Enzyme replacement therapy for alpha-mannosidosis: 12 months follow-up of a single centre, randomised, multiple dose study
- 769 Downloads
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.
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.
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).
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.
KeywordsForce Vital Capacity Intellectual Disability Enzyme Replacement Therapy Pulmonary Function Test Haematopoietic Stem Cell Transplantation
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.
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.
- Harmatz P, Giugliani R, Schwartz IV et al (2008) Long-term follow-up of endurance and safety outcomes during enzyme replacement therapy for mucopolysaccharidosis VI: Final results of three clinical studies of recombinant human N-acetylgalactosamine 4-sulfatase. Mol Genet Metab 94(4):469–475PubMedCrossRefGoogle Scholar
- Malm D, Nilssen O (2008) Alpha-mannosidosis. Orphanet J Rare Dis doi: 10.1186/1750-1172-3-21
- Malm D, Nilssen O (2010) Alpha-Mannosidosis—GeneReviews—NCBI Bookshelf. University of Washington, Seattle Google Scholar
- Scarpa M, Bird T, Pagon R, Dolan C, Stephens K & Adam M (1993) Mucopolysaccharidosis type II. GeneReviews. University of Washington, SeattleGoogle Scholar
- Thomas GH (2001) Disorder of glycoprotein degradation, the metabolic & molecular bases of inherited disease, 8th ednGoogle Scholar
- Zymenex A/S (2012) Investigator’s brochure for LAMAZYM, information for clinical investigatorsGoogle Scholar