Sebelipase Alfa

1 INDICATIONS AND USAGE KANUMA ® is indicated for the treatment of patients with a diagnosis of Lysosomal Acid Lipase (LAL) deficiency. KANUMA ® is a hydrolytic lysosomal cholesteryl ester and triacylglycerol-specific enzyme indicated for the treatment of patients with a diagnosis of Lysosomal Acid Lipase (LAL) deficiency. ( 1 )

2 DOSAGE AND ADMINISTRATION Administration of KANUMA should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. ( 2.1 ) Infants with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life: The recommended starting dosage is 1 mg/kg as an intravenous infusion once weekly. ( 2.2 ) For patients with a suboptimal clinical response, increase the dosage to 3 mg/kg once weekly. ( 2.2 ) For patients with continued suboptimal clinical response, further increase the dosage to 5 mg/kg once weekly. ( 2.2 ) Pediatric and Adult Patients with LAL Deficiency: The recommended dosage is 1 mg/kg as an intravenous infusion once every other week. ( 2.2 ) For patients with a suboptimal clinical response, increase the dosage to 3 mg/kg once every other week. ( 2.2 ) See Full Prescribing Information for complete Dosage and Administration Information. Administration Instructions Infuse over at least 2 hours. ( 2.4 ) Consider further prolonging the infusion time for patients receiving dosages greater than 1 mg/kg or for those who have experienced a hypersensitivity reaction. ( 2.4 ) Consider a 1-hour infusion for the 1 mg/kg dose in patients who tolerate the infusion. ( 2.4 ) 2.1 Recommendations Prior to KANUMA Treatment Administration of KANUMA should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis [see Warnings and Precautions (5.1) ]. Initiate KANUMA in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment [see Warnings and Precautions (5.1) ]. 2.2 Recommended Dosage Infants with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life: The recommended starting dosage is 1 mg/kg administered as an intravenous infusion once weekly. For patients with a suboptimal clinical response, increase the dosage to 3 mg/kg once weekly. For patients with continued suboptimal clinical response on the 3 mg/kg once weekly dosage, further increase the dosage to 5 mg/kg once weekly. A suboptimal clinical response is defined as any of the following: poor growth, deteriorating biochemical markers, or persistent or worsening organomegaly. Pediatric and Adult Patients with LAL Deficiency: The recommended dosage is 1 mg/kg administered as an intravenous infusion once every other week. For patients with a suboptimal clinical response, increase the dosage to 3 mg/kg once every other week. A suboptimal clinical response is defined as any of the following: poor growth, deteriorating biochemical markers [e.g., alanine aminotransferase (ALT), aspartate aminotransferase (AST)], and/or parameters of lipid metabolism [e.g., low-density lipoprotein cholesterol (LDL-c), triglycerides (TG)]. 2.3 Preparation Instructions KANUMA is for intravenous infusion only. Prepare KANUMA using the following steps. Determine the number of vials needed based on the patient's weight and the recommended dose of 1 mg/kg, 3 mg/kg, or 5 mg/kg using the following calculations (a-b): Total dose (mg) = Patient's weight (kg) × Recommended dose (mg/kg) Total number of vials = Total dose (mg) divided by 20 mg/vial Round to the next whole vial and remove the required number of vials from the refrigerator to allow them to reach room temperature. Volume (mL) of calculated total dose = Total dose (mg) divided by the 2 mg/mL concentration Volume (mL) of 0.9% Sodium Chloride for dilution = Total infusion volume (mL) for patient's weight (see Table 1 ) - Volume (mL) of calculated total dose Table 1: Total Infusion Volumes The infusion volume should be based on the prescribed dose and should be prepared to a final KANUMA concentration of 0.1 mg/mL to 1.5 mg/mL. Weight Range (kg) 1 mg/kg dose 3 mg/kg dose 5 mg/kg dose Total Infusion Volume (mL) Total Infusion Volume (mL) Total Infusion Volume (mL) 1 to 2.9 4 8 12 3 to 5.9 6 12 20 6 to 10.9 10 25 50 11 to 24.9 25 50 150 25 to 49.9 50 100 250 50 to 99.9 100 250 500 100 to 120.9 250 500 600 Mix gently by inversion. Do not shake the vials or the prepared infusion. The solution should be inspected visually for particulate matter and discoloration prior to administration. The solution should be a clear to slightly opalescent, colorless to slightly colored solution. Thin, translucent particles or fibers may be present in the vials or diluted solution. Do not use if the solution is cloudy or if other particulate matter is observed. Vials are for single-use only. Discard any unused product. Do not freeze. 2.4 Administration Instructions Administer the diluted solution as an intravenous infusion using a low-protein binding infusion set with an in-line, low-protein binding 0.2 micron filter. Infuse over at least 2 hours. Consider further prolonging the infusion time for patients receiving dosages greater than 1 mg/kg or those who have experienced hypersensitivity reactions [see Warnings and Precautions (5.1) ] . A 1-hour infusion may be considered for those patients receiving the 1 mg/kg dose who tolerate the infusion. 2.5 Storage of Diluted Solution KANUMA contains no preservatives; therefore, product should be used immediately after dilution. If immediate use is not possible, the diluted product may be stored up to 24 hours in the refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze or shake. Protect from light.

