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What is Arginase 1 Deficiency?

What is Arginase 1 Deficiency?

ARG1-D is a chronic genetic condition, driven by elevated plasma arginine levels, resulting in potentially severe manifestations1,2
  • ARG1-D is an ultra-rare, progressive, inherited metabolic disease caused by variants in the ARG1 gene that results in impaired or absent arginase 1 enzyme activity1,3
  • Under normal conditions, arginine is hydrolyzed in the liver by the arginase 1 enzyme into ornithine and urea in the last step of the urea cycle1
  • With impaired or absent enzyme activity, arginine and arginine-related metabolites, such as guanidino compounds, accumulate and are associated with neuromotor pathology1
  • Symptomatic hyperammonemia and hyperammonemic crisis are less common in ARG1-D1
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ARG1-D leads to progressive cognitive and functional decline and may result in early mortality 1,4
Loargys molecular structure

Elevated arginine is the hallmark feature of ARG1-D1

Persistently elevated levels of arginine in patients with ARG1-D are key drivers of disease manifestations, including progressive spasticity, developmental delay, and seizures.1

Current treatment guidelines for ARG1-D recommend lowering plasma arginine levels to reduce disease burden.1,5

Arginine Levels

There is a need for a treatment that can lower arginine

The symptoms and progressive manifestations of ARG1-D are challenging and burdensome for patients and their families.6,7

The current standard of care for ARG1-D does not affect endogenous arginine production and is thus not sufficient for sustainably normalizing plasma arginine levels over time.1,8

The guideline-recommended target level for plasma arginine of <200 micromolar is above the upper limit of normal and may not be an optimal therapeutic target level for arginine.1,5

*The normal range for plasma arginine levels is 40-115 micromolar.1

Treatment Guideline Chart

Prevalence

The exact prevalence of ARG1-D is not known
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Worldwide, ARG1-D occurs with an estimated median prevalence of 1 case per million people in the general population, although ranges are broad.9 
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The estimated median prevalence of ARG1-D within the urea cycle disorder population is 3.8%.9
The prevalence of ARG1-D does not vary by geography, ethnicity, or sex.3,9

ARG1-D may be more common than previously thought

Estimates of ARG1-D prevalence are limited by inconsistencies in newborn screening and high rates of misdiagnosis.10

Infants icon 1
Based on a genetic database analysis, birth and population prevalence in the US are as follows11:
  • 1.5 estimated cases per million live births†
  • ~250 patients (0.75 estimated cases per million people)
†Adjusted for estimated consanguinity rates for the US.11

The clinical presentation of ARG1-D is heterogeneous3

Manifestations typically start in childhood, although symptoms can appear later in life due to accumulating levels of plasma arginine.3

Initial onset is typically confined to the lower limbs; however, as spasticity worsens, the upper limbs can also become affected.3

Persistently high plasma levels of arginine and arginine-related metabolites increase the risk of significant morbidity and early mortality.1

Symptoms often mimic other neurologic and neurometabolic disorders, which can result in misdiagnosis1,3

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Progressive neurological symptoms

Unlike cerebral palsy, which is non-progressive, ARG1-D may show progressive neurological deterioration, including worsening spasticity, loss of motor skills, or intellectual disability.1,3,12
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Family history

ARG1-D is an autosomal recessive disorder, so a family history of similar symptoms or known pathogenic variants can be an indicator.12
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Onset and age of symptoms

While cerebral palsy and hereditary spastic paraplegia typically start early and remain stable, ARG1-D can progress over time, often becoming more noticeable in later childhood or adulthood.3,12,13
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Elevated plasma arginine

ARG1-D is characterized by elevated levels of arginine in the blood due to the deficiency of the enzyme arginase 1, a feature not present in cerebral palsy or hereditary spastic paraplegia.1

ARG1-D is a heterogeneous, progressively debilitating disease‡

‡The associated clinical response of this product is not yet confirmed.
Progression DT v2
Progression MOB v2
If your patient is experiencing ARG1-D–related symptoms, measure arginine levels and consider ordering a genetic test to confirm the diagnosis
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Find information on access and reimbursement when prescribing LOARGYS.

