Pegunigalsidase Alfa

ELFABRIO is indicated for the treatment of adults with confirmed Fabry disease. ELFABRIO is a hydrolytic lysosomal neutral glycosphingolipid-specific enzyme indicated for the treatment of adults with confirmed Fabry disease. ( 1 )

Injection: 20 mg/10 mL or 5 mg/2.5 mL (2 mg/mL) of pegunigalsidase alfa-iwxj in a clear and colorless solution in a single-dose vial. Injection: 20 mg/10 mL or 5 mg/2.5 mL (2 mg/mL) solution in a single-dose vial. ( 3 )

None. None. ( 4 )

Infusion-Associated Reactions: If severe IARs occur, discontinue ELFABRIO and initiate appropriate medical treatment. ( 5.2 ) Membranoproliferative Glomerulonephritis: Monitor serum creatinine and urinary protein to creatinine ratio. Discontinue ELFABRIO if glomerulonephritis is suspected, until a diagnostic evaluation can be conducted. ( 5.3 )

5.1 Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity reactions including anaphylaxis have been reported in ELFABRIO-treated patients. In clinical trials, 20 (14%) of ELFABRIO-treated patients experienced hypersensitivity reactions. In these trials, 4 ELFABRIO-treated patients (3%; 1 naïve to enzyme replacement therapy (ERT) and 3 ERT-experienced patients) experienced anaphylaxis during the initial infusion and were positive for anti-pegunigalsidase alfa-iwxj IgE antibodies (referred to as IgE ADA) [see Adverse Reactions ( 6.1 6. 1 ) and Clinical Pharmacology ( 12.6 ) ] . The risk of pegunigalsidase alfa-iwxj-related hypersensitivity may be increased in certain patients with pre-existing ADA from prior ERT [ see Use In Specific Populations ( 8.6 )]. Anaphylaxis (reported as Type I hypersensitivity reaction, hypersensitivity reaction, or bronchospasm) occurred within 5 to 40 minutes of the start of the initial infusion. Signs and symptoms included headache, nausea, vomiting, throat tightness, facial and oral edema, truncal rash, tachycardia, hypotension, rigors, urticaria, intense pruritus, moderate upper airway obstructions, macroglossia, and mild lip edema. Patients received treatment that included epinephrine, antihistamines and/or systemic corticosteroids. Prior to ELFABRIO administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids. Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available during ELFABRIO administration. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue ELFABRIO immediately and initiate appropriate medical treatment. Consider the risks and benefits of re-administering ELFABRIO following severe hypersensitivity reactions (including anaphylaxis). Patients may be rechallenged using slower infusion rates. In patients with severe hypersensitivity reaction, desensitization measures to ELFABRIO may be considered. If the decision is made to readminister ELFABRIO, ensure the patient tolerates the infusion. If the patient tolerates the infusion, the rate may be increased to reach the recommended rate. If a mild or moderate hypersensitivity reaction occurs, consider temporarily holding the infusion or slowing the infusion rate [ see Dosage and Administratio n ( 2.3 ) ] . Consider monitoring patients who demonstrate hypersensitivity reactions during ELFABRIO treatment for the presence of IgG and IgE ADA [see Clinical Pharmacology ( 12.6 )] .

5.2 Infusion – Associated Reactions Infusion-associated reactions (IARs) have been reported in ELFABRIO-treated patients. In clinical trials, 41 (29%) of ELFABRIO-treated patients experienced one or more IARs, defined as any adverse reaction with onset after start of the infusion and up to 24 hours after the end of infusion. The risk of pegunigalsidase alfa-iwxj-related IARs may be increased in certain patients with pre-existing ADA from prior ERT [ see Use In Specific Populations ( 8.6 )]. IARs included anaphylaxis reactions during the initial ELFABRIO administration [see Warnings and Precautions ( 5.1 )] . In addition to the hypersensitivity reactions described above [see Warnings and Precautions ( 5.1 )] , other IARs included nausea, chills, pruritus, rash, chest pain, dizziness, vomiting, asthenia, pain, sneezing, dyspnea, nasal congestion, throat irritation, abdominal pain, erythema, diarrhea, burning sensation, neuralgia, headache, paresthesia, tremor, agitation, increased body temperature, flushing, bradycardia, myalgia, hypertension, and hypotension [see Adverse Reactions ( 6.1 )] . Up to 40% of patients were pretreated with diphenhydramine, prednisone and/or acetaminophen at least once during the clinical trials. Severe reactions in the trials were generally managed with administration of antipyretics, antihistamines, corticosteroids, intravenous fluids, and/or oxygen. IARs were more frequently observed in ELFABRIO-treated patients who developed IgG anti-drug antibodies (ADA) including patients who had pre-existing IgG ADA [see Adverse Reactions ( 6.1 6.1 ) and Clinical Pharmacology ( 12.6 ) ] . Consider monitoring patients who demonstrate IARs during ELFABRIO treatment for the presence of IgG and IgE ADA. Patients with advanced Fabry disease may have compromised cardiac function which may predispose them to a higher risk of severe complications from IARs. Closely monitor patients with compromised cardiac function if ELFABRIO is administered to these patients. Prior to ELFABRIO administration, consider pre-treating with antihistamines, antipyretics, and/or corticosteroids to reduce the risk of IARs. However, IARs may still occur in patients after receiving pre-treatment. If a severe IAR occurs, discontinue ELFABRIO immediately and initiate appropriate medical treatment. Consider the risks and benefits of re-administering ELFABRIO following a severe IAR. Patients may be rechallenged using slower infusion rates. Once a patient tolerates the infusion, the infusion rate may be increased to reach the recommended infusion rate. If a mild or moderate IAR occurs, consider temporarily holding the infusion or slowing the infusion rate [see Dosage and Administration ( 2.3 )] .