6 ADVERSE REACTIONS The most common adverse reactions are: Infants with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life (≥30%): diarrhea, vomiting, fever, rhinitis, anemia, cough, nasopharyngitis, and urticaria. ( 6.1 ) Pediatric and Adult Patients with LAL Deficiency (≥8%): headache, fever, oropharyngeal pain, nasopharyngitis, asthenia, constipation, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alexion at 1-844-259-6783 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 clinical practice. In clinical trials, a total of 106 patients received treatment with KANUMA. The data described below reflect exposure to KANUMA in 75 patients who received KANUMA at dosages up to 3 mg/kg once weekly in clinical trials: Nine patients (5 males, 4 females) who had growth failure or other evidence of rapidly progressive LAL deficiency presenting within the first 6 months of life received KANUMA for up to 165 weeks (median 60 weeks) at escalating doses ranging between 0.35 mg/kg and 5 mg/kg once weekly [see Clinical Studies (14.1) ] . 66 pediatric and adult patients with LAL deficiency aged 4 to 58 years (33 males, 33 females) received KANUMA 1 mg/kg every other week for up to 36 weeks. Table 2 summarizes the most common adverse reactions occurring in >30% of patients with rapidly progressive LAL deficiency presenting within the first 6 months of life receiving KANUMA in Study 1. Table 2: Adverse Reactions in ≥30% of Infants with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life Receiving KANUMA Adverse Reactions KANUMA N=9 n (%) Diarrhea 6 (67) Vomiting 6 (67) Fever 5 (56) Rhinitis 5 (56) Anemia 4 (44) Cough 3 (33) Nasopharyngitis 3 (33) Urticaria 3 (33) Other less common adverse reactions reported in patients with rapidly progressive disease presenting within the first 6 months of life who received KANUMA included hypotonia, decreased oxygen saturation, retching, sneezing, and tachycardia. For infant patients within Study 1 and Study 3 (n = 19), the following additional adverse reactions were reported in ≥ 30% of infants who received KANUMA since the time of marketing authorization, including patients who received an escalated dose to 5 mg/kg qw: hypersensitivity, respiratory distress, and tachycardia. Table 3 summarizes the most common adverse reactions that occurred in ≥8% of pediatric and adult patients with LAL deficiency receiving KANUMA in Study 2. Table 3: Adverse Reactions in ≥8% of Pediatric and Adult Patients with LAL Deficiency Receiving KANUMA Adverse Reactions KANUMA N = 36 Placebo N = 30 n (%) n (%) Headache 10 (28) 6 (20) Fever 9 (25) 7 (23) Oropharyngeal pain 6 (17) 1 (3) Nasopharyngitis 4 (11) 3 (10) Asthenia 3 (8) 1 (3) Constipation 3 (8) 1 (3) Nausea 3 (8) 2 (7) Other less common adverse reactions reported in pediatric and adult patients who received KANUMA included anxiety and chest discomfort. For pediatric and adult patients (n = 106), the following additional adverse reactions were reported in ≥ 8% of pediatric and adult patients who received KANUMA since the time of marketing authorization, including patients who received an escalated dose to 3 mg/kg qw: hypersensitivity, diarrhea, abdominal pain, and dizziness. Hyperlipidemia Increases in circulating LDL-cholesterol (LDL-c) and triglycerides above pre-treatment values were observed in 29 of 36 (81%) and 21 of 36 (58%) patients, respectively, at 2 and 4 weeks following initiation of KANUMA [see Clinical Pharmacology (12.2) ] . The maximum mean percentage increase was 18% for LDL-c at Week 2 and 5% for triglycerides at Week 4. