Enzyme replacement therapy outcomes across the disease spectrum: Findings from the mucopolysaccharidosis VI Clinical Surveillance Program

Abstract

The impact of galsulfase enzyme replacement therapy in patients with mucopolysaccharidosis (MPS) VI with phenotypes at either end of the disease spectrum was evaluated. The MPS VI Clinical Surveillance Program (CSP) was established to collect long-term observational data from routine clinical and laboratory assessments. A subanalysis of the CSP was performed in patients with pretreatment urinary glycosaminoglycan (uGAG) levels <100 μg/mg and ≥200 μg/mg creatinine (low-and high-uGAG) who had received galsulfase for ≥6 months. uGAG, 6-minute walk test (6MWT), 3-minute stair climb test (3MSCT), pulmonary function measures, height/growth, cardiac function, and safety were evaluated. Patients with a high-uGAG level at pre-treatment baseline (N = 68) showed greater impairments in endurance and pulmonary function than those with low-baseline uGAG levels (N = 39). From pre-treatment baseline, the distance walked on the 6MWT in the low-and high-uGAG groups increased by a mean (±SD) of 49 (±151) meters and 42 (±165) meters (median follow-up 5.5 and 7.7 years), respectively. The number of stairs/min climbed in the 3MSCT in the low-and high-uGAG groups increased by a mean of 18 (±33) and 30 (±45) (median follow-up 2.8 and 3.5 years), respectively. Overall, pulmonary function remained unchanged for both groups. No impact was seen on cardiac function. Galsulfase was generally well tolerated in both groups, with most adverse events being MPS-related complications unrelated to galsulfase. Results of this CSP sub-analysis suggest that galsulfase stabilizes MPS VI in the long-term and has an acceptable safety profile, regardless of baseline disease severity. K E Y W O R D S disease severity, urinary GAG, efficacy, enzyme replacement therapy, galsulfase, Maroteaux-Lamy syndrome, mucopolysaccharidosis VI, registry, safety

Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations

“…Improvement or stabilization of 6MWT have been reported for MPS I, II, IV and VI after 1-3 years of treatment [36,[38][39][40][41][42][43]51,52,96,97]. For MPS II and VI there are data of longer observations for 4-7 years showing a mean increase around 65 m or more [37,40,42,70]. 3MSC (used to test MPS IV and VI patients) and 12MWT (used only for MPS VI) gave similar results [39,42,52,70,96,97].…”

“…For MPS II and VI there are data of longer observations for 4-7 years showing a mean increase around 65 m or more [37,40,42,70]. 3MSC (used to test MPS IV and VI patients) and 12MWT (used only for MPS VI) gave similar results [39,42,52,70,96,97]. Berger et al showed very limited improvement of 6MWT and 3MSC after one year in relatively well-doing Morquio A patients enrolled in the MOR-008 trial.…”

“…Some of these studies are the phase III extension studies and involve the same patients previously enrolled in the Phase III trials [36][37][38][39]71,96,114]. The others are mostly observational studies conducted in a single center on a limited number of cases, or studies performed on data extracted from disease registries [29,34,37,[40][41][42][43][44][47][48][49][50][51][52]70,74,77,84,85,97,116]. Disease registries are a helpful tool to collect data on rare diseases and there is now a huge number of disease registries available for many rare diseases.…”

“…During the years of observation of ERT-treated MPS patients, it has become clear that ERT is not effective neither on tracheal cartilage deformities nor in clearing the extrinsic mediastinal storage [65][66][67][68]. Nevertheless, improvements were seen in spirometric evaluations (FEV1, FVC and MVV) according to most of the long-term studies [36][37][38]43,49,[69][70][71][72]. Muenzer et al found improvement of FVC only in patients younger than 18 [38].…”

“…Muenzer et al found improvement of FVC only in patients younger than 18 [38]. FEV1 and FVC were stabilized from baseline in severe and less severe MPS VI patients after 8.2 and 6.2 years, respectively [70]. Cardiopulmonary exercise tests performed on a small group of Morquio A patients enrolled in the MOR-008 study suggested that ERT improves aerobic efficiency, as demonstrated by an increased performance of work at reduced metabolic demand [140].…”