4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

NAGLAZYME is indicated for long-term enzyme replacement therapy in patients with Mucopolysaccharidosis VI (MPS VI, N-acetylgalactosamine 4-sulfatase deficiency, Maroteaux-Lamy syndrome).

4.2 Posology and Method of Administration

As for all lysosomal genetic disorders, it is of primary importance, especially in severe forms, to initiate treatment as early as possible, before appearance of non-reversible clinical manifestations of the disease.

Naglazyme treatment should be supervised by a physician experienced in the management of patients with MPS VI or other inherited metabolic diseases. Naglazyme should be administered by a healthcare professional in an appropriate clinical setting where resuscitation equipment to manage medical emergencies would be readily available.

4.2.1 Posology

The recommended dosage regimen of NAGLAZYME is 1 mg/kg body weight administered once weekly as an intravenous infusion over a period of no less than 4 hours.

4.2.1.1 Special Populations

Renal and Hepatic Impairment
The safety and efficacy of NAGLAZYME in patients with renal or hepatic insufficiency have not been evaluated and no alternative dose regimen can be recommended in these patients

Elderly (Geriatric Use)
The safety and efficacy of NAGLAZYME in patients older than 65 years has not been established, and no alternative dosage regimen can be recommended in these patients. It is not known whether older patients respond differently from younger patients.

Pediatric Use
There is no evidence for special considerations when NAGLAZYME is administered to the pediatric population. However, data from patients ≤ 1 year of age are limited [see Adverse Reactions (4.8) and Mechanism of Action (5.1)].

4.2.2 Method of Administration

NAGLAZYME must be diluted with 0.9% Sodium Chloride Injection, USP to a total volume of 100 mL or 250 mL based on the patient’s weight, prior to infusion [see Dilution and Administration Instructions (6.2.1)]. Patients who are susceptible to fluid overload or with a body weight of 20 kg or less should receive a total volume of 100 mL. Patients with a body weight greater than 20 kg should receive a total volume of 250 mL.
Adjust the initial infusion rate to allow approximately 2.5% of the total solution to be infused within the first hour.

4.3 Contraindications

Severe or life-threatening hypersensitivity to the active substance or to any of the excipients, if hypersensitivity is not controllable.

4.4 Warnings and Precautions

4.4.1 Spinal or Cervical Cord Compression

Spinal/cervical cord compression (SCC) with resultant myelopathy is a known and serious complication of MPS VI. SCC is expected to occur in the natural history of the disease, including in patients on NAGLAZYME. There have been post-marketing reports of patients treated with NAGLAZYME who experienced the onset or worsening of SCC requiring decompression surgery. Patients with MPS VI should be monitored for signs and symptoms of spinal/cervical cord compression (including back pain, paralysis of limbs below the level of compression, urinary and fecal incontinence) and given appropriate clinical care.

4.4.2 Anaphylaxis and Allergic Reactions

Anaphylaxis and severe allergic reactions have been observed in patients during and up to 24 hours after NAGLAZYME infusion. Some of the reactions were life-threatening and included anaphylaxis, shock, respiratory distress, dyspnea, bronchospasm, laryngeal edema, and hypotension. If anaphylaxis or other severe allergic reactions occur, NAGLAZYME should be immediately discontinued, and appropriate medical treatment should be initiated. In patients who have experienced anaphylaxis or other severe allergic reactions during infusion with NAGLAZYME, caution should be exercised upon rechallenge; appropriately trained personnel and equipment for emergency resuscitation (including epinephrine) should be available during infusion.

4.4.3 Immune-mediated Reactions

Type III immune complex-mediated reactions including membranous glomerulonephritis have been observed with NAGLAZYME, as with other enzyme replacement therapies. If immune-mediated reactions occur, discontinuation of the administration of NAGLAZYME should be considered, and appropriate medical treatment initiated. The risks and benefits of re-administering NAGLAZYME following an immune-mediated reaction should be considered. Some patients have successfully been re-challenged and have continued to receive NAGLAZYME under close clinical supervision.

