NAGLAZYME (galsulfase) for Treatment of Mucopolysaccharide VI (MPS VI)

NAGLAZYME (galsulfase) injection for intravenous use

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, C alpha-formylglycine, which is required for enzyme activity. 

 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. 

CLINICAL PHARMACOLOGY 

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. 

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

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.

Initial U.S. Approval: 2005 

RECENT MAJOR CHANGES

Warnings and Precautions, Spinal or Cervical Cord Compression -3/2013 

INDICATIONS AND USAGE

NAGLAZYME is a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme indicated for patients with Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome). NAGLAZYME has been shown to improve walking and stair-climbing capacity 

DOSAGE AND ADMINISTRATION

1 mg per kg of body weight administered once weekly as an intravenous infusion 

DOSAGE FORMS AND STRENGTHS

Injection: 5 mg per 5 mL vial.

CONTRAINDICATIONS

None 

WARNINGS AND PRECAUTIONS

• Anaphylaxis and Allergic Reactions:Life-threatening anaphylactic reactions have been observed in some patients during NAGLAZYME infusions and up to 24 hours after infusion. If anaphylaxis or severe allergic reactions occur, immediately discontinue infusion and initiate appropriate treatment, which may include resuscitation, epinephrine, administering additional antihistamines, antipyretics or corticosteroids.
•  Immune-mediated Reactions: Immune-mediated reactions can occur with NAGLAZYME. Monitor patients for the development of immune complex-mediated reactions while receiving NAGLAZYME.  
• Risk of Acute Cardiorespiratory Failure: Caution should be exercised when administering NAGLAZYME to patients susceptible to fluid volume overload. Consider a decreased total infusion volume and infusion rate when administering NAGLAZYME to these patients. Appropriate medical monitoring and support measures should be available during infusion.
• Acute Respiratory Complications: Sleep apnea is common in MPS VI patients and antihistamine pretreatment may increase the risk of apneic episodes. Appropriate respiratory support should be available during infusion. 
• Infusion Reactions: Pretreatment with antihistamines with or without antipyretics is recommended prior to the start of infusion to reduce the risk of infusion-reactions. If infusion reactions occur, decreasing the infusion rate, temporarily stopping the infusion, or administering additional antihistamines and/or antipyretics is recommended. 

ADVERSE REACTIONS

The most common adverse reactions (≥10%) are: rash, pain, urticaria, pyrexia, pruritus, chills, headache, nausea, vomiting, abdominal pain and dyspnea. The most common adverse reactions requiring interventions are infusion-related reactions 

USE IN SPECIFIC POPULATIONS

Pregnancy and Nursing Mothers: Clinical Surveillance Program available

Reference: FDA Package Insert