Pegzilarginase-nbln (Loargys)

Number: 1101

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

---

Policy

Scope of Policy

This Clinical Policy Bulletin addresses pegzilarginase-nbln (Loargys) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

Precertification of pegzilarginase-nbln (Loargys) is required of all Aetna participating providers and members in applicable plan designs. For precertification of pegzilarginase-nbln (Loargys), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

Note: Site of Care Utilization Management Policy applies. For information on site of service for pegzilarginase-nbln (Loargys), see Utilization Management Policy on Site of Care for Specialty Drug Infusions. 

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with a physician who specializes in the treatment of enzyme or metabolic disorders.

2. Criteria for Initial Approval

   Aetna considers pegzilarginase-nbln (Loargys) medically necessary for the treatment of arginase 1 deficiency (ARG1-D) when all of the following criteria are met:

   1. The member is 2 to less than 32 years of age; and
   2. The member has elevated plasma arginine levels (i.e., greater than or equal to 250 micromol/L) prior to initiating therapy with the requested medication; and
   3. The diagnosis of ARG1-D is confirmed by one of the following:
      
       i. Pathogenic (or likely pathogenic) variant in the ARG1 gene; or
      ii. Enzyme assay demonstrating a deficiency of arginase enzyme activity (i.e., less than 1% of normal) in erythrocytes; and
      
      
   4. The requested medication will be used in conjunction with dietary protein restriction; and
   5. The member has not had active infection requiring anti-infective therapy within 3 weeks of initiating treatment with the requested medication; and
   6. The member does not have known, active infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C; and
   7. The member does not have a history of hypersensitivity to polyethylene glycol that, in the opinion of the provider, puts the member at unacceptable risk for adverse events; and
   8. The member has not received previous liver or hematopoietic transplant procedure; and
   9. Baseline and subsequent pre-dose plasma arginine levels will be collected and monitored as outlined in the manufacturer’s prescribing information; and
   10. The dose of the requested medication will be adjusted as outlined in the manufacturer’s prescribing information if the member’s pre-dose plasma arginine levels fall outside of the therapeutic range (i.e., 50 micromol/L to 150 micromol/L); and
   11. Initial and subsequent doses of the requested medication will not exceed 0.2 mg/kg once weekly.

   Aetna considers all other indications as experimental, investigational, or unproven.

3. Continuation of Therapy

   Aetna considers continuation of pegzilarginase-nbln (Loargys) therapy medically necessary in members requesting reauthorization for the treatment of ARG1-D when all of the following criteria are met:

   1. The member has not received liver or hematopoietic transplant procedure; and
   2. Either of the following criteria apply:
       
      1. The member has achieved a pre-dose plasma arginine level between 50 micromol/L and 150 micromol/L; or
      2. The member has not achieved a pre-dose plasma arginine level between 50 micromol/L and 150 micromol/L, and the dose of the requested medication will be adjusted as outlined in the manufacturer’s prescribing information; and

   3. The requested dose does not exceed 0.2 mg/kg once weekly.

Dosage and Administration

Loargys is available in single-dose vials containing either 2 mg/0.4 mL or 5 mg/1 mL for intravenous or subcutaneous injection. Loargys is administered under the supervision of a healthcare provider experienced in managing hypersensitivity reactions, including anaphylaxis, and is initiated in a healthcare setting equipped with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment.

The recommended starting dosage is 0.1 mg/kg administered via intravenous infusion once weekly. Maximum recommended dosage is 0.2 mg/kg once weekly. 

After 8 weeks of once weekly intravenous dosing, persons may be switched to once weekly subcutaneous Loargys at the same dosage of the intravenous therapy. 

See Full Prescribing Information for additional dosage and administration information.

