Long-term endurance and safety of elosulfase alfa enzyme replacement therapy in patients with Morquio A syndrome

Long-term efficacy and safety of elosulfase alfa enzyme replacement therapy were evaluated in Morquio A patients over 96 weeks (reaching 120 weeks in total from pre-treatment baseline) in an open-label, multi-center, phase III extension study. During this extension of a 24-week placebo-controlled phase III study, all patients initially received 2.0 mg/kg elosulfase alfa either weekly or every other week, prior to establishment of 2.0 mg/kg/week as the recommended dose, at which point all patients received weekly treatment. Efficacy measures were compared to baseline of the initial 24-week study, enabling analyses of changes over 120 weeks. In addition to performing analyses for the entire intent-to-treat (ITT) population (N = 173), analyses were also performed for a modified per-protocol (MPP) population (N = 124), which excluded patients who had orthopedic surgery during the extension study or were non-compliant with the study protocol (as determined by ≥ 20% missed infusions). Six-minute walk test (6MWT) was the primary efficacy measure; three-minute stair climb test (3MSCT) and normalized urine keratan sulfate (uKS) were secondary efficacy measures. Mean (SE) change from baseline to Week 120 in 6MWT distance was 32.0 (11.3) m and 39.9 (10.1) m for patients receiving elosulfase alfa at 2.0 mg/kg/week throughout the study (N = 56) and 15.1 (7.1) m and 31.7 (6.8) m in all patients combined, regardless of dosing regimen, for the ITT and MPP populations, respectively. Further analyses revealed that durability of 6MWT improvements was not impacted by baseline 6MWT distance, use of a walking aid, or age. Mean (SE) change at Week 120 in the 3MSCT was 5.5 (1.9) and 6.7 (2.0) stairs/min for patients receiving elosulfase alfa at 2.0 mg/kg/week throughout the study and 4.3 (1.2) and 6.8 (1.3) stairs/min in all patients combined, regardless of dosing regimen, for the ITT and MPP populations, respectively Across all patients, mean (SE) change at Week 120 in normalized uKS was − 59.4 (1.8)% and − 62.3 (1.8)% in the ITT and MPP populations, respectively. In the absence of a placebo group, significance of the sustained improvements could not be evaluated directly. However, to provide context for interpretation of results, comparisons were performed with untreated patients from a Morquio A natural history study. In contrast to the results of the extension study, the untreated patients experienced constant uKS levels and a gradual decline in endurance test results over a similar period of time. Differences from the untreated natural history study patients were significant for 6MWT, 3MSCT, and uKS outcomes for the cohort of patients receiving optimal dosing throughout the study and for all cohorts pooled together, for both ITT and MPP populations (P < 0.05). Safety findings were consistent with those of the initial 24-week study, with no new safety signals identified.