2026-07-06 | Efficacy and safety of pegzilarginase in patients below 2 years of age with arginase 1 deficiency: a phase 3, open-label, multi-centre study.
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. 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. 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. In patients with ARG1-D <2 years of age, pegzilarginase demonstrated pharmacokinetic and pharmacodynamic responses comparable to older children and a favourable safety profile. Immedica Pharma AB.
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2026-05-27 | Pegzilarginase in Arginase 1 Deficiency: Clinical and Biochemical Effects of Treatment Initiation, Discontinuation and Re-Initiation.
Arginase 1 deficiency (ARG1-D) is an ultra-rare urea cycle disorder characterized by hyperargininemia and progressive neurological impairment, including spasticity, loss of motor function, and reduced quality of life. Conventional management based on dietary protein restriction and ammonia scavengers rarely achieves adequate metabolic control or prevents neurological deterioration. Pegzilarginase, a recombinant human arginase 1 enzyme, is the first disease-modifying therapy for ARG1-D. We report the first Italian real-world experience with pegzilarginase in three pediatric patients with genetically confirmed ARG1-D enrolled in the phase 3 PEACE trial. Clinical, biochemical, functional, nutritional and quality-of-life data were retrospectively collected over a long-term follow-up (2003-2025). Outcomes were evaluated across three phases: treatment initiation (Start), a 13-month treatment interruption due to trial closure (Stop), and therapy re-initiation through an early access program (Restart). Pegzilarginase rapidly normalized plasma arginine levels and was associated with improvements in motor function, spasticity, walking endurance, dietary protein tolerance, bone mineral density, and quality of life. During treatment interruption, all patients experienced biochemical worsening and clinical deterioration, including increased spasticity, reduced mobility, and emotional distress. Re-initiation of pegzilarginase restored metabolic control and led to progressive neurological and functional recovery, including partial reversal of long-standing motor deficits. This real-world experience supports pegzilarginase as a disease-modifying therapy for ARG1-D. Sustained normalization of plasma arginine, rather than subthreshold biochemical control, correlates with functional and neurological improvement and may partially reverse non-lesional metabolic brain injury. Early initiation of pegzilarginase, including in newborn-screened patients, may further modify the natural history of ARG1-D.
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2026-05-13 | Extracellular Vesicles Delivered a Functional ARG1 Enzyme and Restored Its Activity in a Mouse Model of ARG1-D Resulting in Improved Lifespan.
Arginase 1 (ARG1) deficiency (ARG1-D) is a rare genetic disorder due to loss of ARG1, the final enzyme in the urea cycle. ARG1-D hepatocytes are impaired in converting arginine into urea, resulting in elevated peripheral arginine and ammonia, which leads to progressive neurological symptoms. Current therapeutic strategies mainly focus on managing plasma arginine and ammonia level, but long-term outcomes remain poor. While no approved treatment specific for ARG1-D is available in the United States, a recombinant protein-based enzyme replacement therapy is available in Europe. Recently, extracellular vesicles (EVs) are emerging as a powerful therapeutic vehicle. By using Capricor's StealthXTM platform, EVs were engineered to express human ARG1 on their surface or encapsulated within. Regardless of their localization on the EV membrane, nanograms of ARG1 carried by EVs were biologically active and able to convert arginine into urea as potent as micrograms of human recombinant ARG1 (rHuArg1). Furthermore, ARG1-encapsulating EVs (STX-Arg1-in) were able to deliver ARG1 intracellularly but not EVs carrying ARG1 on their surface or rHuArg1. STX-Arg1-in EVs were further evaluated in a series of in vivo studies, and the results showed that STX-Arg1-in EVs were non-toxic and able to restore arginase activities in the liver of Arg1-/- mice, which led to a lowered plasma arginine concentration similar to that in wild-type mice. Most importantly, Arg1-in EVs expanded the lifespan of the lethal neonatal Arg1 deficiency mouse model. Taken together, our data suggested StealthXTM-engineered STX-Arg1-in EVs have a better safety profile due to the extremely low dosage and have great potential as a novel enzyme replacement strategy for patients suffering from ARG1-D. Significance statement: Intracellular delivery of recombinant protein and improved llifespanare endpoints of successful enzyme replacement therapy for the treatment of ARG1-D. Using the StealthX platform, a fully functional ARG1 enzyme was engineered to be carried inside of the extracellular vesicles, which allowed for the intracellular delivery of ARG1 protein in vitro and in vivo, with an improvement of lifespan in a lethal neonatal mouse model of Arg1 deficiency. More importantly, no toxicity was observed, and efficacy was achieved with a low dose, setting the base for an improved therapeutic approach.
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