5.3 Membranoproliferative Glomerulonephritis A case of membranoproliferative glomerulonephritis with immune depositions in the kidney was reported during clinical trials [see Adverse Reactions ( 6.1 ) ] . This event led to a decline in renal function that slowly improved upon discontinuation of ELFABRIO but did not return to baseline by the end of the trial. Monitor serum creatinine and urinary protein to creatinine ratio. If glomerulonephritis is suspected, discontinue ELFABRIO until a diagnostic evaluation can be conducted.

The following clinically significant adverse reactions are described elsewhere in labeling: Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions ( 5.1 ) ] Infusion-Associated Reactions (IARs) [see Warnings and Precautions ( 5.2 )] Membranoproliferative Glomerulonephritis [see Warnings and Precautions ( 5.3 )] Most common adverse reactions (≥15%) are: infusion-associated reactions, nasopharyngitis, headache, diarrhea, fatigue, nausea, back pain, pain in extremity, and sinusitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chiesi USA, Inc. at 1-888-661-9260 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 trial of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions From Trial 2 The safety of ELFABRIO in adults with confirmed Fabry disease who had been previously treated with agalsidase beta was evaluated in Trial 2 which included a total of 52 ELFABRIO-treated patients (29 male, 23 female aged 20 to 60 years old) with Fabry disease [see Clinical Studies ( 14 )] . Patients received 1 mg/kg of ELFABRIO given intravenously every 2 weeks for at least 104 weeks. The most common adverse reactions (≥15%) reported with ELFABRIO were infusion-associated reactions which occurred in 17 patients (32%); followed by, nasopharyngitis and headache each in 11 patients (21%); diarrhea in 10 patients (19%); fatigue and nausea each in 9 patients (17%); and back pain, pain in extremity, and sinusitis each in 8 patients (15%) . One ELFABRIO-treated patient experienced a severe hypersensitivity reaction during the first infusion. The patient withdrew from the trial following a moderate hypersensitivity reaction during the second infusion. Table 3 lists adverse reactions reported in at least 5% of ELFABRIO-treated patients in Trial 2. Table 3: Adverse Reactions in Adults With Fabry Disease (Trial 2) 1 Adverse Reaction ELFABRIO N=52 n (%) Agalsidase beta N=25 n (%) Infusion-Associated Reaction 2,4 17 (32) 8 (32) Nasopharyngitis 11 (21) 4 (16) Headache 11 (21) 5 (20) Diarrhea 10 (19) 6 (24) Fatigue 9 (17) 4 (16) Nausea 9 (17) 3 (12) Back pain 8 (15) 5 (20) Pain in Extremity 8 (15) 4 (16) Sinusitis 8 (15) 3 (12) Abdominal Pain 6 (12) 0 (0) Proteinuria 6 (12) 0 (0) Hypersensitivity 3,4 5 (9) 4 (16) Upper Respiratory Tract Congestion 4 (8) 0 (0) Neuralgia 4 (8) 0 (0) Peripheral Neuropathy 3 (6) 0 (0) Sciatica 3 (6) 0 (0) Infusion Site Extravasation 3 (6) 0 (0) Hematuria 3 (6) 0 (0) 1 Adverse reactions were those that occurred in ≥ 5% of ELFABRIO-treated patients. 2 “Infusion-associated reaction” includes nausea, vomiting, abdominal pain, diarrhea, fatigue, chills, malaise, non-cardiac chest pain, hypersensitivity, body temperature increased, burning sensation, neuralgia, agitation, throat irritation, pruritic rash, and flushing. Events occurring within 24 hours. 3 “Hypersensitivity” includes macular rash, pruritic rash, and face swelling. Events occurring within 24 hours. 4 The events of hypersensitivity and pruritic rash fall in both hypersensitivity and IAR categories. Membranoproliferative Glomerulonephritis A case of membranoproliferative glomerulonephritis with immune depositions in the kidney was reported in an ELFABRIO-treated patient. Immunogenicity: Anti – D rug Antibody-Associated Adverse Reactions Of the patients who experienced serious hypersensitivity reactions during the first ELFABRIO infusion and had pre-infusion samples and samples available for testing at the time of the event, all but one had pre-existing IgE ADAs and all tested positive for IgE ADAs at the time of the reaction. In the overall clinical program, IARs occurred in 51% (19/37) of patients who were IgG ADA positive at baseline compared to 16% (13/84) in IgG ADA negative patients [see Clinical Pharmacology ( 12.6 )] .

