Efficacy and safety of Velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial

• Published in: Journal of inherited metabolic disease Vol. 41; no. 6; pp. 1215 - 1223
• Main Authors: Borgwardt, Line, Guffon, Nathalie, Amraoui, Yasmina, Dali, Christine I., De Meirleir, Linda, Gil-Campos, Mercedes, Heron, Bénédicte, Geraci, Silvia, Ardigò, Diego, Cattaneo, Federica, Fogh, Jens, Van den Hout, J. M. Hannerieke, Beck, Michael, Jones, Simon A., Tylki-Szymanska, Anna, Haugsted, Ulla, Lund, Allan M.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01-12-2018; Blackwell Publishing Ltd
• Subjects: Adolescent; Adult; alpha-Mannosidase - adverse effects; alpha-Mannosidase - therapeutic use; alpha-Mannosidosis - enzymology; alpha-Mannosidosis - therapy; Biochemistry; Child; Child, Preschool; Double-Blind Method; Double-blind studies; Enzyme Replacement Therapy; Europe; Female; Human Genetics; Humans; Internal Medicine; Male; Mannosidosis; Medicine; Medicine & Public Health; Metabolic Diseases; Oligosaccharides; Original; Original Article; Patients; Pediatrics; Quality of Life; Recombinant Proteins - adverse effects; Recombinant Proteins - therapeutic use; Severity of Illness Index; Treatment Outcome; Young Adult; Europe
• ISSN: 0141-8955; 1573-2665
• DOI: 10.1007/s10545-018-0185-0

Introduction
This 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.
Methods
Twenty-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).
Results
Mean 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.
Conclusions
These 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.