Enzyme replacement therapy for treating mucopolysaccharidosis type IVA (Morquio A syndrome): effect and limitations

Abstract

Introduction Following a Phase III, randomized, double-blind, placebo (PBO)-controlled, multinational study in subjects with mucopolysaccharidosis IVA (MPS IVA), enzyme replacement therapy (ERT) of elosulfase alfa has been approved in several countries. The study was designed to evaluate safety and efficacy of elosulfase alfa in patients with MPS IVA aged 5 years and older. Areas covered Outcomes of clinical trials for MPS IVA have been described. Subjects received either 2.0 mg/kg/week, 2.0 mg/kg/every other week, or PBO, for 24 weeks. The primary endpoint was the change from baseline 6-min walk test (6MWT) distance compared to PBO. The 6MWT results improved in patients receiving 2 mg/kg weekly compared to PBO. The every other week regimen resulted in walk distances comparable to PBO. There was no change from baseline in the 3 Min Stair Climb Test in both treatment groups. Following completion of the initial study, patients, who continued to receive elosulfase alfa 2 mg/kg weekly (QW) for another 48 weeks (for a total of up to 72-week exposure), did not show additional improvement on 6MWT. Expert opinion We suggest that ERT is a therapeutic option for MPS IVA, providing a modest effect and the majority of the effects are seen in the soft tissues.

Mucopolysaccharidosis IVA and glycosaminoglycans

“…Patients in the 2 mg/kg QW treatment group showed a significant change, 22.5 m (95% CI 4.0, 40.9; P = 0.017) in the 6MWT, compared to placebo at week 24, while patients in the 2 mg/kg QOW treatment group performed similarly to those in the placebo group [55]. Several exploratory analyses were conducted by the FDA Advisory Committee to better assess the clinical meaningfulness of this result [121,122]. Patients who walked shorter distances at baseline (6MWT ≤ 200 m) had a greater improvement in walking distance than those who walked >200 m at baseline.…”

“…Patients who walked ≤200 m at baseline showed a mean change in 6MWT from baseline to week 24 of 53 ± 67 m on 2 mg/kg QW treatment vs. 13 ± 39 m on placebo; while patients who walked >200 m at baseline showed a mean change in 6MWT from baseline to week 24 of 25 ± 49 m on 2 mg/kg QW treatment vs. 14 ± 57 m on placebo [55,123]. Based on long-term data from an extension study, patients who continued to receive 2 mg/kg QW for another 48 weeks (a total of 72-weeks treatment), did not show further improvement on 6MWT beyond what was demonstrated during the first 24-week placebo-controlled trial [122]. There was no comparable placebo group in this extension trial [124].…”

“…There was no comparable placebo group in this extension trial [124]. It is noteworthy that patients, who received placebo during the initial 24-week controlled trial and were subsequently randomized to receive 2 mg/kg QW in the extension study, did not show any improvement in 6MWT compared to baseline [93,121,122]. …”

“…The 6MWT was originally developed to measure the sub maximal level of functional capacity in adult patients with moderate to severe heart or lung diseases, as a predictor of morbidity and mortality in these patients [122]. The 6MWT has been adopted to indicate clinical improvement in several LSDs prior to U.S. marketing approval, including Pompe disease, MPS I, MPS II, and MPS VI.…”

“…Two therapies, ERT and HSCT, are clinically available for MPS IVA [32,33,50,51,53–57]. Management of difficult airway and anesthesia procedures have also improved the lives of these patients [32,51,58,59].…”