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Enzyme replacement therapy for alpha-mannosidosis: 12 months follow-up of a single centre, randomised, multiple dose study

  • Original Article
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Journal of Inherited Metabolic Disease

Abstract

Background

Alpha-mannosidosis (OMIM 248500) is a rare lysosomal storage disease (LSD) caused by alpha-mannosidase deficiency. Manifestations include intellectual disabilities, facial characteristics and hearing impairment. A recombinant human alpha-mannosidase (rhLAMAN) has been developed for weekly intravenous enzyme replacement therapy (ERT). We present the preliminary data after 12 months of treatment.

Methods

This is a phase I-II study to evaluate safety and efficacy of rhLAMAN. Ten patients (7–17 y) were treated. We investigated efficacy by testing motor function (6-minutes-Walk-Test (6-MWT), 3-min-Stair-Climb-Test (3-MSCT), The Bruininks-Oseretsky Test of Motor Proficiency (BOT2), cognitive function (Leiter-R), oligosaccharides in serum, urine and CSF and Tau- and GFA-protein in CSF.

Results

Oligosaccharides: S-, U- and CSF-oligosaccharides decreased 88.6 % (CI −92.0 −85.2, p < 0.001), 54.1 % (CI −69.5- −38.7, p < 0,001), and 25.7 % (CI −44.3- −7.1, p < 0.05), respectively. Biomarkers: CSF-Tau- and GFA-protein decreased 15 %, p < 0.009) and 32.5, p < 0.001 respectively. Motor function: Improvements in 3MSCT (31 steps (CI 6.8-40.5, p < 0.01) and in 6MWT (60.4 m (CI −8.9 −51.1, NS) were achieved. Cognitive function: Improvement in the total Equivalence Age of 4 months (0.34) was achieved in the Leiter R test (CI −0.2-0.8, NS).

Conclusions

These data suggest that rhLAMAN may be an encouraging new treatment for patients with alpha-mannosidosis.The study is designed to continue for a total of 18 months. Longer-term follow-up of patients in this study and the future placebo-controlled phase 3 trial are needed to provide greater support for the findings in this study.

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Acknowledgments

We thank our study-site personnel Marianne Luiten, Sanni Mahncke, Kamille Fogh; Camilla Sørensen, Anne Sylvest Olsen, Kirsten Glarborg, Department of Clinical Genetics; Birgitte Hanel, Paediatric Pulmonary Service, Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Denmark; Pia Ringholm and Susanne Rodholm, Lene Skammelsen Zymenex A/S, Hillerød, Denmark; Elisabeth Jameson, St. Mary’s hospital, Manchester, UK; Laila Arash, Yasmina Amraoui, Johannes Gutenberg University Hospital, Mainz, Germany; Dorthe Grønnegaard Mejer, Jesper Nelby Kristiansen, Maike Dideriksen, Larix A/S, Skovlunde, Denmark, EU-framework 7 program for supporting the ALPHA-MAN project economically.

Special thanks to the patients and families for their participation and dedicated efforts in the study.

Funding

The study is funded by the EU in the “ALPHA-MAN” project through a Framework 7 grant of 5,887,150 Euro for a period of 36 months. The entire grant covers both scientific programs and clinical programs. The clinical program of the funding covers all clinical trials (phases 1, 2a, 2b and 3) and all the support for the clinical trial such as transport of patients, monitoring of the trial procedures, data management and analysis etc.

Conflict of interest

Zymenex provides the investigational recombinant human enzyme Lamazym (rhLAMAN) for the clinical trials. The investigators or any other study-site personnel are not employed by Zymenex.

Dr. Line Borgwardt has received travel expenses for a scientific meeting by Zymenex. No other reimbursements/fees/funds/salaries have been accepted.

The authors; expect Fogh J who is employed at Zymenex; confirms independence from the sponsors; the content of the article has not been influenced by the sponsors.

Author information

Authors and Affiliations

  1. Department of Clinical Genetics, Centre for Inherited Metabolic Disorders, Copenhagen University hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark

    L. Borgwardt, C. I. Dali, F. Wibrand & A. M. Lund

  2. Zymenex A/S, Hilleroed, Denmark

    J. Fogh

  3. Department of Psychiatry and Neurochemistry, Institue of Neuroscience and Physiology, Sahlgrenska University Hospital, Molndal, Sweden

    J. E. Månsson

  4. Larix, CRO, Ballerup, Denmark

    K. J. Olsen

  5. Centre for Clinical Proteomics, Department of Clinical Biochemeistry and Pharmocology, Odense University Hospital, Odense, Denmark

    H. C. Beck

  6. Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Paediatric Pulmonary Service, Copenhagen, Denmark

    K. G. Nielsen

  7. Department of Otorhinolaryngology, Head & Neck Surgery, University Hospital, Rigshospitalet, Copenhagen, Denmark

    L. H. Nielsen & S. O. E. Olsen

  8. Department of Medical Genetics, Division of Child and Adolescent Health, University of Northern Norway, Tromsø, Norway

    H. M. F. Riise Stensland

  9. Department of Clinical Medicine, Medical Genetics, University of Tromsø, Tromsø, Norway

    O. Nilssen

  10. Psykolog2, Virum, Denmark

    A. M. Thuesen

  11. Department of Occupational Therapy and Physiotherapy, Rigshospitalet, Copenhagen, Denmark

    T. Pearl & U. Haugsted

  12. Biochemisches Institut, Christian-Albrechts-Universität Kiel, Kiel, Germany

    P. Saftig & J. Blanz

  13. Genetic Medicine, St Mary’s Hospital, University of Manchester, Manchester, UK

    S. A. Jones

  14. Department of Metabolic Diseases, The Children´s Memorial Institute Poland, Warszawa, Poland

    A. Tylki-Szymanska

  15. Service de Pédiatre, Hopital Eduard Herriot, Lyon, France

    N. Guffon-Fouiloux

  16. Villa Metabolica Universitäts-Kinderklinik Mainz, Mainz, Germany

    M. Beck

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  1. L. Borgwardt
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  2. C. I. Dali
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  4. J. E. Månsson
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  7. K. G. Nielsen
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  8. L. H. Nielsen
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  9. S. O. E. Olsen
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  14. T. Pearl
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  17. J. Blanz
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  18. S. A. Jones
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  20. N. Guffon-Fouiloux
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  21. M. Beck
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  22. A. M. Lund
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Corresponding author

Correspondence to L. Borgwardt.

Additional information

Communicated by:Maurizio Scarpa

EudraCT number: 2010-022084-36 and 2010-022085-26

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Borgwardt, L., Dali, C.I., Fogh, J. et al. Enzyme replacement therapy for alpha-mannosidosis: 12 months follow-up of a single centre, randomised, multiple dose study. J Inherit Metab Dis 36, 1015–1024 (2013). https://doi.org/10.1007/s10545-013-9595-1

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  • DOI: https://doi.org/10.1007/s10545-013-9595-1

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