Harmatz, PaulCattaneo, FedericaArdigo, DiegoGeraci, SilviaHennermann, Julia B.Guffon, NathalieLund, AllanHendriksz, Christian J.Borgwardt, Line2019-10-152019-10-152018-06Harmatz, P., Cattaneo, F., Ardigo, D. et al. 2018, 'Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase) : novel global treatment response model and outcomes in patients with alpha-mannosidosis', Molecular Genetics and Metabolism, vol. 124, pp. 152-160.1096-7182 (print)1096-7206 (online)10.1016/j.ymgme.2018.04.003http://hdl.handle.net/2263/71823Alpha-mannosidosis is an ultra-rare monogenic disorder resulting from a deficiency in the lysosomal enzyme alpha-mannosidase, with a prevalence estimated to be as low as 1:1,000,000 live births. The resulting accumulation of mannose-rich oligosaccharides in all tissues leads to a very heterogeneous disorder with a continuum of clinical manifestations with no distinctive phenotypes. Long-term enzyme replacement therapy (ERT) with velmanase alfa is approved in Europe for the treatment of non-neurological manifestations in patients with mild to moderate alpha-mannosidosis. The clinical heterogeneity and rarity of the disease limit the sensitivity of single parameters to detect clinically relevant treatment effects. Thus, we propose a novel multiple variable responder analysis to evaluate the efficacy of ERT for alpha-mannosidosis and present efficacy analyses for velmanase alfa using this method. Global treatment response to velmanase alfa (defined by response to ≥2 domains comprising pharmacodynamic, functional, and quality of life outcomes) was applied post hoc to data from the pivotal placebo-controlled rhLAMAN-05 study and to the longer-term integrated data from all patients in the clinical development program (rhLAMAN-10). After 12 months of treatment, a global treatment response was achieved by 87% of patients receiving velmanase alfa (n=15) compared with 30% of patients receiving placebo (n=10). Longer-term data from all patients in the clinical program (n=33) showed 88% of patients were global responders, including all (100%) pediatric patients (n=19) and the majority (71%) of adult patients (n=14). The responder analysis model demonstrates a clinically meaningful treatment effect with velmanase alfa and supports the early initiation and continued benefit of longer-term treatment of all patients with alpha-mannosidosis with this ERT.en© 2018 The Authors. This is an open access article under the CC BY-NC-ND license.Alpha-mannosidosisVelmanase alfaGlobal treatment response modelOMIM 248500Enzyme Commission number: 3.2.1.24Enzyme replacement therapy (ERT)Article