NAGLAZYME (Page 3 of 5)

6.2 Immunogenicity

As with all the therapeutic proteins, there is potential for immunogenicity. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibodies in an assay may be influenced by several factors including 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 galsulfase products may be misleading.

Ninety-eight percent (53/54) of patients treated with NAGLAZYME and evaluable for the presence of antibodies to galsulfase developed anti-galsulfase IgG antibodies within 4 to 8 weeks of treatment (in four clinical studies). In 19 patients treated with NAGLAZYME from the placebo-controlled study, serum samples were evaluated for a potential relationship of anti-galsulfase antibody development to clinical outcome measures. All 19 patients treated with NAGLAZYME developed antibodies specific to galsulfase; however, the analysis revealed no consistent predictive relationship between total antibody titer, neutralizing or IgE antibodies, and infusion‑associated reactions, urinary glycosaminoglycan (GAG) levels, or endurance measures. Antibodies were assessed for the ability to inhibit enzymatic activity but not cellular uptake.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post approval use of NAGLAZYME. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Serious infusion reactions: anaphylaxis, shock, hypotension, bronchospasm, and respiratory failure [see Warnings and Precautions (5.1)].

Additional infusion reactions: pyrexia, erythema, pallor, bradycardia, tachycardia, hypoxia, cyanosis, tachypnea, and paresthesia.

During postmarketing surveillance, there has been a single case of membranous nephropathy and rare cases of thrombocytopenia reported. In the case of membranous nephropathy, renal biopsy revealed galsulfase‑immunoglobulin complexes in the glomeruli. With both membranous nephropathy and thrombocytopenia, patients have been successfully rechallenged and have continued to receive NAGLAZYME.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data from case reports and postmarketing experience with NAGLAZYME use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, galsulfase administered intravenously to pregnant rats and rabbits during the period of organogenesis, showed no evidence of harm to the fetus at doses of about 0.5 and 0.97 times, respectively for rats and rabbits, the recommended human dose of 1 mg/kg based on body surface area (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, 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.

Clinical Considerations

Disease-associated maternal and embryo/fetal risk

Pregnancy can exacerbate preexisting clinical manifestations of MPS and lead to adverse pregnancy outcomes for both mother and fetus.

Data

Animal Data

Reproduction studies have been performed with intravenous galsulfase during the period of organogenesis in pregnant rats at doses of galsulfase up to 3 mg/kg/day (about 0.5 times the recommended human dose of 1 mg/kg based on the body surface area) and in pregnant rabbits at doses up to 3 mg/kg/day (about 0.97 times the recommended human dose of 1 mg/kg based on the body surface area) and have revealed no evidence of harm to the fetus due to galsulfase.

8.2 Lactation

Risk Summary

There are no data on the presence of galsulfase in human 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 NAGLAZYME and any potential adverse effects on the breastfed infant from NAGLAZYME or from the underlying maternal condition.

8.4 Pediatric Use

Clinical studies with NAGLAZYME were conducted in 56 patients, ages 5 to 29 years, with the majority of these patients in the pediatric age group [see Clinical Studies (14)]. In addition, an open-label study was conducted in four infants (3 months to 12.7 months) treated with 1 mg/kg (n = 2) or 2 mg/kg (n = 2) of NAGLAZYME. Safety results in infants were consistent with results observed in patients 5 to 29 years old [see Adverse Reactions (6)].

8.5 Geriatric Use

Clinical studies of NAGLAZYME did not include patients older than 29 years of age. It is not known whether older patients respond differently from younger patients.

11 DESCRIPTION

NAGLAZYME is a formulation of galsulfase, which is a purified human enzyme that is produced by recombinant DNA technology in a Chinese hamster ovary cell line. Galsulfase (glycosaminoglycan N –acetylgalactosamine 4-sulfatase, EC 3.1.6.12) is a lysosomal enzyme that catalyzes the cleavage of the sulfate ester from terminal N –acetylgalactosamine 4-sulfate residues of glycosaminoglycans (GAG), chondroitin 4-sulfate and dermatan sulfate.

Galsulfase is a glycoprotein with a molecular weight of approximately 56 kDa. The recombinant protein consists of 495 amino acids and possesses six asparagine‑linked glycosylation sites, four of which carry a bis‑mannose–6–phosphate residue for specific cellular recognition. Post-translational modification of Cys53 produces the catalytic amino acid residue, Cα-formylglycine, which is required for enzyme activity. NAGLAZYME has a specific activity of approximately 70 units per mg of protein content. One activity unit is defined as the amount of enzyme required to convert 1 micromole of 4-methylumbelliferyl sulfate to 4-methylumbelliferone and free sulfate per minute at 37°C.

NAGLAZYME is intended for intravenous infusion and is supplied as a sterile, nonpyrogenic, colorless to pale yellow, clear to slightly opalescent solution that must be diluted with 0.9% Sodium Chloride Injection, USP, prior to administration. NAGLAZYME is supplied in clear Type I glass 5 mL vials. Each vial provides 5 mg galsulfase, 43.8 mg sodium chloride, 6.20 mg sodium phosphate monobasic monohydrate, 1.34 mg sodium phosphate dibasic heptahydrate, and 0.25 mg polysorbate 80 in a 5 mL extractable solution with pH of approximately 5.8. NAGLAZYME does not contain preservatives. Each vial is for single use only.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of GAG. MPS VI is characterized by the absence or marked reduction in N –acetylgalactosamine 4-sulfatase. The sulfatase activity deficiency results in the accumulation of the GAG substrate, dermatan sulfate, throughout the body. This accumulation leads to widespread cellular, tissue, and organ dysfunction. NAGLAZYME is intended to provide an exogenous enzyme that will be taken up into lysosomes and increase the catabolism of GAG. Galsulfase uptake by cells into lysosomes is most likely mediated by the binding of mannose-6-phosphate-terminated oligosaccharide chains of galsulfase to specific mannose-6-phosphate receptors.

12.2 Pharmacodynamics

The responsiveness of urinary GAG to dosage alterations of NAGLAZYME is unknown, and the relationship of urinary GAG to other measures of clinical response has not been established. No association was observed between antibody development and urinary GAG levels [see Adverse Reactions (6.2)].

12.3 Pharmacokinetics

The pharmacokinetic parameters of galsulfase were evaluated in 13 patients with MPS VI who received 1 mg/kg of NAGLAZYME as a weekly 4-hour infusion for 24 weeks. The pharmacokinetic parameters at Week 1 and Week 24 are shown in Table 2.

Table 2: Pharmacokinetic Parameters (Median, Range) of Galsulfase in Patients with MPS VI
*
Area under the plasma galsulfase concentration-time curve from start of infusion to 60 minutes post infusion.
Pharmacokinetic Parameter Week 1 Week 24
Cmax (mcg/mL) 0.8 (0.4 to 1.3) 1.5 (0.2 to 5.5)
AUC0-t (hr•mcg/mL)* 2.3 (1.0 to 3.5) 4.3 (0.3 to 14.2)
Vz (mL/kg) 103 (56 to 323) 69 (59 to 2,799)
CL (mL/kg/min) 7.2 (4.7 to 10.5) 3.7 (1.1 to 55.9)
Half-life (min) 9 (6 to 21) 26 (8 to 40)

Galsulfase pharmacokinetic parameters listed in Table 2 require cautious interpretation because of large assay variability. Development of anti-galsulfase antibodies appears to affect galsulfase pharmacokinetics, however, the data are limited.

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