Use of the Bruininks-Oseretsky test of motor proficiency (BOT-2) to assess efficacy of velmanase alfa as enzyme therapy for alpha-mannosidosis

Dawn Phillips, Julia B Hennermann, Anna Tylki-Szymanska, Line Borgwardt, Mercedes Gil-Campos, Nathalie Guffon, Yasmina Amraoui, Silvia Geraci, Diego Ardigò, Federica Cattaneo, Allan M Lund, Dawn Phillips, Julia B Hennermann, Anna Tylki-Szymanska, Line Borgwardt, Mercedes Gil-Campos, Nathalie Guffon, Yasmina Amraoui, Silvia Geraci, Diego Ardigò, Federica Cattaneo, Allan M Lund

Abstract

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.

© 2020 The Authors.

Figures

Fig. 1
Fig. 1
Numbers of patients and contributing studies to integrated analysis.
Fig. 2
Fig. 2
The BOT-2 test includes subtests for fine motor precision, fine motor integration. Manual dexterity, upper limb and bilateral coordination, balance, running speed and agility, and strength. Subset point scores can be used to derive scaled and age-adjusted scores in pediatric patients.
Fig. 3
Fig. 3
BOT-2 total point score by time point and age groups. The median BOT-2 total point score absolute values are plotted for the total population, and pediatric and adult groups for time points with greater than 2 observations (numbers next to symbols indicate number of observations).

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