvovec Administered to Pediatric Patients With Aromatic L‐Amino Acid Decarboxylase Deficiency Using an MR ‐Compatible Cannula: 48 Weeks of Follow‐Up

ABSTRACT Aromatic ʟ‐amino acid decarboxylase (AADC) deficiency is a rare pediatric neurotransmitter disorder that typically necessitates lifelong care, and that carries a risk of childhood mortality. Eladocagene exuparvovec gene therapy is designed to restore AADC production. Study GT‐002 (NCT04903288) is a phase 2, multicenter, open‐label trial assessing the pharmacodynamics, safety, and efficacy of eladocagene exuparvovec administered to the putamen bilaterally in pediatric patients with AADC deficiency using a magnetic resonance (MR)‐compatible cannula. Patients received eladocagene exuparvovec at 1.8 × 10 11 vector genomes via the SmartFlow MR‐compatible cannula in a single operative session. Endpoints include the change from baseline in cerebrospinal fluid homovanillic acid levels, motor milestone achievement, and safety. Here we report results from 48 weeks of follow‐up. Mean (SD) cerebrospinal fluid homovanillic acid levels increased from baseline (22.5 [32.3] nmol/L; n = 13) to week 48 (55.3 [45.6] nmol/L; change from baseline: 28.3 [13.7] nmol/L; p = 0.0003; n = 9), indicating de novo dopamine production. At baseline ( n = 13), all patients showed severe motor developmental delay; at week 48 ( n = 12), nine achieved full head control, four could sit unassisted, two could stand with support, and two could walk independently to a toy. Overall, 260 treatment‐emergent adverse events were reported in 13 patients; 259 were deemed unrelated and one likely unrelated to the MR‐compatible cannula. No treatment‐emergent adverse events led to study withdrawal and no deaths occurred. This study provides further evidence of the favorable pharmacodynamic, efficacy, and safety profile of eladocagene exuparvovec in children with AADC deficiency; intraputaminal administration using an MR‐compatible cannula was well tolerated. Study GT‐002 (NCT04903288) provides further evidence of the favourable pharmacodynamic, efficacy and safety profile of eladocagene exuparvovec gene therapy in children with AADC deficiency over 48 weeks and demonstrates that intraputaminal administration using an MR‐compatible cannula was well tolerated, allowing for real‐time MRI confirmation of cannula placement and infusate coverage, and for accurate dosing to the putamen.