Objectives: Alpha-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. 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. Results: Patients 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. Conclusions: There 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.
Phillips, D., Hennermann, J. B., Tylki-Szymanska, A., Borgwardt, L., Gil-Campos, M., Guffon, N., … Lund, A. M. (2020). Use of the Bruininks-Oseretsky test of motor proficiency (BOT-2) to assess efficacy of velmanase alfa as enzyme therapy for alpha-mannosidosis. Molecular Genetics and Metabolism Reports, 23. https://doi.org/10.1016/j.ymgmr.2020.100586