Pegzilarginase 2mg/0.4ml solution for injection vials

ABSTRACT Arginase 1 deficiency (ARG1‐D) is an autosomal recessive urea cycle disorder characterised by chronic hyperargininaemia, progressive spasticity, loss of mobility, and cognitive dysfunction. Standard of care (SOC), based on dietary protein restriction, rarely prevents progression. Pegzilarginase, a recombinant human enzyme, is the first approved disease‐modifying therapy. We report outcomes from Study 102A ( n  = 14; up to 5 years) and the PEACE long‐term extension (LTE) ( n  = 31; up to 3 years). Weekly pegzilarginase was administered with SOC. Outcomes included functional mobility (2‐/6‐minute walk tests [2MWT/6MWT], Gross Motor Function Measure [GMFM] D/E), spasticity (Modified Ashworth Scale [MAS]), plasma arginine, guanidino compounds, and safety. In PEACE, LTE arms were named according to initial 24‐week double‐blind treatment: placebo–pegzilarginase or pegzilarginase–pegzilarginase. Of 39 evaluable participants, 37 (95%) met composite response or achieved maximum score in ≥ 1 motor function domain. In 102A, mean 6MWT improved to 68.2 m (+19%; n  = 12); GMFM‐D/E increased by 2.7/3.7. In PEACE (pegzilarginase–pegzilarginase; placebo–pegzilarginase), 2MWT improved to 16.5 m (+25%; n  = 6) and 13.5 m (+16%; n  = 2); GMFM‐D/E improved by 4.3/6.0 ( n  = 6) and 5.3/11.3 ( n  = 3). Spasticity improved in 21/25 (84%), with 12 reaching MAS 0 (no spasticity). Pegzilarginase sustained plasma arginine control: in 102A, means were 118 μmol/L at Week 192 ( n  = 9); in PEACE,  50%. Most adverse events were mild/moderate; no treatment‐related discontinuations or persistent antibodies occurred. Pegzilarginase produced sustained improvements in mobility, spasticity and biochemical control, supporting early intervention, long‐term use and disease modification in ARG1‐D.

Abstract licence: CC BY 4.0

Arginase 1 deficiency (ARG1‐D) is an ultra‐rare inherited metabolic disorder of the urea cycle, caused by partial or complete loss of arginase 1 function, characterised by hyperargininaemia and a distinct, progressive neurological phenotype. The clinical development programme of pegzilarginase, a recombinant human ARG1 enzyme therapy, provides an opportunity to study the largest ARG1‐D cohort to date. The analysis included 48 paediatric and adult subjects (≥ 2 years) enrolled in the pegzilarginase trials. Baseline data collected before treatment included demographics, genotypes, red blood cell arginase activity, biochemical measures, age of symptom onset, neuromotor and neurological characteristics, growth indicators, quality of life, and use of treatments and assistive devices. The mean (SD) age of onset was 2.2 (3.6) years, which preceded diagnosis at 3.7 (5.0) years. Clinical features included motor impairment (48/48, 100%), spasticity (33/48, 69%), cognitive deficits (31/48, 65%), intellectual disability (23/36, 64%), speech and language deficits (26/48, 54%), and seizures (18/48, 38%), with symptom‐onset data consistent with a progressive phenotype. Median GMFCS Level II indicated moderate mobility limitation; two‐thirds scored < 69 on FSIQ, and mean PedsQL total proxy scores were around 20% lower than typically developing peers. All subjects followed a protein‐restricted diet, and 90% used ammonia scavengers. ARG1‐D presents with a heterogeneous array of progressive and debilitating neurologic symptoms. These findings reflect the progressive impact of the disease and offer insights into its burden and natural history based on a large cohort, assessed using standardised neuromotor, cognitive, and quality‐of‐life instruments across international sites.

Abstract licence: CC BY

Background: 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. Methods: 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). Results: 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. Conclusions: 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.

Abstract licence: CC BY 4.0

ABSTRACT Pegzilarginase is the first disease‐modifying drug for arginase 1 deficiency. In clinical trials, pegzilarginase effectively normalised plasma arginine (pArg), which was associated with clinically relevant improvements in neuromotor outcomes. We report from a French early access scheme the first report on experience from pegzilarginase therapy outside a clinical trial. Sixteen patients were started in the programme between September 2022 and September 2024. Six had previously participated in a clinical trial (PCT) and 10 were treatment naïve (TN). Clinical data was collected at baseline, after 3 months, and then 6‐monthly. Mean pegzilarginase exposure was 78.9 weeks. Fourteen patients had been treated for ≥ 12 months. At the 3‐month follow‐up, mean pArg had dropped from 430 to 128 μmol/L (70%) for the TN group and from 168 to 107 μmol/L (36%) for the PCT group. Interestingly, one patient discontinued after 69 weeks of therapy due to absence of decrease of pArg despite stepwise increase of dose. After discontinuation of pegzilarginase, the presence of anti‐drug antibodies (ADAs) was confirmed. For the whole cohort, average daily intake of dietary protein increased from 0.61 to 0.91 g/kg/day during the first 12 months (p = 0.02). No firm conclusions could be drawn from quality‐of‐life data, but trends were positive. In conclusion, our results are in line with what has been previously reported from clinical trials.

Abstract licence: CC BY 4.0

AbstractHyperargininemia in patients with arginase 1 deficiency (ARG1‐D) is considered a key driver of disease manifestations, including spasticity, developmental delay, and seizures. Pegzilarginase (AEB1102) is an investigational enzyme therapy which is being developed as a novel arginine lowering approach. We report the safety and efficacy of intravenously (IV) administered pegzilarginase in pediatric and adult ARG1‐D patients (n = 16) from a Phase 1/2 study (101A) and the first 12 weeks of an open‐label extension study (102A). Substantial disease burden at baseline included lower‐limb spasticity, developmental delay, and previous hyperammonemic episodes in 75%, 56%, and 44% of patients, respectively. Baseline plasma arginine (pArg) was elevated (median 389 μM, range 238‐566) on standard disease management. Once weekly repeat dosing resulted in a median decrease of pArg of 277 μM after 20 cumulative doses (n = 14) with pArg in the normal range (40 to 115 μM) in 50% of patients at 168 hours post dose (mean pegzilarginase dose 0.10 mg/kg). Lowering pArg was accompanied by improvements in one or more key mobility assessments (6MWT, GMFM‐D & E) in 79% of patients. In 101A, seven hypersensitivity reactions occurred in four patients (out of 162 infusions administered). Other common treatment‐related adverse events (AEs) included vomiting, hyperammonemia, pruritus, and abdominal pain. Treatment‐related serious AEs that occurred in five patients were all observed in 101A. Pegzilarginase was effective in lowering pArg levels with an accompanying clinical response in patients with ARG1‐D. The improvements with pegzilarginase occurred in patients receiving standard treatment approaches, which suggests that pegzilarginase could offer benefit over existing disease management.

Abstract licence: CC BY-NC-ND 4.0