Source: Immedica Pharma US, 2026a

---

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
Testing Pathogenic (or likely pathogenic) variant in the ARG1 gene - No specific code
38204	Management of recipient hematopoietic progenitor cell donor search and cell acquisition
38205	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; allogeneic
38206	autologous
38207	Transplant preparation of hematopoietic progenitor cells; cryopreservation and storage
38208	thawing of previously frozen harvest, without washing, per donor
38209	thawing of previously frozen harvest, with washing, per donor
38210	specific cell depletion within harvest, T-cell depletion
38211	tumor cell depletion
38212	red blood cell removal
38213	platelet depletion
38214	plasma (volume) depletion
38215	cell concentration in plasma, mononuclear, or buffy coat layer
38230	Bone marrow harvesting for transplantation; allogeneic
38232	autologous
38240	Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38241	autologous transplantation
38243	HPC boost
47133	Donor hepatectomy (including cold preservation), from cadaver donor
47135	Liver allotransplantation, orthotopic, partial or whole, from cadaver or living donor, any age
47140	Donor hepatectomy (including cold preservation), from living donor; left lateral segment only (segments II and III)
47141	total left lobectomy (segments II, III and IV)
47142	total right lobectomy (segments V, VI, VII and VIII)
47143	Backbench standard preparation of cadaver donor whole liver graft prior to allotransplantation, including cholecystectomy, if necessary, and dissection and removal of surrounding soft tissues to prepare the vena cava, portal vein, hepatic artery, and common bile duct for implantation; without trisegment or lobe split
47144	with trisegment split of whole liver graft into 2 partial liver grafts (ie, left lateral segment [segments II and III] and right trisegment [segments I and IV through VIII])
47145	with lobe split of whole liver graft into 2 partial liver grafts (ie, left lobe [segments II, III, and IV] and right lobe [segments I and V through VIII])
47146	Backbench reconstruction of cadaver or living donor liver graft prior to allotransplantation; venous anastomosis, each
47147	arterial anastomosis, each
82131	Amino acids; single, quantitative, each specimen
82657	Enzyme activity in blood cells, cultured cells, or tissue, not elsewhere specified; nonradioactive substrate, each specimen
96365 – 96368	Intravenous infusion, for therapy, prophylaxis, or diagnosis
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met::
Pegzilarginase-nbln (Loargys) - No specific code
Other HCPCS codes related to the CPB:
S2140	Cord blood harvesting for transplantation, allogeneic
S2142	Cord blood-derived stem-cell transplantation, allogeneic
S2150	Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days of pre-and post-transplant care in the global definition
ICD-10 codes covered if selection criteria are met:
E72.21	Argininemia
ICD-10 codes not covered for indications listed in the CPB:
B16.0 – B16.9	Acute hepatitis B
B17.0	Acute delta-(super) infection of hepatitis B carrier
B17.10 – B17.11	Acute hepatitis C
B18.0	Chronic viral hepatitis B with delta-agent
B18.1	Chronic viral hepatitis B without delta-agent
B18.2	Chronic viral hepatitis C
B19.20 – B19.21	Unspecified viral hepatitis C
B20	Human immunodeficiency virus [HIV] disease
Z21	Asymptomatic human immunodeficiency virus [HIV] infection status
Z88.8	Allergy status to other drugs, medicaments and biological substances [history of hypersensitivity to polyethylene glycol]

---

Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Loargys is indicated for the treatment of hyperargininemia in adult and pediatric patients two 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.

Pegzilarginase-nbln, branded as Loargys (Immedica Pharma US, Inc.), is a recombinant, human arginase-1 enzyme that provides an exogenous source of the deficient human arginase 1 enzyme activity in patients with arginase 1 deficiency. It works by converting plasma arginine into urea and ornithine, thereby reducing arginine levels.

While there are no reported contraindications for Loargys, it does come with boxed warnings and precautions for hypersensitivity reactions, including anaphylaxis. Life-threatening hypersensitivity reactions have been reported in patients receiving enzyme replacement therapies (ERTs) like Loargys. In clinical trials, 13% (6 out of 48) of patients treated with Loargys experienced mild to moderate hypersensitivity reactions, which included facial swelling, rash, flushing, and dyspnea. The reactions generally occurred with the first few doses, but may also occur later in treatment. Patients receiving Loargys who developed anti-drug antibodies (ADA) had a higher incidence of hypersensitivity reactions compared to those who did not. Anaphylaxis has been observed both early in the course of ERT and after prolonged treatment.

There is currently no data available on the use of Loargys in pregnant women to assess the risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Animal reproduction studies have shown that intravenous administration of pegzilarginase-nbln to pregnant rats and rabbits during organogenesis resulted in maternal toxicity and an increased incidence of fetal growth deficiencies. The background risk of major birth defects and miscarriage in the indicated population remains unknown, although all pregnancies carry a baseline risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is between 2% to 4% and 15% to 20%, respectively. Additionally, there is no information regarding the presence of pegzilarginase-nbln in human or animal milk, its effects on breastfed infants, or its impact on milk production.