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other sebelipase alfa products may be misleading. Approximately 8% (9/106) of pediatric and adult patients with LAL deficiency developed antibodies to sebelipase alfa (anti-drug antibodies or ADA) following treatment with KANUMA across all clinical studies. Among the 9 patients who developed ADA, 2 patients were positive for neutralizing antibodies (NAb). Approximately 53% (10/19) of infants with rapidly progressive LAL deficiency developed ADA following treatment with KANUMA across all clinical studies. Among the 10 patients who developed ADA, 9 patients were positive for NAb. Study 1: Patients with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life Seven of the 9 infants with rapidly progressive disease had at least one post-treatment ADA assessment, and 4 of these 7 (57%) patients developed ADA during treatment with KANUMA. All of the 4 ADA-positive patients were determined to be positive for neutralizing antibodies that inhibit in vitro enzyme activity and/or cellular uptake of the enzyme. At the time of initial ADA positivity, 3 patients were receiving a dosage of 1 mg/kg once weekly and 1 patient was receiving a dosage of 3 mg/kg once weekly. Three of the 4 ADA-positive patients had ADA titers monitored from the initiation of treatment and developed measurable ADA titers within the first 2 months of exposure. Persistent ADA was observed in all 4 patients. Hypersensitivity reactions occurred in all 4 of the ADA-positive patients, whereas they occurred in only 1 of the 3 ADA-negative patients. None of the patients discontinued treatment. In 1 patient, decreased growth velocity in a setting of neutralizing antibodies to KANUMA was observed. Study 2: Pediatric and Adult Patients with LAL Deficiency Five of 35 (14%) KANUMA-treated pediatric and adult patients who completed the 20-week double-blind period of study treatment developed ADA. All patients were receiving 1 mg/kg once every other week. All 5 ADA-positive patients first developed measurable ADA titers within the first 3 months of exposure. Two of the 5 ADA-positive patients had a measurable ADA titer at only one time point. In the 3 patients with measurable ADA titers at multiple time points, ADA titers decreased to undetectable levels during continued treatment. Two patients developed in vitro neutralizing antibodies during the open-label extension phase after 20 weeks and 52 weeks of treatment with KANUMA, respectively. There is no clear association between the development of ADA and decreased efficacy in pediatric and adult patients treated with KANUMA.

12.3 Pharmacokinetics The pharmacokinetic profile of sebelipase alfa was nonlinear with a greater than dose-proportional increase in exposure between 1 and 3 mg/kg based on non-compartmental analysis of data from 26 adults. No accumulation was observed following once weekly or once every other week dosing. Using a population pharmacokinetic model, sebelipase alfa pharmacokinetic parameters were estimated for 65 pediatric and adult patients who received intravenous infusions of KANUMA at 1 mg/kg at Week 22 (Table 4); 24 patients were 4 to 11 years old, 23 were 12 to 17 years old, and 18 were adults. The pharmacokinetic profiles of sebelipase alfa were similar between adolescents and adults. The T max and T 1/2 were similar across all age groups. Table 4: Mean (SD) Pharmacokinetics Parameters at Week 22 in Pediatric and Adult Patients Receiving 1 mg/kg Once Every Other Week Parameter 4-11 years old 12-17 years old ≥18 years old N=24 N=23 N=18 Parameter values were estimated using a population pharmacokinetic model. AUC = Area under the plasma concentration time curve. C max = Maximum concentration. T max = Time to maximum concentration. CL = Clearance. V c = Central volume of distribution. T 1/2 = Half-life. AUC (ng∙hr/mL) 942 (388) 1454 (699) 1861 (599) C max (ng/mL) 490 (205) 784 (480) 957 (303) T max (hr) 1.3 (0.6) 1.1 (0.3) 1.3 (0.6) CL (L/hr) 31.1 (7.1) 37.4 (12.4) 38.2 (12.5) V c (L) 3.6 (3.0) 5.4 (2.4) 5.3 (1.6) T 1/2 (min) 5.4 (4.3) 6.6 (3.7) 6.6 (3.7)