Vestronidase Alfa

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 )

Injection: 10 mg/5 mL (2 mg/mL) as a colorless to slightly yellow liquid in a single-dose vial. Injection: 10 mg/5 mL (2 mg/mL) in a single-dose vial ( 3 )

None. None ( 4 )

5.1 Anaphylaxis Anaphylaxis to MEPSEVII was reported in 2 of 20 patients in the clinical program [see Adverse Reactions ( 6.1 )] . These reactions occurred during MEPSEVII infusion and were observed as early as the first dose of MEPSEVII for one patient. Manifestations included respiratory distress, cyanosis, decreased oxygen saturation, and hypotension. The two patients with anaphylaxis to MEPSEVII during the clinical trials had one occurrence each and tolerated subsequent infusions of MEPSEVII, without recurrence. Anaphylaxis can be life-threatening. MEPSEVII should be administered under the supervision of a healthcare professional with the capability to manage anaphylaxis. Patients should be observed for 60 minutes after MEPSEVII administration. If severe systemic reactions occur, including anaphylaxis, immediately discontinue the MEPSEVII infusion and provide appropriate medical treatment. Prior to discharge, inform patients of the signs and symptoms of anaphylaxis and instruct them to seek immediate medical care if symptoms occur. Consider the risks and benefits of re-administering MEPSEVII following anaphylaxis.

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).

8.1 Pregnancy Risk Summary There are no available data on MEPSEVII use in pregnant women to determine a drug-associated risk of adverse developmental outcomes. In embryofetal development studies, vestronidase alfa-vjbk administered intravenously to pregnant rats and rabbits during the period of organogenesis showed no adverse developmental outcomes at doses up to 1.6 and 10 times, respectively for rats and rabbits, the exposure at the recommended human dose. In a pre- and post-natal development study in rats, an increased number of stillbirths were observed at exposures less than the recommended human dose (see Data). The clinical relevance of these animal findings is uncertain. The estimated 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 embryofetal development studies, vestronidase alfa-vjbk administered intravenously to pregnant rats (once a week) and rabbits (once every 3 days) during the period of organogenesis showed no adverse developmental outcomes at doses up to 20 mg/kg. The 20 mg/kg dose in rats and rabbits provides approximately 1.6 and 10 times the human exposure (AUC) of 57.9 hr*mcg/mL at the 4 mg/kg dose administered once every other week, respectively. In a pre- and post-natal developmental study in rats, vestronidase alfa-vjbk was administered every 3 days from gestation day 7 through lactation day 20 at doses of 2 mg/kg, 6 mg/kg, and 20 mg/kg. Mortality and adverse clinical signs were observed in the maternal animals at the 20 mg/kg dose (1.6 times the human exposure (AUC) at the recommended human dose of 4 mg/kg). Subsequently, the 20 mg/kg dose was reduced to 12 mg/kg. Maternal toxicity with mortality in one animal was also observed at the 6 mg/kg dose (0.17 times the AUC at the recommended human dose of 4 mg/kg). At the 2 mg/kg dose (0.01 times the AUC at the recommended human dose of 4 mg/kg), no adverse effects were observed in the maternal animals; however, there was a statistically significant decrease in the number of live births and subsequent increase in the number of stillbirths at this dose.

8.2 Lactation Risk Summary There are no data on the presence of vestronidase alfa-vjbk 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 MEPSEVII and any potential adverse effects on the breastfed infant from vestronidase alfa-vjbk or from the underlying maternal condition. 8. 4 Pediatric Use The safety and effectiveness of MEPSEVII have been established in pediatric patients less than 18 years of age [see Adverse Reactions ( 6 ) , Clinical Studies ( 14 )] . 8. 5 Geriatric Use Clinical trials of MEPSEVII did not include any patients aged 65 and over. It is not known whether elderly patients respond differently from younger patients.

Mucopolysaccharidosis VII (MPS VII or Sly syndrome) is a lysosomal disorder characterized by the deficiency of GUS that results in GAG accumulation in cells throughout the body leading to multisystem tissue and organ damage. Vestronidase alfa-vjbk is a recombinant form of human GUS and is intended to provide exogenous GUS enzyme for uptake into cellular lysosomes. Mannose-6-phosphate (M6P) residues on the oligosaccharide chains allow binding of the enzyme to cell surface receptors, leading to cellular uptake of the enzyme, targeting to lysosomes and subsequent catabolism of accumulated GAGs in affected tissues.