Abstract:
Alpha-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.
