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

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.

• Authors: L Borgwardt, C I Dali, J Fogh, J E Månsson, K J Olsen, H C Beck, K G Nielsen, L H Nielsen, S O E Olsen, H M F Riise Stensland, O Nilssen, F Wibrand, A M Thuesen, T Pearl, U Haugsted, P Saftig, J Blanz, S A Jones, A Tylki-Szymanska, N Guffon-Fouiloux, M Beck, A M Lund
• Journal: Journal of inherited metabolic disease (J Inherit Metab Dis) Vol. 36 Issue 6 Pg. 1015-24 (Nov 2013) ISSN: 1573-2665 [Electronic] United States
• PMID: 23494656 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Recombinant Proteins
• alpha-Mannosidase

Topics

• Adolescent
• Child
• Cognition (drug effects)
• Dose-Response Relationship, Drug
• Enzyme Replacement Therapy (adverse effects, methods)
• Exercise Test
• Follow-Up Studies
• Humans
• Psychomotor Performance (drug effects)
• Recombinant Proteins (administration & dosage, adverse effects, immunology, pharmacokinetics)
• Treatment Outcome
• alpha-Mannosidase (administration & dosage, adverse effects, immunology, pharmacokinetics)
• alpha-Mannosidosis (drug therapy)