Loargys

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION • Administer LOARGYS under the supervision of a health care provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. ( 2.1 ) • Initiate LOARGYS in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. ( 2.1 ) • Consider pre‑medication with antihistamines. ( 2.1 ) • Obtain a baseline plasma arginine concentration prior to initiating treatment. ( 2.1 ) • Recommended starting dosage of LOARGYS is 0.1 mg/kg administered by intravenous infusion once weekly. ( 2.2 ) • Maximum recommended dosage is 0.2 mg/kg once weekly. ( 2.2 ) • See the Full Prescribing Information for recommended titration and maintenance dosage and recommended plasma arginine level testing during treatment. ( 2.2 ) • After eight weeks of once weekly intravenous LOARGYS, patients may be switched to once weekly subcutaneous LOARGYS at the same dosage of intravenous therapy. ( 2.4 ) • See Full Prescribing Information for dosage and administration modifications due to hypersensitivity reactions. ( 2.5 ) • See Full Prescribing Information for instructions on preparation, storage, and administration. ( 2.7 , 2.8 , 2.9 , 2.10 ) 2.1 Recommendations Prior to LOARGYS Treatment • Administer LOARGYS under the supervision of a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis [see Warnings and Precautions ( 5.1 )] . • Initiate LOARGYS in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment [see Warnings and Precautions ( 5.1 )] . • Obtain a baseline plasma arginine concentration. • Consider pre-medication with antihistamines [see Warnings and Precautions ( 5.1 )] . 2.2 Recommended Dosage and Administration The recommended starting dosage of LOARGYS is 0.1 mg/kg administered via intravenous infusion once weekly [see Dosage and Administration ( 2.9 )] . For the recommended dosage use actual body weight. Recommended Adjustment, Maximum Dosage, and Monitoring To maximize the time within the normal range of 40 to 115 micromolar, dose adjustments should be aimed at achieving a pre-dose level of plasma arginine near the upper limit of normal (ULN). After four weeks of LOARGYS administration, measure pre-dose plasma arginine (168 hours after prior dose) to determine the need for dosage adjustment. If two consecutive weekly pre-dose plasma arginine measurements are not in the desired therapeutic range, increase or decrease the weekly LOARGYS dosage as follows: • Below 50 micromolar, reduce the weekly LOARGYS dosage by 0.05 mg/kg. • Above 150 micromolar, increase the weekly LOARGYS dosage by 0.05 mg/kg. The maximum recommended LOARGYS dosage is 0.2 mg/kg once weekly. Monitor plasma arginine levels (prior to LOARGYS dosing) weekly for 2 weeks after any LOARGYS dosage adjustment and as clinically indicated. Patients may be switched from intravenous administration of LOARGYS to subcutaneous administration [see Dosage and Administration ( 2.4 )] . 2.3 Collect Plasma Arginine Using Specific Collection Tubes and Measure Arginine Concentration Using a Specific Assay Collect samples into Immedica Pharma’s Nor-NOHA Blood Collection Tubes, which contain Nω-hydroxy-nor-Arginine (nor-NOHA), an enzyme inhibitor used to inhibit post-sampling degradation of arginine by LOARGYS, and measure arginine concentration using Immedica Pharma’s LOARGYS Arginine Assay. LOARGYS is only available to a patient if the patient is enrolled in Study IMM-PEG-005 to obtain Immedica Pharma’s Nor-NOHA Blood Collection Tubes and LOARGYS Arginine Assay. Further information is available by contacting Immedica Pharma at 1‑844‑627‑4687. 2.4 Switching Patients from Intravenous to Subcutaneous LOARGYS Administration After eight weeks of once weekly intravenous LOARGYS, patients may be switched to once weekly subcutaneous LOARGYS at the same dosage of intravenous therapy. 2.5 Dosage and Administration Modifications Due to Hypersensitivity Reactions In the event of a severe hypersensitivity reaction (e.g., anaphylaxis), discontinue LOARGYS and immediately initiate appropriate medical treatment, including use of epinephrine. For additional recommendations in the event of a severe hypersensitivity reaction, [see Warnings and Precautions ( 5.1 )] . In the event of a mild or moderate hypersensitivity reaction, consider treatment with antihistamines and/or corticosteroids. For intravenous administration, consider temporarily holding the infusion or slowing the infusion rate. 2.6 Recommendation Regarding a Missed Dose If a dose is missed, administer LOARGYS as soon as possible. Do not administer two LOARGYS doses on the same day or within four days of another dose to make up for a missed dose. Ensure there is a minimum of four days between doses. 2.7 Preparation Instructions for Subcutaneous or Intravenous Administration Use aseptic technique when preparing and administering LOARGYS for subcutaneous or intravenous administration. 1. Determine the number of LOARGYS vials needed based on actual body weight in kg and the recommended dose [see Dosage and Administration ( 2.2 )] . Round the calculated volume of LOARGYS to nearest 0.1 mL. 2. Remove the vial(s) from the refrigerator and allow the vial(s) to reach room temperature. 3. Visually inspect the solution in the vials for particulate matter and discoloration. The solution should be clear to slightly opalescent, colorless to slightly yellow or slightly pink. Discard the vial(s) if the solution is not consistent with this appearance or if visible particulate matter is present. 4. Use a syringe to withdraw the calculated volume from the vial(s). 5. Discard unused portion. Do not dilute the withdrawn volume of LOARGYS solution for subcutaneous administration. However, dilute the withdrawn volume of LOARGYS solution for intravenous administration. Dilution Instructions for Intravenous Administration 1. Dilute the withdrawn volume of LOARGYS solution in 0.9% Sodium Chloride Injection to a maximum concentration of 0.5 mg/mL. 2. Gently invert the infusion bag to mix the solution. Avoid vigorous shaking or agitation. 2.8 Storage of the Diluted LOARGYS Solution for Intravenous Use and the Undiluted LOARGYS Solution for Subcutaneous Use Use LOARGYS immediately after preparation. If not used immediately, store the diluted solution for intravenous use in the infusion container, and the undiluted solution for subcutaneous use in the syringe for up to: • 2 hours at room temperature at 20°C to 25°C (68°F to 77°F) or • 4 hours if stored refrigerated at 2°C to 8°C (36°F to 46°F). Discard LOARGYS if not administered within these time frames, including total infusion time if administered intravenously. 2.9 Intravenous or Subcutaneous Administration Instructions For Intravenous Administration • Administer the diluted LOARGYS infusion intravenously over at least 30 minutes. • After LOARGYS infusion, use 0.9% Sodium Chloride Injection to flush the line. • Do not mix other drugs with LOARGYS or co-administer other drugs through the same intravenous line. For Subcutaneous Administration • Administer the undiluted solution subcutaneously into the abdomen, lateral part of the thigh, or the side or back of the upper arms. If injecting into the abdomen, avoid the area directly surrounding the navel. • If more than 1 injection is needed for a single dose of LOARGYS, the injection sites should be at least 1 inch apart. • Do not inject into scar tissue or areas that are reddened, inflamed, or swollen. • Rotate injection sites between doses. 2.10 Subcutaneous Administration of LOARGYS at Home If patients tolerate maintenance subcutaneous administration of LOARGYS, they may receive subcutaneous administration at home under the supervision of a healthcare provider. When switching patients from subcutaneous administration in a supervised clinical setting to the home, initially use the same dose. Do not change the dose without supervision of a healthcare provider. In the case of a missed dose or delayed injection, contact a healthcare provider as subsequent injections may need to occur in a supervised clinical setting.

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS 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.

6 ADVERSE REACTIONS 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.