2024 American Academy of Neurology Abstract Website

Phillip Pearl¹, Donald Gilbert², Bruria Ben-Zeev³, Daniel Curry⁴, Scellig Stone¹, Matthew Vestal⁵, Rafael Sierra⁶, Vinay Penematsa⁶, Antonia Wang⁶, Lee Golden⁶, Paul Wuh-Liang Hwu⁷
¹Deparment of Neurology, Boston Children's Hospital, Harvard Medical School, ²Pediatrics and Neurology Cincinnati Children's Hospital Medical Center, ³Sackler Faculty of Medicine, Tel Aviv University, ⁴Department of Neurosurgery, Section of Pediatric Neurosurgery, Baylor College of Medicine, ⁵Deparment of Neurosurgery, Duke University School of Medicine, ⁶PTC Therapeutics Inc., ⁷National Taiwan University

Objective:

The primary objectives of this open-label study were to assess the pharmacodynamics of eladocagene exuparvovec and the safety of the SmartFlow magnetic resonance (MR)-compatible ventricular cannula for administering eladocagene exuparvovec in pediatric participants with ʟ-amino acid decarboxylase (AADC) deficiency.

Background:

Eladocagene exuparvovec gene therapy, delivered via bilateral intraputaminal infusion, has been evaluated in participants with the rare neurotransmitter disorder AADC deficiency in three clinical trials.

Design/Methods:

Thirteen children (aged 16–129 months) with AADC deficiency received eladocagene exuparvovec using the SmartFlow MR-compatible ventricular cannula in this phase 2 multicenter open-label trial in the USA, Israel and Taiwan. Cerebrospinal fluid (CSF) homovanillic acid (HVA) levels and intraputaminal uptake of [¹⁸F] fluorodopa (F-DOPA) were assessed at week 8 to evaluate pharmacodynamic evidence of dopamine production. Safety and tolerability of the cannula used for gene therapy delivery were assessed over 8 weeks.

Results:

Baseline mean (SD) age of the 13 participants was 45.2 (29.5) months. All participants showed motor developmental delay. Floppiness was recorded as severe, moderate or mild in nine (69.2%), two (15.4%) and two (15.4%) participants, respectively. Post-gene therapy, mean (SD) CSF HVA levels increased significantly from 22.5 (32.3) nmol/L at baseline to 53.9 (44.4) nmol/L at week 8 (p<0.001). F-DOPA levels increased significantly from 0.098 (0.074) at baseline to 0.343 (0.040) at week 8 (p<0.001). Common adverse events (AEs) recorded in >20% of participants in the 8 weeks post-gene therapy included pyrexia, dyskinesia, hypotension, anemia, diarrhea, hypokalemia and hypophosphatemia. Treatment-emergent AEs were deemed unrelated (n=12 participants) or unlikely related (n=1 participant) to the SmartFlow MR-compatible surgical device.

Conclusions:

CSF HVA levels and F-DOPA uptake increased significantly 8 weeks post-eladocagene exuparvovec gene therapy in pediatric participants with AADC deficiency, indicating dopamine production. No treatment-emergent AEs were deemed related to the SmartFlow MR-compatible surgical device used for gene therapy delivery.