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

ObjectiveTo assess the efficacy and safety of enzyme replacement therapy (ERT) with BMN 110 (elosulfase alfa) in patients with Morquio A syndrome (mucopolysaccharidosis IVA).MethodsPatients 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.ResultsAt 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.ConclusionsElosulfase 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-014-9715-6) contains supplementary material, which is available to authorized users.

Safety and physiological effects of two different doses of elosulfase alfa in patients with morquio a syndrome: A randomized, double‐blind, pilot study

“…Safety results were similar for the two dosing groups, with AEs reported by the investigator as study drug‐related occurring in similar system organ classes and of similar type. In line with what has been described previously [Hendriksz et al, 2012; Hendriksz et al, [Link]], study drug‐related AEs were mild to moderate in severity. The only SAE that was reported, hospitalization for medical device removal, was unrelated to the study drug.…”

“…Median age was 11.5 years, with only three patients (in the 2.0 mg/kg/week group) who were older than 18 years. Patients showed better endurance in the 6MWT and 3MSCT (Table I) than the subjects assessed in the previous phase 3 study in Morquio A in which the entry criterion was 6MWT distance ≥30 and ≤325 m during screening (mean 6MWT distance 372.2 m in this study vs. 203.9–211.9 m in the phase 3 study; mean 3MSCT result 65.0 stairs/min in this study, vs. 27.1–30.0 stairs/min in the phase 3 study) [Hendriksz et al, [Link]]. Only one patient in this study, in the 2.0 mg/kg/week group, used a walking aid during the test.…”

“…In the past, several studies have used endurance tests such as the 6MWT, and more recently the 3MSCT, to assess the impact of ERT on overall disease progression in MPS disorders [Harmatz et al, 2006; Hendriksz et al, [Link]; Muenzer et al, 2006; Wraith et al, 2004]. However, the physiological correlates of these tests are not well characterized.…”

“…Several studies provided consistent evidence of clinically meaningful and sustained improvement in health and function of Morquio A patients treated with elosulfase alfa at 2.0 mg/kg/week as assessed by measures of endurance (e.g., 6‐min walk test [6MWT]), respiratory function, growth, and quality of life [Hendriksz et al, 2012; Hendriksz et al, [Link]; Jones et al, 2015]. In the pivotal phase 3, double‐blind, placebo‐controlled study including 176 Morquio A patients with impaired endurance/mobility, elosulfase alfa showed an acceptable safety profile, comparable with ERTs for other MPS disorders, and a statistically significant impact on walking distance in the 6MWT after 24 weeks of treatment.…”

“…No significant impact was seen in the 3‐min stair climb test (3MSCT). In addition, a rapid and sustained reduction in urine KS (uKS) levels and numerical improvements in several other efficacy outcomes, including respiratory function and growth, were observed [Hendriksz et al, [Link]; Hendriksz et al, 2015b]. …”