Pegzilarginase

LOARGYS is 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 [see Clinical Studies ( 14 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 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. ( 1 ) This indication is approved under accelerated approval based on reduction of plasma arginine. ( 14 ) Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. ( 1 )

LOARGYS (pegzilarginase-nbln) is a clear to slightly opalescent, colorless to slightly yellow or slightly pink solution. Injection: 2 mg/0.4 mL or 5 mg/mL in a single-dose vial. Injection: 2 mg/0.4 mL and 5 mg/mL in a single-dose vial. ( 3 )

None. None. ( 4 )

Hypersensitivity : If a severe hypersensitivity reaction occurs, discontinue LOARGYS and immediately initiate appropriate medical treatment, including epinephrine. ( 5.1 )

5.1 Hypersensitivity Reactions Including Anaphylaxis Life-threatening hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with enzyme replacement therapies (ERTs) including LOARGYS. Hypersensitivity reactions that were mild to moderate in severity occurred in 13% (6/48) of LOARGYS-treated patients in clinical trials [see Adverse Reactions ( 6 )] . Hypersensitivity reactions have included facial swelling, rash, flushing and dyspnea. The reactions generally occurred with the first few doses, but may also occur later in treatment. LOARGYS-treated patients who developed anti-drug antibodies (ADA) generally had a greater incidence of hypersensitivity reactions compared to those who did not develop ADA [see Adverse Reactions ( 6.1 )] . Anaphylaxis has occurred during the early course of ERT and after extended duration of ERT. Administration of LOARGYS should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Consider pre‑medication with an antihistamine. Corticosteroids can be considered in patients who have previously developed a hypersensitivity reaction. 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. Consider the risks and benefits of re-administering LOARGYS following a severe hypersensitivity reaction (including anaphylaxis). Caution should be exercised upon rechallenge. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur.
• If a mild or moderate hypersensitivity reaction occurs, consider treatment with antihistamines and/or corticosteroids. For intravenous administration, consider temporarily holding the infusion or slowing the infusion rate.

The following adverse reactions are described below and elsewhere in the labeling:

• Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] . Most common adverse reactions (>10%) are vomiting, pyrexia, infusion associated reactions and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Immedica at toll-free phone 1-844-627-4687 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of LOARGYS was evaluated in a randomized, double-blind, placebo-controlled trial in pediatric and adult patients with ARG1-D (Trial 1). Additional safety information was derived from Trial 2, a Phase 1 open-label trial that evaluated 16 patients between the ages of 5 to 31 years to assess safety, PK and PD of LOARGYS, and Trial 3, an open-label extension including 14 patients from Trial 2. Adverse Reactions from Trial 1 (Double-Blind Period) A total of 21 patients between the ages of 2 and 28 years of age, at enrollment, received intravenous LOARGYS dosages up to 0.2 mg/kg once weekly and 11 patients received placebo for 24 weeks [see Clinical Studies ( 14 )] . Table 1 summarizes the adverse reactions reported in ≥ 2 LOARGYS-treated patients and at a higher incidence in LOARGYS-treated patients compared to placebo-treated patients in Trial 1. Table 1: Common Adverse Reactions a in Pediatric and Adult Patients with ARG1-D in Trial 1 a Common adverse reactions were those that occurred in ≥ 2 LOARGYS-treated patients and at a higher incidence in LOARGYS-treated patients compared to placebo-treated patients. b Infusion-associated reactions are defined as reactions occurring within 4 hours after the infusion and included pruritus, arm swelling, and abdominal pain in LOARGYS-treated patients. c Includes reactions that were classified as hypersensitivity during the trial and reactions that were assessed as hypersensitivity based on symptoms and temporal relationship with drug. Adverse Reaction LOARGYS N = 21 n (%) Placebo N = 11 n (%) Vomiting 7 (33) 3 (27) Pyrexia 4 (19) 1 (9) Infusion Associated Reaction b 3 (14) 1 (9) Constipation 3 (14) 1 (9) Dizziness 2 (10) 0 Fall 2 (10) 0 Hypersensitivity c 2 (10) 0 Nasopharyngitis 2 (10) 0 Rhinorrhoea 2 (10) 0 Alanine aminotransferase increased 2 (10) 0 Aspartate aminotransferase increased 2 (10) 0 Description of Selected Adverse Reactions Hypersensitivity Reactions : Hypersensitivity reactions with symptoms including facial swelling, rash, flushing and dyspnea were reported in 13% (6/48) of LOARGYS-treated patients during clinical trials [see Warnings and Precautions ( 5.1 )] . Injection Site Reactions : Injection site reactions were reported in 14% (6/44) of patients after subcutaneous LOARGYS administration during the open-label extension periods in Trial 1 and Trial 3. Signs and symptoms included pain, erythema, swelling, irritation, and rash at the injection site. Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions Across Trials 1, 2, and 3, in patients with ARG1-D, the incidence of hypersensitivity reactions was 42% (5/12) in LOARGYS-treated patients who developed anti-drug antibodies (ADA) (i.e., anti-pegzilarginase-nbln antibodies and/or anti-PEG antibodies) and 3% (1/36) in those who were ADA-negative [see Clinical Pharmacology ( 12.6 )] .

