Vestronidase Alfa

1 INDICATIONS AND USAGE MEPSEVII is indicated in pediatric and adult patients for the treatment of Mucopolysaccharidosis VII (MPS VII, Sly syndrome). Limitations of Use The effect of MEPSEVII on the central nervous system manifestations of MPS VII has not been determined. MEPSEVII is a recombinant human lysosomal beta glucuronidase indicated in pediatric and adult patients for the treatment of Mucopolysaccharidosis VII (MPS VII, Sly syndrome). Limitations of Use The effect of MEPSEVII on the central nervous system manifestations of MPS VII has not been determined. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage is 4 mg/kg administered every two weeks as an intravenous infusion. ( 2.1 ) Premedication with a non-sedating antihistamine with or without an anti-pyretic is recommended 30 to 60 minutes prior to the start of the infusion. ( 2.2 , 5.1 ) Administer the infusion over approximately 4 hours. In the first hour of infusion, infuse 2.5% of the total volume. After the first hour, the rate can be increased to infuse the remainder of the volume over 3 hours as tolerated. See Table 1 in the full prescribing information for the rate of infusion by dose and body weight. ( 2.4 ) For additional information on preparation, administration, and storage see the full prescribing information. ( 2.3 , 2.4 ) 2.1 Recommended Dosage MEPSEVII should be administered under the supervision of a healthcare professional with the capability to manage anaphylaxis. Premedication is recommended 30 to 60 minutes prior to the start of the infusion [see Dosage and Administration ( 2.2 )]. The recommended dosage of MEPSEVII is 4 mg/kg administered by intravenous infusion every two weeks. Administer the infusion over approximately 4 hours. Infuse the first 2.5% of the total volume over the first hour. After the first hour, increase the infusion rate as tolerated in order to complete infusion over the following 3 hours according to the recommended rate guidelines in Table 1 [see Dosage and Administration ( 2.4 )]. 2.2 Premedication Administration of a non-sedating antihistamine with or without an anti-pyretic medication is recommended 30 to 60 minutes prior to the start of the infusion for patient comfort. Follow the instructions in Table 1 for the rate of MEPSEVII infusion [see Dosage and Administration ( 2.4 )] . Observe patients closely during the infusion and following the infusion for a minimum of 60 minutes for the development of anaphylaxis [see Warnings and Precautions ( 5.1 )] . Discontinue the infusion immediately if the patient experiences a severe systemic reaction, including anaphylaxis [see Warnings and Precautions ( 5.1 )]. 2. 3 Preparation Instructions Prepare MEPSEVII according to the following steps using aseptic technique: 1. Determine the number of vials to be diluted based on the patient's actual weight and the recommended dose of 4 mg/kg, using the following calculations (a-b): a. Total dose (mg) = Patient's weight (kg) x 4 mg/kg (recommended dose) b. Total number of vials = Total dose (mg) divided by 10 mg/vial 2. Round to the next whole vial and remove the required number of vials from the refrigerator to allow them to reach room temperature. Do not heat, microwave or shake vials. a. Volume (mL) of calculated dose = Total dose (mg) divided by the 2 mg/mL concentration 3. The final solution will be a 1:1 dilution of MEPSEVII with 0.9% Sodium Chloride Injection, USP. More than 1:1 dilution may be used if the patient can tolerate additional infusion volume, taking into consideration cardiac function and fluid status. 