Dataset Information

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.

SUBMITTER: Hendriksz CJ

PROVIDER: S-EPMC4206772 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Managed access agreements provide a crucial mechanism whereby real-world data can be collected systematically to reduce uncertainty around available clinical and economic data, whilst providing the opportunity to identify patient sub-populations who are most likely to benefit from a new treatment. This manuscript aims to share learnings from the first managed access agreement, which was initiated following positive conditional approval in 2015 from the National Institute for Health and Care Excellence (NICE) for elosulfase alfa, an enzyme replacement therapy for the treatment of mucopolysaccharidosis type IVA (MPS IVA). This managed access agreement enabled the collection of comprehensive real-world data for patients with MPS IVA, with results demonstrating that patients starting elosulfase alfa treatment showed gains similar to those seen in the pivotal trial for outcomes including endurance, respiratory and cardiac function, pain, quality of life measures and urinary keratan sulfate levels. In addition, former trial patients continued to see benefits in both clinical assessments and quality of life/activities of daily living nine years after beginning treatment. Key strengths of the process included recruitment of a high proportion of MPS IVA patients treated in England (72/89 known eligible patients) with a wide range of ages (2-58 years). Participation of a patient organisation (the MPS society) ensured that the patient voice was present throughout the process, whilst a contract research organisation (Rare Disease Research Partners) ensured that patients were represented when interpreting agreement criteria and during patient assessment meetings. Longer-term follow-up will be required for several MPS IVA outcomes (e.g. skeletal measures) to further reduce uncertainty, and continued follow-up of patients who had stopped treatment was found to be challenging. The burden associated with this managed access agreement was found to be high for patients, physicians, patient organisations, NHS England and the manufacturer, therefore costs and benefits of future agreements should be considered carefully before initiation. Through evaluation of the strengths and limitations of this process, it is hoped that learnings from this managed access agreement can be used to inform future agreements.