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References: 1. Diaz GA, et al. The role and control of arginine levels in arginase 1 deficiency. J Inherit Metab Dis. 2023;46(1):3-14. 2. Amayreh W, et al. Treatment of arginase deficiency revisited: guanidinoacetate as a therapeutic target and biomarker for therapeutic monitoring. Dev Med Child Neurol. 2014;56:1021-1024. 3. Carvalho DR, et al. Clinical features and neurologic progression of hyperargininemia. Pediatr Neurol. 2012;46:369-374. 4. Schlune A, et al. Hyperargininemia due to arginase I deficiency: the original patients and their natural history, and a review of the literature. Amino Acids. 2015;47:1751-1762. 5. Häberle J, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. 2019;1-39. 6. Olofsson S, et al. Disease burden among patients with Arginase 1 deficiency and their caregivers: A multinational, cross-sectional survey. J Inherit Metab Dis. 2024;65:450-460. 7. Olofsson S, et al. Societal costs and quality of life associated with arginase 1 deficiency in a European setting – a multinational, cross-sectional survey. J Med Econ. 2024;27(1):1146-1156. 8. Burrage LC, et al. Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency. Hum Mol Genet. 2015;24(22):6417-6427. 9. Bin Sawad A, et al. Epidemiology, methods of diagnosis, and clinical management of patients with arginase 1 deficiency (ARG1-D): a systematic review. Mol Genet Metab. 2022;137(1-2):153-163. 10. Therrell BL, et al. Newborn screening for hyperargininemia due to arginase 1 deficiency. Mol Gen Metab. 2017;121:308-313. 11. Catsburg C, et al. Arginase 1 deficiency: using genetic databases as a tool to establish global prevalence. Orphanet J Rare Dis. 2022;17(1):94. 12. Sun A, et al. Arginase deficiency. In: Adams MP, et al, eds. GeneReviews®. Seattle, WA: University of Washington, Seattle; 2020. 13. Sin YY, et al. Arginase-1 deficiency. J Mol Med (Berl). 2015;93:1287-1296. 14. McNutt MC, et al. Arginase 1 deficiency in patients initially diagnosed with hereditary spastic paraplegia. Mov Discord Clin Pract. 2022;10(1):109-114.

IMPORTANT SAFETY INFORMATION

WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS
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Initiate LOARGYS in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue LOARGYS, and immediately initiate appropriate medical treatment, including use of epinephrine.

WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions Including Anaphylaxis: Life-threatening hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with enzyme replacement therapies, including LOARGYS. Hypersensitivity reactions that were mild to moderate in severity occurred in 13% (6/48) of LOARGYS-treated subjects in clinical trials. Hypersensitivity reactions have included facial swelling, rash, flushing and dyspnea. The reactions generally occurred with the first few doses but may occur later in treatment.

Administration of LOARGYS should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis in a healthcare setting with appropriate medical monitoring and support measures. Premedication with an antihistamine and/or corticosteroid should be considered in patients who previously have developed a hypersensitivity reaction. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue LOARGYS and immediately initiate appropriate medical treatment, including use of epinephrine. Consider the risks and benefits of re-administering LOARGYS in patients who have experienced a severe hypersensitivity reaction. Caution should be exercised upon rechallenge. Inform patients of the symptoms of life-threatening hypersensitivity reactions and to seek immediate medical attention should symptoms occur. If a mild or moderate reaction occurs, consider treatment with antihistamines and/or corticosteroids.

ADVERSE REACTIONS

The most common adverse reactions are vomiting, pyrexia, infusion associated reactions and constipation.

USE IN SPECIFIC POPULATIONS

Pregnancy: There are no available data on LOARGYS use in pregnant females to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

Lactation: There is no data on the presence of LOARGYS in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LOARGYS and any potential adverse effects on the breast-fed infant from LOARGYS or from the underlying maternal condition.

Pediatric: The safety and effectiveness of LOARGYS have been established for the reduction of plasma arginine in pediatric patients 2 years and older with ARG-1 D, in conjunction with dietary protein restriction. The safety and effectiveness of LOARGYS have not been established for the reduction of plasma arginine in pediatric patients aged less than 2 years with ARG-1 D.

Geriatric: Clinical studies of LOARGYS did not include subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.

Indication

LOARGYS is an arginine specific enzyme indicated for the treatment of hyperargininemia in adult and pediatric patients 2 years of age and older with Arginase 1 Deficiency (ARG1-D), in conjunction with dietary protein restriction.

This indication is approved under accelerated approval based on reduction of plasma arginine. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.