4. For a 1:1 dilution, prepare the solution at room temperature, as follows: a. Select an empty infusion bag, sized upon the total volume of the final solution. b. Prior to withdrawing MEPSEVII from the vial, visually inspect the solution for particulate matter and discoloration. Because this is a protein solution, slight flocculation (thin translucent fibers) may occur. The MEPSEVII solution should be colorless to slightly yellow. Discard if the solution is discolored or if there is particulate matter in the solution. c. Slowly withdraw the volume of the calculated MEPSEVII dose from the appropriate number of vials (step 2a) using caution to avoid excessive agitation and any air or frothing. Use a sufficiently large needle (18 gauge) to minimize bubbles in the solution. d. Slowly add MEPSEVII to the infusion bag using care to avoid agitation, ensuring liquid to liquid contact without generating bubbles or turbulence. e. Add 0.9% Sodium Chloride Injection, USP equal to the volume of MEPSEVII to the infusion bag. f. Gently rock the infusion bag to ensure proper distribution of MEPSEVII. Do not shake the solution. 2.4 Administration Instructions Administer MEPSEVII as follows: The rate of infusion: In the first hour infuse 2.5% of the total volume, and infuse the remaining volume over the subsequent three hours (see Table 1). Account for any dead space in the lines to ensure 2.5% of the total infusion volume is delivered into the patient's bloodstream during the first hour of infusion. Use an infusion set equipped with an in-line, low-protein binding 0.2 micron filter to administer the diluted MEPSEVII solution. Do not flush the line containing MEPSEVII to avoid a rapid bolus of infused enzyme. Due to the low infusion rate, additional saline may be added through a separate line (piggyback or Y tube) to maintain sufficient intravenous flow to prevent clotting or line blockage. Do not infuse with other products in the infusion tubing. Compatibility with other products has not been evaluated. Use MEPSEVII immediately after dilution and complete the infusion within 42 hours from the time of dilution. Discard any unused product. Stability If immediate use is not possible, the diluted solution may be stored up to 36 hours under refrigeration at 2°C to 8°C (36°F to 46°F) followed by up to 6 hours at room temperature up to a maximum of 25°C (77°F). Table 1. Recommended Infusion Rate Schedule by Patient Weight for Administration of MEPSEVII at Recommended Dose of 4 mg/kg Patient Weight Range (kg) Total MEPSEVII Dose Range (mg) Total MEPSEVII Volume (rounded) (mL) Total Infusion Volume of Drug and diluent (infused over 4 hours) (mL) Infusion Rate for 1 st Hour (2.5%) (mL/h) Infusion Rate per Hour for Subsequent 3 Hours (97.5%/3) (mL/h) 3.5-5.9 14-23.6 10 20 0.5 6.5 6-8.4 24-33.6 15 30 0.8 9.8 8.5-10.9 34-43.6 20 40 1 13 11-13.4 44-53.6 25 50 1.3 16.3 13.5-15.9 54-63.6 30 60 1.5 19.5 16-18.4 64-73.6 35 70 1.8 22.8 18.5-20.9 74-83.6 40 80 2 26 21-23.4 84-93.6 45 90 2.3 29.3 23.5-25.9 94-103.6 50 100 2.5 32.5 26-28.4 104-113.6 55 110 2.8 35.8 28.5-30.9 114-123.6 60 120 3 39 31-33.4 124-133.6 65 130 3.3 42.3 33.5-35.9 134-143.6 70 140 3.5 45.5 36-38.4 144-153.6 75 150 3.8 48.8 38.5-40.9 154-163.6 80 160 4 52 41-43.4 164-173.6 85 170 4.3 55.3 43.5-45.9 174-183.6 90 180 4.5 58.5 46-48.4 184-193.6 95 190 4.8 61.8 48.5-50.9 194-203.6 100 200 5 65 51-53.4 204-213.6 105 210 5.3 68.3 53.5-55.9 214-223.6 110 220 5.5 71.5 56-58.4 224-233.6 115 230 5.8 74.8 58.5-60.9 234-243.6 120 240 6 78 61-63.4 244-253.6 125 250 6.3 81.3 63.5-65.9 254-263.6 130 260 6.5 84.5 66-68.4 264-273.6 135 270 6.8 87.8 68.5-70.9 274-283.6 140 280 7 91

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Anaphylaxis [see Warnings and Precautions ( 5.1 )] Most common adverse reactions (≥1 patient) are: Infusion site extravasation, diarrhea, rash, anaphylaxis, infusion site swelling, peripheral swelling and pruritus. