Summary Basis of Decision for Naglazyme

 

Clinical Pharmacology

Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycan (GAG). Mucopolysaccharidosis VI (MPS VI) is characterized by the absence or marked reduction in N-acetylgalactosamine 4-sulfatase which results in the accumulation of the GAG substrate, dermatan sulfate, throughout the body. This accumulation leads to widespread cellular, tissue, and organ dysfunction.

Galsulfase, the medicinal ingredient of 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.

The pharmacokinetic parametres of Naglazyme were evaluated in 13 patients with MPS VI who received 1 mg/kg of galsulfase as a weekly 4-hour infusion for 24 weeks. Development of anti-galsulfase antibodies appears to affect galsulfase pharmacokinetics however the data are limited. Due to the large assay variability, these data are difficult to interpret and the impact of the observed drug immunogenicity on clinical efficacy remains unclear. This has been captured in the Naglazyme Product Monograph.

In vivo pharmacodynamics studies, ranging from 5 weeks to 15  months duration, were conducted utilizing cats with the MPS VI genotype. Routes of administration were intravenous (IV), intraarticular (IA) and intrathecal (IT). Results of these studies revealed that long-term treatment of MPS VI -affected cats with Naglazyme was well tolerated by all routes and improved many characteristic morphological changes associated with the disease. Findings included decreased urinary GAG excretion, reduction of storage vacuoles in Kupffer cells and connective tissue, an increase in bone mineral volume, greater mobility and flexibility, and improvement in the neurological symptoms secondary to spinal cord compression. When treatment was initiated before symptoms were evident, that is (i.e.) shortly after birth, there was also a significant positive impact on bone growth and remodeling.

Rapid degradation and elimination of stored GAG did not induce toxicity, and weekly dosing was sufficient to maintain adequate tissue levels. The lowest dose that resulted in significant clinical improvement in affected cats was 1.0 mg/kg body weight (bw)/week. Naglazyme was generally well-tolerated in single and repeat-dose toxicity studies at doses up to 20 mg/kg bw. Reproductive toxicity studies demonstrated that Naglazyme did not impair fertility potential/implantation, and did not result in maternal toxicity, embryo-fetal toxicity nor teratogenicity. The primary findings across all toxicology studies were reddening of the skin inside the ears and/or facial edema in dogs, swelling of the mouth, nose, and/or paws in rats, and serocellular/pustular epidermititis in monkeys. These findings were, in part, considered to be related to the repeated administration of a heterologous protein with or without the subsequent development of an anaphylactic type hypersensitivity reaction, and/or to the polysorbate 80 in the Naglazyme formulation, which has been shown to have histamine-releasing properties. A statement was therefore included in the product monograph to indicate that there is the potential for a hypersensitivity reaction while on treatment.

The non-clinical toxicology data base was considered adequate to assess the safety profile of Naglazyme and support its use in the proposed clinical populations provided adequate safety precautions are taken to monitor for hypersensitivity reactions during infusion.

For further details, please refer to the Naglazyme Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Naglazyme was primarily evaluated in one Phase III, double-blind, placebo-controlled study (ASB-03-05). In addition, an open-label extension study (ASB-03-06), and four open-label clinical studies, including ASB-00-01, ASB-01-04, ASB-008, (conducted in four infants) were evaluated. A Phase 4 study, the Clinical Surveillance Program (CSP) to evaluate long-term safety and efficacy data is ongoing.

The Phase III study was a randomized, double-blind, placebo-controlled study 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 vs. 10.7 years, respectively). Enrollment was restricted to patients with a 12 minute walk distance of 5 to 400 metres. All patients were treated with antihistamines prior to each infusion. Following the 24-week placebo-controlled study period, 38 patients received open-label Naglazyme for 72 weeks.

The primary endpoint in this pivotal study was the distance walked in the 12 minute walk test (12 MWT). The secondary endpoints were a 3-minute stair climb test and urinary GAG levels.

The Naglazyme-treated group showed greater mean increases in the distance walked in 12 minutes (12 minute walk test, 12-MWT) compared with the placebo group. In the 3-minute stair climb test, the rate in the Naglazyme-treated group increased over time [mean (± standard deviation (SD))]: 19 ± 13 stairs per minute at baseline and 27 ± 17 stairs per minute at Week 24. The placebo group showed a nearly constant rate of number of stairs climbed over time [mean (± SD)]: 31 ± 18 stairs per minute at baseline and 33 ± 20 stairs per minute at Week 24). The difference in change in rates [mean (± SD)] for the Naglazyme and placebo patients was 6 ± 3 stairs per minute (p = 0.053).

Following the 24-week placebo-controlled study period, 38 patients received open-label Naglazyme for 72 weeks (Study ASB-03-06). Among the 19 patients who were initially randomized in 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 metres 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 metres 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.

The four open-label clinical studies (ASB-00-01, ASB-01-04, ASB-03-06, ASB-008 CSP) were conducted in MPS VI patients aged 3  months to 29 years with Naglazyme administered at doses of 0.2 mg/kg [number (n) = 2], 1 mg/kg (n = 55), and 2 mg/kg (n = 2). The mean exposure to the recommended dose of Naglazyme (1 mg/kg) was 138 weeks (range = 54 to 261 weeks). Two infants (12.1  months and 12.7 months) were exposed to 2 mg/kg of Naglazyme for 105 and 81 weeks, respectively. Observed adverse events (AEs) in the four open-label clinical studies (up to 261 weeks treatment) were not different in nature or severity to those observed in the Phase III study. No patients discontinued during open-label treatment with Naglazyme due to AEs. Safety results in infants were consistent with results observed in patients 5 to 29 years old.

During ASB-008 a Phase IV, randomized, two-dose level study, four MPS VI patients (3 months to 12.7 months) 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.

Based on the efficacy results from the Phase III study, and on the safety results from all Naglazyme studies and post-marketing data, the benefit-risk of Naglazyme therapy is considered favourable for MPS VI patients in Canada. Safety and efficacy data were updated in the Naglazyme Product Monograph.

For more information, refer to the Naglazyme Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

Due to the low number of patients in clinical studies conducted, the clinical safety evaluation was based on adverse event (AE) data from all Naglazyme studies (previously described in the Clinical Efficacy section) that were combined and reviewed in a single, clinical safety analysis.

All patients treated with Naglazyme (59/59) in clinical studies conducted reported at least one adverse event (AE). The majority (42/59; 71%) of patients experienced at least one adverse drug reaction (ADR). The most common adverse reactions were pyrexia (50%), rash, pruritus, urticaria, chills/rigors, nausea, headache, abdominal pain, vomiting and dyspnea (3%). Serious adverse reactions included laryngeal edema, apnea, pyrexia, urticaria, respiratory distress, angioedema, asthma, and anaphylactoid reaction.

Because of the potential for infusion reactions, patients should receive antihistamines with or without antipyretics prior to infusion. Despite routine pre-treatment with antihistamines, infusion reactions, some severe, have 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.

In a study with 19 patients treated with Naglazyme compared to 20 patients treated with placebo, the most common ADRs were pain (abdominal, ear, joint, and general pain, 47-32% vs. 35-5%, respectively), conjunctivitis (21% vs. 0) and chills (21% vs 0).

In addition to infusion reactions reported in clinical studies, serious reactions which occurred during Naglazyme infusion in the worldwide marketing experience include anaphylaxis, shock, hypotension, bronchospasm, and respiratory failure. Appropriate warnings and precautions are in place in the approved Naglazyme Product Monograph to address the identified safety concerns.

For more information, refer to the Naglazyme Product Monograph, approved by Health Canada and available through the Drug Product Database.