Abstract
ObjectivesAlpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder resulting from deficient lysosomal alpha-mannosidase activity. Clinical manifestations include progressive balance disorders, immune deficiency, skeletal abnormalities and cognitive deficits beginning in early childhood. Enzyme replacement therapy with recombinant human alpha-mannosidase (velmanase alfa) is scheduled for clinical development in the US beginning in 2020 and has been approved in the EU for treatment of non-neurological manifestations in cases of mild to moderate disease. This study assessed effects of velmanase alfa on fine and gross motor proficiency in children and adults. MethodsIntegrated Bruininks-Oseretsky (BOT-2) test of Motor Proficiency data from velmanase alfa clinical trials was stratified by age for 14 adults and 19 children treated for up to 4 years. ResultsPatients showed global developmental delays at baseline. For the combined adult and pediatric group there was a statistically significant increase (improvement) in BOT-2 total point score of 13% (p = .035, 95% CI 1.0, 25.0) from baseline to last observation. When stratified by pediatric versus adult patients, there was improvement in BOT-2 total point score in patients <18 years (mean percent increase from baseline to last observation 23%) compared to adults (mean decrease of −0.7%). Subtest analysis of individual BOT-2 items captured some improvement following velmanase alfa treatment in pediatric patients. ConclusionsThere was limited ability to assess the BOT-2 change responses in adults. Pediatric patients showed stability or improvement in scaled scores relative to healthy peers, indicating continued skill acquisition, which may increase independence and contribute to improved patient quality of life.
Highlights
Data on BOT-2 and other functional outcomes were obtained from an integrated analysis of long-term safety and efficacy of velmanase alfa in 33 pediatric and adult patients with alpha-mannosidosis
Individual patient data from previous phase 1, 2 or 3 velmanase alfa trials and extension studies were integrated into a single database for analyses
Data were included for patients receiving weekly intravenous infusions of 1 mg/kg velmanase alfa through either followon extension studies or compassionate use programs
Summary
Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder resulting from deficient lysosomal alpha-mannosidase activity. This study assessed effects of velmanase alfa on fine and gross motor proficiency in children and adults. Methods: Integrated Bruininks-Oseretsky (BOT-2) test of Motor Proficiency data from velmanase alfa clinical trials was stratified by age for 14 adults and 19 children treated for up to 4 years. For the combined adult and pediatric group there was a statistically significant increase (improvement) in BOT-2 total point score of 13% (p = .035, 95% CI 1.0, 25.0) from baseline to last observation. When stratified by pediatric versus adult patients, there was improvement in BOT-2 total point score in patients < 18 years (mean percent increase from baseline to last observation 23%) compared to adults (mean decrease of −0.7%). Pediatric patients showed stability or improvement in scaled scores relative to healthy peers, indicating continued skill acquisition, which may increase independence and contribute to improved patient quality of life
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