The most common adverse reactions (10% or more) includes vomiting, pyrexia, infusion associated reactions and constipation.

Arginase 1 Deficiency

Arginase 1 deficiency (ARG1‑D) is a debilitating genetic metabolic disorder and autosomal recessive urea cycle disorder caused by pathogenic variants in the ARG1 gene, resulting in impaired arginine metabolism and persistent hyperargininemia. Unlike other urea cycle disorders characterized by recurrent severe hyperammonemia, ARG1‑D typically presents in early childhood with a progressive neurodegenerative phenotype dominated by spastic diplegia or quadriplegia, developmental and motor delays, intellectual disability, and seizures. Early symptoms may include irritability, feeding difficulties, vomiting, and failure to thrive, with hyperammonemia occurring less frequently and generally with lower severity than in proximal urea cycle defects. If untreated, the disorder is associated with cumulative neurologic injury and significant lifelong morbidity (Bin Sawad et al., 2022; Sun et al., 2020). ARG1‑D is rare, affecting an estimated 250 people living in the U.S (Immedica Pharma US, 2026a). Global birth prevalence is estimated at 2.8 cases per million live births, with population prevalence at 1.4 cases per million people (approximately 1 in 726,000 individuals) (Catsburg et al., 2022). Management of ARG1-D focuses on lowering chronically elevated plasma arginine and managing nitrogen buildup to prevent progressive spasticity, seizures, and cognitive decline. Therapy includes a strictly controlled low-protein diet with essential amino acid supplementation, alongside nitrogen-scavenger medications (Diaz et al., 2023; Sun et al., 2020).

In February 2026, the U.S. Food and Drug Administration (FDA) granted accelerated approval of Loargys for the treatment of hyperargininemia in adult and pediatric patients 2 years of age and older with ARG1-D, in conjunction with dietary protein restriction. Approval was based on efficacy results from a multicenter, randomized, double‑blind, placebo‑controlled study (NCT03921541), which included a long‑term open‑label extension period of up to 150 weeks, that evaluated pegzilarginase for the treatment of hyperargininemia in pediatric and adult patients with ARG1‑D. The trial took place across seven countries (i.e., United States, United Kingdom, Canada, Austria, France, Germany, and Italy). During the 24‑week double‑blind period, 32 patients were randomized 2:1 to receive weekly intravenous pegzilarginase (n=21) or placebo (n=11), in addition to background dietary management and ammonia scavenger therapy, as applicable. Enrolled patients ranged in age from 2 to 29 years, with 90% pediatric. The primary efficacy endpoint was the change from baseline in plasma arginine levels at Week 24, while key secondary endpoints included the change from baseline at Week 24 in the Gross Motor Function Measure part E (GMFM-E) and the 2-minute walk test (2MWT). Study outcomes show that pegzilarginase‑treated patients demonstrated a statistically significant and clinically meaningful reduction in plasma arginine compared with placebo, with a mean reduction of 74% from baseline and 90% of treated patients achieving plasma arginine levels below 200 μM, compared with 0% of placebo‑treated patients. All patients who completed the double‑blind phase entered the open‑label extension, with a median pegzilarginase exposure of 94 weeks (range, 62 to 152 weeks) excluding the double‑blind period. During this extension, patients who crossed over from placebo to pegzilarginase achieved reductions in mean plasma arginine levels comparable to those observed in patients treated with pegzilarginase from study initiation. Pegzilarginase was well-tolerated, with adverse events primarily being transient and of mild to moderate severity (Immedica Pharma US, 2026b; Russo et al., 2024).

In summary, arginase 1 deficiency is a rare, debilitating genetic metabolic disorder associated with progressive neurologic morbidity and substantial lifelong burden despite standard dietary and supportive management. Loargys is approved under the FDA’s accelerated approval pathway based on its ability to significantly reduce plasma arginine levels, a surrogate biochemical endpoint reasonably likely to predict clinical benefit. Loargys has the potential to impact the management of ARG1-D in patients with few clinical options. Continued approval for this indication may be contingent upon verification and description of clinical benefit in an ongoing or future confirmatory trial.

---

References