4.4.4 Risk of Acute Cardio-respiratory Failure

Caution should be exercised when administering NAGLAZYME to patients susceptible to fluid volume overload such as in patients weighing 20 kg or less, patients with acute underlying respiratory illness, or patients with compromised cardiac and/or respiratory function, because congestive heart failure may result. Appropriate medical support and monitoring measures should be readily available during NAGLAZYME infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient.

4.4.5 Acute Respiratory Complications Associated with Administration

Sleep apnea is common in MPS VI patients and antihistamine pretreatment may increase the risk of apneic episodes. Evaluation of airway patency should be considered prior to initiation of treatment. Patients using supplemental oxygen or continuous positive airway pressure (CPAP) during sleep should have these treatments readily available during infusion in the event of an infusion reaction, or extreme drowsiness/sleep induced by antihistamine use.

Consider delaying NAGLAZYME infusions in patients who present with an acute febrile or respiratory illness because of the possibility of acute respiratory compromise during infusion of NAGLAZYME.

4.4.6 Infusion Reactions

Because of the potential for infusion reactions, patients should receive antihistamines with or without antipyretics prior to infusion. Despite routine pretreatment with antihistamines, infusion reactions, some severe, occurred in 33 of 59 (56%) patients treated with NAGLAZYME. Serious adverse reactions during infusion included laryngeal edema, apnea, pyrexia, urticaria, respiratory distress, angioedema, and anaphylactoid reaction. Severe adverse reactions included urticaria, chest pain, rash, dyspnea, apnea, laryngeal edema, and conjunctivitis.

The most common symptoms of drug-related infusion reactions were pyrexia, chills/rigors, rash, urticaria, dyspnea, nausea, vomiting, pruritis, erythema, abdominal pain, hypertension, and headache. Respiratory distress, chest pain, hypotension, angioedema, conjunctivitis, tremor, and cough were also reported. Infusion reactions began as early as Week 1 and as late as Week 146 of NAGLAZYME treatment. Twenty-three of 33 patients (70%) experienced recurrent infusion reactions during multiple infusions though not always in consecutive weeks.

Symptoms typically abated with slowing or temporary interruption of the infusion and administration of additional antihistamines, antipyretics, and occasionally corticosteroids. Most patients were able to complete their infusions. Subsequent infusions were managed with a slower rate of NAGLAZYME administration, treatment with additional prophylactic antihistamines, and, in the event of a more severe reaction, treatment with prophylactic corticosteroids.

If severe infusion reactions occur, immediately discontinue the infusion of NAGLAZYME and initiate appropriate treatment. The risks and benefits of re-administering NAGLAZYME following a severe reaction should be considered.

No factors were identified that predisposed patients to infusion reactions. There was no association between severity of infusion reactions and titer of anti-galsulfase antibodies.

4.5 Interactions with Other Medicinal Products and Other Forms of Interactions

No interaction studies have been performed.

4.6 Fertility, Pregnancy, Lactation, Carcinogenesis, Mutagenesis

4.6.1 Fertility

Reproduction studies have been performed in rats and rabbits at doses up to 3 mg/kg/day and have revealed no evidence of impaired fertility or harm to the embryo or fetus due to NAGLAZYME. [see Pre-clinical Safety (5.4)]

4.6.2 Pregnancy

Studies have not been conducted with NAGLAZYME in pregnant women. NAGLAZYME should be used during pregnancy only if clearly needed.

Reproduction studies have been performed in rats at intravenous doses 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 rabbits at intravenous 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 impaired fertility or harm to the fetus due to NAGLAZYME.

4.6.3 Lactation

It is not known whether NAGLAZYME is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NAGLAZYME is administered to a nursing mother.

4.6.4 Carcinogenesis, Mutagenesis

Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with NAGLAZYME.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Adverse Reactions

NAGLAZYME was studied in a randomized, double-blind, placebo-controlled trial in which 19 patients received weekly infusions of 1 mg/kg NAGLAZYME and 20 patients received placebo; of the 39 patients, 66% were female, and 62% were white, non-Hispanic. Patients were aged 5 years to 29 years. NAGLAZYME-treated patients were approximately 3 years older than placebo-treated patients (mean age 13.7 years versus 10.7 years, respectively).

