Abstract
IntroductionThis phase III, double-blind, randomised, placebo-controlled trial (and extension phase) was designed to assess the efficacy and safety of velmanase alfa (VA) in alpha-mannosidosis (AM) patients.MethodsTwenty-five patients were randomised to weekly 1 mg/kg VA or placebo for 52 weeks. At study conclusion, placebo patients switched to VA; 23 patients continued receiving VA in compassionate-use/follow-on studies and were evaluated in the extension phase [last observation (LO)]. Co-primary endpoints were changes in serum oligosaccharide (S-oligo) and in the 3-min stair-climb test (3MSCT).ResultsMean relative change in S-oligo in the VA arm was −77.6% [95% confidence interval (CI) −81.6 to −72.8] at week 52 and −62.9% (95% CI −85.8 to −40.0) at LO; mean relative change in the placebo arm was −24.1% (95% CI −40.3 to −3.6) at week 52 and −55.7% (95% CI −76.4 to −34.9) at LO after switch to active treatment. Mean relative change in 3MSCT at week 52 was −1.1% (95% CI −9.0 to 7.6) and − % (95% CI −13.4 to 6.5) for VA and placebo, respectively. At LO, the mean relative change was 3.9% (95% CI −5.5 to 13.2) in the VA arm and 9.0% (95% CI −10.3 to 28.3) in placebo patients after switch to active treatment. Similar improvement pattern was observed in secondary parameters. A post hoc analysis investigated whether some factors at baseline could account for treatment outcome; none of those factors were predictive of the response to VA, besides age.ConclusionsThese findings support the utility of VA for the treatment of AM, with more evident benefit over time and when treatment is started in the paediatric age.
Highlights
Introduction This phaseIII, double-blind, randomised, placebo-controlled trial was designed to assess the efficacy and safety of velmanase alfa (VA) in alpha-mannosidosis (AM) patients
Prespecified criteria for early discontinuation due to demonstrated efficacy were not reached at week 26
Long-term follow-up data were available for 23 patients (Supplementary Fig. 1)
Summary
Introduction This phaseIII, double-blind, randomised, placebo-controlled trial (and extension phase) was designed to assess the efficacy and safety of velmanase alfa (VA) in alpha-mannosidosis (AM) patients. At LO, the mean relative change was 3.9% (95% CI −5.5 to 13.2) in the VA arm and 9.0% (95% CI −10.3 to 28.3) in placebo patients after switch to active treatment. AM is characterised by a deficiency of the lysosomal enzyme, alpha-mannosidase, caused by pathogenic sequence variants in the MAN2B1 gene. This deficiency leads to accumulation of mannose-rich oligosaccharides, causing impaired cellular function and apoptosis, which leads to significant and diverse adverse clinical manifestations (Beck et al 2013; Borgwardt et al 2015). Not all patients are eligible for HSCT or can be matched with compatible donors; HSCT results are variable, and treatment carries mortality risks (Mynarek et al 2012; Danielsen et al 2013)
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