Efficacy and safety of pegzilarginase in patients below 2 years of age with arginase 1 deficiency: a phase 3, open-label, multi-centre study

Background Arginase 1 Deficiency (ARG1-D) is a rare metabolic disorder characterized by marked hyperargininaemia and progressive neurological impairment. Dietary protein restriction alone is often insufficient to normalize plasma arginine (pArg) or prevent disease progression. Pegzilarginase, a recombinant human ARG1 enzyme therapy, has demonstrated pArg normalization and improved clinical outcomes in patients ≥2 years. This study evaluated safety, pharmacokinetics (PK), and activity of pegzilarginase in patients <2 years. Methods In this phase 3, open-label, single-arm study (NCT06582524, EU CT 2024-510797-25), conducted in United Kingdom, Austria and Portugal, patients received once-weekly subcutaneous pegzilarginase. As primary endpoint, change in pArg at 12 weeks was assessed. Secondary endpoints included safety, PK, plasma ornithine and Gross Motor Function Measure (GMFM-66). Descriptive analyses were performed on the Full Analysis Set. Findings Three patients (mean age 20.3 months) were included between 30 August 2024 and 17 June 2025. After 12 weeks, mean (SD) pArg decreased by 221.5 (81.3) μmol/L, a 70.6% (4.3) reduction, reaching normal range by Visit 4 (114.1 [68.4] μmol/L). Plasma ornithine increased and plasma ammonia remained largely normal. GMFM-66 total scores improved by 21.0 (13.9) points (18.1% [5.8%]). Pegzilarginase exposure was consistent with previous studies; AUC and half-life were similar, whereas clearance and volume of distribution were lower, as expected in infants. No new safety findings were observed. Interpretation In patients with ARG1-D <2 years of age, pegzilarginase demonstrated pharmacokinetic and pharmacodynamic responses comparable to older children and a favourable safety profile. Funding Immedica Pharma AB.