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ultragenyx at 1-888-756-8657 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 MEPSEVII clinical program included 23 patients aged 5 months to 25 years who received treatment with MEPSEVII at doses up to 4 mg/kg once every two weeks for up to 187 weeks. Nineteen patients were younger than 18 years of age. Table 2 summarizes the adverse reactions that occurred in Study 301, a randomized start trial in 12 patients with MPS VII between the ages of 8 and 25 years [see Clinical Studies ( 14 )] . Adverse reactions in Table 2 occurred in one or more patients treated with MEPSEVII at a dosage of 4 mg/kg at a higher patient frequency than placebo. Adverse reaction incidence rates are presented in the table below to account for the different duration of exposure to active treatment vs. placebo. Table 2. Adverse Reactions in Patients with MPS VII in Study 301 Adverse Reaction MEPSEVII N =12 n ( Incidence Rate*) Placebo N= 9 n ( Incidence Rate*) Infusion site extravasation 4 (0.5) 1 (0.4) Diarrhea 3 (0.4) 0 (0.0) Rash 3 (0.4) 2 (0.7) Anaphylaxis 2 (0.2) 0 (0.0) Infusion site swelling 1 (0.1) 0 (0.0) Peripheral swelling 1 (0.1) 0 (0.0) Pruritus 1 (0.1) 0 (0.0) n = number of reactions *Adverse reaction incidence rates calculated per 8.3 patient years for exposure to MEPSEVII, and 2.7 years of exposure for placebo Febrile Convulsion One patient receiving a dose of 4 mg/kg experienced a febrile convulsion during MEPSEVII treatment at Week 66. The infusion was stopped, the patient received anticonvulsants, antipyretics and antibiotics, and the adverse reaction resolved. The patient subsequently was re-challenged without recurrence and continued on treatment. 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. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay 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 to other vestronidase alfa products may be misleading. Immunogenicity data were available from 23 patients who received MEPSEVII for up to 187 weeks of treatment. Eighteen out of 23 (78%) patients developed anti-vestronidase alfa-vjbk antibodies (ADA). Ten of the 18 (55.6%) ADA-positive patients were tested positive for neutralizing antibodies (NAb). There is no correlation between ADA titer and NAb development. Six treatment-naïve patients had pre-existing ADA titers at baseline. ADAs were detected in five of these six patients post-treatment. The post-treatment ADA titers were the same as or below the baseline ADA titer values in two patients, but one of these two patients was positive for NAb. ADA titer values after treatment increased 64-fold, 128-fold, and 364-fold, respectively, in the other three patients. The presence of ADA titer did not appear to affect reduction in urinary glycosaminoglycans (uGAGs).

12.3 Pharmacokinetics The pharmacokinetics of vestronidase alfa-vjbk were evaluated in a total of 23 MPS VII patients including 19 pediatric patients and 4 adults. Serum exposures of vestronidase alfa-vjbk appeared to increase approximately proportionally from 1 mg/kg (0.25 times the approved recommended dosage) to 2 mg/kg (0.5 times the approved recommended dosage), and 4 mg/kg (the recommended dosage). After repeated dosing of 4 mg/kg every other week, the mean ± standard deviation of maximal concentration (Cmax) was 17.3 ± 9.6 mcg/mL (range: 4.7 to 35.7 mcg/mL); and the mean ± standard deviation of area under the concentration-time curve from time zero to the last measurable concentration (AUC0-t) was 50.9 ± 32.2 mcg*hr/mL (range: 17.4 to 153 mcg*hr/mL). Vestronidase alfa-vjbk concentrations in pediatric patients less than 5 years of age were similar to the concentrations in older children and adults. Distribution After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard deviation of the total volume of distribution (Vss) was 251 ± 140 mL/kg (range: 97 to 598 mL/kg). Elimination After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard deviation of the total clearance (CL) was 83.6 ± 43.2 mL/hr/kg (range: 38.3 to 184mL/hr/kg); the mean ± standard deviation of the elimination half-life (t1/2) was 2.33 ± 0.75 hours (range: 0.86 to 3.03 hours). The inter-subject variability (coefficient of variation) in total clearance (CL) was 52%. Metabolism Vestronidase alfa-vjbk is a recombinant human enzyme and is therefore eliminated by proteolytic degradation into small peptides and amino acids. Excretion No excretion studies have been conducted in humans. Vestronidase alfa-vjbk is not expected to be eliminated through renal or fecal excretion.