Serious adverse reactions experienced in this trial included apnea, pyrexia and respiratory distress. Severe adverse reactions included chest pain, dyspnea, laryngeal edema, and conjunctivitis.

The most common adverse reactions requiring interventions were infusion reactions.

Table 1 summarizes the adverse reactions that occurred in the placebo-controlled trial in at least 2 patients more in the NAGLAZYME treated group than in the placebo-treated group.

Table 1: Adverse Reactions that Occurred in the Placebo-Controlled Trial in at least 2 Patients More in the NAGLAZYME Group than in the Placebo Group

5 PHARMACOLOGICAL PROPERTIES

5.1 Mechanism of Action

Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycan (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.

Clinical efficacy

A total of 56 patients with MPS VI, ages 5 years to 29 years, were enrolled in three clinical studies. The majority of patients had severe manifestations of the disease as evidenced by poor performance on a test of physical endurance.

Study ASB-03-05

In the randomized, double-blind, multicenter, placebo-controlled Phase III clinical study, 39 patients, aged 5 years to 29 years, with MPS VI received 1 mg/kg NAGLAZYME or placebo, once-weekly for 24 weeks. The primary efficacy endpoint was the number of meters walked in 12 minutes at Week 24 compared to the number of meters walked at baseline. Enrollment was restricted to patients who could walk more than 5 meters but less than 250 meters in 6 minutes of a 12-minute walk test (12-MWT) or no more than 400 meters at the 12-minute time point at baseline, (Table 2). All patients were treated with antihistamines prior to each infusion. The secondary efficacy endpoints were the rate of stairs climbed in three minutes and the urinary glycosaminoglycan (GAG) excretion of treated patients compared to placebo at Week 24 (Table 2).

The NAGLAZYME-treated group showed greater mean increase in the distance walked in 12 minutes (12-MWT) compared with the placebo group. Treated patients experienced a 5.7 stair per minute improvement in the 3 Minute Stair Climb relative to placebo-treated patients (Table 2). Treated patients also experienced a mean decrease in urinary GAG excretion of 238 ± 17.8 μg/mg creatinine (± Standard Error [SE]) following 24 weeks of treatment relative to placebo-treated patients. GAG results approached the normal range for age in the NAGLAZYME-treated group.

Table 2: Results from Placebo-Controlled Clinical Study (Study ASB-03-05)

Study ASB-03-06

Following the 24-week placebo-controlled study period, 38 patients from study ASB-03-05 received open-label NAGLAZYME for 72 weeks. Among the 19 patients who were initially randomized to NAGLAZYME and who continued to receive treatment for 72 weeks (total of 96 weeks), increases in the 12-MWT distance and in the rate of stair climbing were observed, compared to the start of the open-label period (mean [ ± SD] change): 72 ± 116 meters and 5.6 ± 10.6 stairs/minute, respectively). Among the 19 patients who were randomized initially to placebo for 24 weeks, and then crossed over to treatment with NAGLAZYME, the increases after 72 weeks of NAGLAZYME treatment compared to the start of the open-label period, (mean [ ± SD] change): were 118 ± 127 meters and 11.1 ± 10.0 stairs/minute, for the 12-MWT and the rate of stair climbing, respectively.

Bioactivity was evaluated with urinary GAG concentration. Overall, 95% of patients showed at least a 50% reduction in urinary GAG levels after 72 weeks of treatment with NAGLAZYME. No patient receiving NAGLAZYME reached the normal range for urinary GAG levels.

Study ASB-008

In an additional Phase 4, randomized, two-dose level study, four MPS VI patients <1 year of age were treated at 1 or 2 mg/kg/week for 53 to 153 weeks. Safety results in infants were consistent with results observed in patients 5 to 29 years old (see Adverse Reactions 4.8).

5.2 Pharmacodynamic Properties

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.

5.3 Pharmacokinetic Properties

The pharmacokinetic parameters of NAGLAZYME 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 3.

Table 3: Pharmacokinetic Parameters (Median, Range)