8.1 Pregnancy Risk Summary There are no available data on ELFABRIO use in pregnant females to evaluate a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes; however, as an enzyme replacement, ELFABRIO is not expected to cause adverse outcomes . Animal reproduction studies have been conducted with pegunigalsidase alfa-iwxj in pregnant rats and rabbits. No adverse effects on embryofetal development were observed in pregnant rats intravenously administered pegunigalsidase alfa-iwxj twice per week at exposures up to 3.6 times that of the maximum recommended human dose (MRHD) (based on area under the concentration-time curve (AUC)). Maternal toxicity was observed in pregnant rabbits intravenously administered pegunigalsidase alfa-iwxj twice per week at doses that were ≥ 3.2 times the MRHD (based on human equivalent dose) [ see Data ] . The estimated background risk of major birth defects and miscarriage in 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. There is a pregnancy safety study for ELFABRIO. If a patient becomes pregnant while receiving ELFABRIO, healthcare providers should report ELFABRIO exposure by calling 1-888-661-9260 or visiting https://chiesirarediseases.com/contact-us/medical-information-form. Data Animal Data In an embryofetal development study in the rat, pegunigalsidase alfa-iwxj was administered during the period of organogenesis on gestation day 6, 9, 12, and 15. No maternal or fetal adverse effects were noted at exposures that were up to 3.6-fold greater than the recommended dose of 1 mg/kg every two weeks. In an embryofetal development study in the rabbit, administration of pegunigalsidase alfa-iwxj during the period of organogenesis on gestation day 6, 9, 12, 15, and 18, resulted in maternal toxicity, including maternal mortality, decreased body weight, and decreased feed consumption. These effects were observed at exposures that were ≥ 3.2-fold greater than the recommended dose of 1 mg/kg every two weeks. Adverse embryofetal effects included abortion, increased late resorptions, number of does with resorptions, and increased post-implantation loss at exposures that were 6.5 fold greater than the recommended dose of 1 mg/kg every two weeks. Decreased fetal body weight was observed at exposures that were ≥ 3.2 times greater than the recommended dose of 1 mg/kg every two weeks. There was no increase in fetal external, skeletal, or visceral malformations.

8.2 Lactation Risk Summary There are no data on the presence of pegunigalsidase alfa-iwxj 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 ELFABRIO and any potential adverse effects on the breastfed infant from pegunigalsidase alfa-iwxj or from the underlying maternal condition. 8. 4 Pediatric Use The safety and effectiveness of ELFABRIO have not been established in pediatric patients. 8. 5 Geriatric Use Clinical trials of ELFABRIO did not include patients 65 years of age and older to determine if they respond differently from younger adult patients.

8.6 Patients with Prior Enzyme Replacement Therapy Patients that received prior ERT are more likely to have pre-existing anti-drug antibodies (ADA) to pegunigalsidase alfa-iwxj which could be due to the ADA cross-reactivity to pegunigalsidase alfa-iwxj by prior ERT. When switching from other ERT to ELFABRIO: Pre-existing ADA may reduce the plasma pegunigalsidase alfa-iwxj concentrations, which may reduce ELFABRIO efficacy [see Clinical Pharmacology ( 12.2 , 12.6 ) ]. The risk of ELFABRIO-related hypersensitivity and infusion-associated reactions may be increased in certain patients with pre-existing ADA from prior ERT [ see Warnings and Precautions ( 5.1 , 5.2 ) and Adverse Reactions ( 6.1 )] . Consider monitoring clinical or pharmacodynamic responses (e.g., plasma lyso-Gb3 levels) when switching from agalsidase beta to ELFABRIO, in patients with pre-existing ADA.

Fabry disease is caused by deficiency of the lysosomal enzyme alpha-galactosidase A. ELFABRIO provides an exogenous source of alpha-galactosidase A. ELFABRIO is internalized and transported into lysosomes where it is thought to exert enzymatic activity and reduce accumulated globotriaosylceramide (Gb3).