Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study

Abstract

Objective: To assess the efficacy and safety of enzyme replacement therapy (ERT) with BMN 110 (elosulfase alfa) in patients with Morquio A syndrome (mucopolysaccharidosis IVA).

Methods: Patients with Morquio A aged ≥5 years (N = 176) were randomised (1:1:1) to receive elosulfase alfa 2.0 mg/kg/every other week (qow), elosulfase alfa 2.0 mg/kg/week (weekly) or placebo for 24 weeks in this phase 3, double-blind, randomised study. The primary efficacy measure was 6-min walk test (6MWT) distance. Secondary efficacy measures were 3-min stair climb test (3MSCT) followed by change in urine keratan sulfate (KS). Various exploratory measures included respiratory function tests. Patient safety was also evaluated.

Results: At week 24, the estimated mean effect on the 6MWT versus placebo was 22.5 m (95 % CI 4.0, 40.9; P = 0.017) for weekly and 0.5 m (95 % CI -17.8, 18.9; P = 0.954) for qow. The estimated mean effect on 3MSCT was 1.1 stairs/min (95 % CI -2.1, 4.4; P = 0.494) for weekly and -0.5 stairs/min (95 % CI -3.7, 2.8; P = 0.778) for qow. Normalised urine KS was reduced at 24 weeks in both regimens. In the weekly dose group, 22.4 % of patients had adverse events leading to an infusion interruption/discontinuation requiring medical intervention (only 1.3 % of all infusions in this group) over 6 months. No adverse events led to permanent treatment discontinuation.

Conclusions: Elosulfase alfa improved endurance as measured by the 6MWT in the weekly but not qow dose group, did not improve endurance on the 3MSCT, reduced urine KS, and had an acceptable safety profile.

Fig. 1

a Mean change from baseline over time in distance walked in a 6-min walk test (6MWT) (model-based repeated measures ANCOVA). Error bars represent 95 % CI of least squared mean change from baseline. *P-value vs. placebo. Qow: every other week. b Cumulative distribution plot of response in 6 min walk test (6MWT) distance (ITT population) based on observed data at week 24: for any selected walk test distance on the x-axis the proportion of subjects achieving the 6MWT distance is shown for each treatment group

Fig. 2

Mean percent change from baseline over time in normalised urine keratan sulfate (KS) (model-based repeated measures ANCOVA). Error bars represent standard error of least squared mean change from baseline. No P-values are given as a step-down testing procedure was used as an adjustment for multiplicity with the secondary endpoints; this testing procedure implied that the urine KS results could only be declared significant if the 3-min stair climb test showed a significant result. qow: every other week