Comprehensive long-term efficacy and safety of recombinant human alpha-mannosidase (velmanase alfa) treatment in patients with alpha-mannosidosis

Abstract

Introduction: Long-term outcome data provide important insights into the clinical utility of enzyme replacement therapies. Such data are presented for velmanase alfa in the treatment of alpha-mannosidosis (AM).

Methods: Patient data (n = 33; 14 adults, 19 paediatric) from the clinical development programme for velmanase alfa were integrated in this prospectively-designed analysis of long-term efficacy and safety. Patients who participated in the phase I/II or phase III trials and were continuing to receive treatment after completion of the trials were invited to participate in a comprehensive evaluation visit to assess long-term outcomes. Primary endpoints were changes in serum oligosaccharide and the 3-minute stair climb test (3MSCT).

Results: Mean (SD) treatment exposure was 29.3 (15.2) months. Serum oligosaccharide levels were significantly reduced in the overall population at 12 months (mean change: -72.7%, P < 0.001) and remained statistically significant at last observation (-62.8%, P < 0.001). A mean improvement of +9.3% in 3MSCT was observed at 12 months (P = 0.013), which also remained statistically significant at last observation (+13.8%, P = 0.004), with a more pronounced improvement detected in the paediatric subgroup. No treatment-emergent adverse events were reported leading to permanent treatment discontinuation.

Conclusions: Patients treated with velmanase alfa experienced improvements in biochemical and functional measures that were maintained for up to 4 years. Long term follow-up is important and further supports the use of velmanase alfa as an effective and well-tolerated treatment for AM. Based on the currently available data set, no baseline characteristic can be predictive of treatment outcome. Early treatment during paediatric age showed better outcome in functional endpoints.

Keywords: Alpha-mannosidosis; Enzyme replacement therapy; Integrated analysis; Lysosomal storage disorder; Recombinant human alpha-mannosidase; Velmanase alfa.

Conflict of interest statement

Competing interests

AML, LB, NG, MGC, LDM, BH, SAJ were investigators in at least one of the rhLAMAN-02, −03, −04 and − 05 studies that were sponsored by Zymenex and part of the ALPHA-MAN project funded by the EU. AML and NG have received investigator’s fees from Zymenex and Chiesi as Principal Investigators in the rhLAMAN-07 or − 09 studies. DP has received consultancy fees from Chiesi. DC has received research funds, consultancy fees and speaker honoraria from Sanofi-Genzyme, research and service support funding, and funding for travel and meeting expenses from Shire, and funding for travel and meeting expenses from Biomarin. PH reports consulting fees from BioMarin, Inventiva, Armagen, PTC and REGENXBIO, and consulting fees, travel and honoraria from Chiesi, Shire, Sanofi-Genzyme and Alexion. DA, FC, SG are employees of Chiesi Farmaceutici S.p.A. JF is an employee and board member of Zymenex A/S. SAJ has received consulting fees from Genzyme, Shire, Biomarin, Alexion, Ultragenyx and Orchard Therapeutics. YA has received consulting fee from Chiesi Farmaceutici S.p.A. LB has received travel reimbursement from Chiesi for participation in two congresses when presenting the study data. C. Laroche, P. Dolhem, A. Tylki-Szymanska, M. Lopez-Rodriguez, E. Guillén-Navarro, C. I. Dali, N. Muschol, B. Héron, and J. M. H. Van den declare that they have no conflict of interest.

Ethical approval and patient consent statement

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Written informed consent was obtained from the patient or his/her legally authorised guardian(s) prior to performing any trial-related activities.

The study was conducted with the Good Clinical Practice guidelines, and following all other requirements of local laws.

Figures

Fig. 1

Patient disposition by parental trial and by trial/CU programme at the time of enrolment in rhLAMAN-10 (enrolment in follow-up trial or CU programme determined by national regulations). * Patient 56 participated in rhLAMAN-02 and rhLAMAN-03, discontinued treatment due to an AE but later enrolled in rhLAMAN-05. This patient is only counted once within the integrated analysis. ‡ Patient 58 participated in the rhLAMAN-05 study in the active arm. After completing the rhLAMAN-05 study the patient received velmanase alfa in the compassionate use programme but did not participate in the rhLAMAN-10 study. Since the subject received velmanase alfa for 12 months in the rhLAMAN-05 study, data from this patient are included in the integrated analysis. § Patient 67 participated in the rhLAMAN-05 study in the placebo arm and entered the compassionate use programme but did not participate in the rhLAMAN-10 study. As this patient did not have any data collected during active treatment, he was excluded from the integrated analysis

Fig. 2

Changes from baseline in a) serum oligosaccharides and b) 3MSCT 3MSCT, 3-min stair climb test.