Abstract
BACKGROUND: Arginase 1 Deficiency (ARG1-D) is a rare debilitating, progressive, inherited, metabolic disease characterized by marked increases in plasma arginine (pArg) and its metabolites, with increased morbidity, substantial reductions in quality of life, and premature mortality. Effective treatments that can lower arginine and improve clinical outcomes is currently lacking. Pegzilarginase is a novel human arginase 1 enzyme therapy. The present trial aimed to demonstrate efficacy of pegzilarginase on pArg and key mobility outcomes. METHODS: This Phase 3 randomized, double-blind, placebo-controlled, parallel-group clinical trial (clinicaltrials.govNCT03921541, EudraCT 2018-004837-34), randomized patients with ARG1-D 2:1 to intravenously/subcutaneously once-weekly pegzilarginase or placebo in conjunction with their individualized disease management. It was conducted in 7 countries; United States, United Kingdom, Canada, Austria, France, Germany, Italy. Primary endpoint was change from baseline in pArg after 24 weeks; key secondary endpoints were change from baseline at Week 24 in Gross Motor Function Measure part E (GMFM-E) and 2-min walk test (2MWT). Full Analysis Set was used for the analyses. FINDINGS: From 01 May 2019 to 29 March 2021, 32 patients were enrolled and randomized (pegzilarginase, n = 21; placebo, n = 11). Pegzilarginase lowered geometric mean pArg from 354.0 μmol/L to 86.4 μmol/L at Week 24 vs 464.7 to 426.6 μmol/L for placebo (95% CI: -67.1%, -83.5%; p < 0.0001) and normalized levels in 90.5% of patients (vs 0% with placebo). In addition, clinically relevant functional mobility improvements were demonstrated with pegzilarginase treatment. These effects were sustained long-term through additional 24 weeks of subsequent exposure. Pegzilarginase was well-tolerated, with adverse events being mostly transient and mild/moderate in severity. INTERPRETATION: These results support pegzilarginase as the first potential treatment to normalize pArg in ARG1-D and achieve clinically meaningful improvements in functional mobility. FUNDING: Aeglea BioTherapeutics.