8.1 Pregnancy Risk Summary 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. In animal reproduction studies, intravenous administration of pegzilarginase-nbln to pregnant rats and rabbits during organogenesis resulted in maternal toxicity with associated increased incidence of fetal growth deficiencies (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, 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 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryofetal development study in pregnant rats with normal circulating arginine levels, intravenous pegzilarginase-nbln was administered throughout organogenesis at 0.1, 0.3, and 1 mg/kg/dose on gestation days 6, 11, and 16. Maternal toxicity was observed as reduced body weight, reduced body weight gain, reduced food consumption and reduced mean gravid uterine weights at 1 mg/kg/dose (8-fold the human exposure, based on AUC at the maximum recommended human dose (MRHD), with associated decreases in fetal body weights and increased fetal developmental malformations and variations at this dose. In an embryofetal development study in pregnant rabbits with normal circulating arginine levels, intravenous pegzilarginase-nbln was administered throughout organogenesis at 0.06, 0.1, and 0.3 mg/kg/dose on gestation days 6, 13, and 20. Maternal toxicity was observed as decreased maternal body weights, food consumption and mean gravid uterine weights at 0.3 mg/kg/dose (3-fold the human exposure, based on AUC at the MRHD), with associated decreases in fetal body weights and increased developmental malformations and variations at this dose. In a pre- and postnatal development study in pregnant rats with normal circulating arginine levels, intravenous pegzilarginase-nbln was administered at 0.1, 0.3 and 1 mg/kg/dose once weekly from gestation day 6 to lactation day 20. Maternal toxicity included reduced body weight and food consumption during gestation and lactation with associated reduced pup body weight at 1 mg/kg/dose (8-fold the human exposure based on AUC at the MRHD). Male pups exposed to 1 mg/kg/dose through gestation and lactation also had impaired learning and memory in the passive avoidance test.

8.2 Lactation Risk Summary There are no data on the presence of pegzilarginase-nbln 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.

8.4 Pediatric Use The safety and effectiveness of LOARGYS have been established under accelerated approval for the treatment of hyperargininemia in pediatric patients 2 years of age and older with ARG1-D, in conjunction with dietary protein restriction [see Indications and Usage ( 1 )] . Use of LOARGYS for this indication is supported by evidence from an adequate and well-controlled trial in adult and pediatric patients that included 29 pediatric patients 2 to 17 years of age with ARG1-D (Trial 1) and additional safety information from an open-label extension trial in adult and pediatric patients that included 9 pediatric patients (Trial 3) [see Adverse Reactions ( 6.1 )] . The safety and effectiveness of LOARGYS have not been established for the treatment of hyperargininemia in pediatric patients less than 2 years of age with ARG1-D. Juvenile Animal Toxicity Data Juvenile rats with normal circulating arginine levels were administered once weekly intravenous pegzilarginase-nbln doses of 0.1, 0.3 and 1 mg/kg/dose from postnatal day 21 (the equivalent of a 2-year-old human) up to 13 weeks of age. At 1 mg/kg (15-fold the human exposure based on AUC at the MRHD), male and female rats showed increased incidence of tremors, salivation, and piloerection, along with reduced body weight and body weight gain. Reproductive organ effects were observed in male rats administered 1 mg/kg, including decreased sperm motility and total sperm count, increased percentage of abnormal sperm, and decreased epididymis, testes and prostate gland weights.

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

ARG1-D is an inherited metabolic disease characterized by deficiency of the arginase 1 enzyme and associated with the persistent elevation of plasma arginine. LOARGYS provides an exogenous source of the deficient human arginase 1 enzyme activity in patients with ARG1-D and reduces plasma arginine by converting it to urea and ornithine.