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

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Abstract

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.

Electronic supplementary material

The online version of this article (10.1007/s10545-018-0185-0) contains supplementary material, which is available to authorized users.

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Most cited references 12

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Early initiation of enzyme replacement therapy for the mucopolysaccharidoses.

Joseph Muenzer (2014)

The mucopolysaccharidoses (MPS), a group of rare genetic disorders caused by defects in glycosaminoglycan (GAG) catabolism, are progressive, multi-systemic diseases with a high burden of morbidity. Enzyme replacement therapy (ERT) is available for MPS I, II, and VI, and may improve walking ability, endurance, and pulmonary function as evidenced by data from pivotal trials and extension studies. Despite these demonstrable benefits, cardiac valve disease, joint disease, and skeletal disease, all of which cause significant morbidity, do not generally improve with ERT if pathological changes are already established. Airway disease improves, but usually does not normalize. These limitations can be well understood by considering the varied functions of GAG in the body. Disruption of GAG catabolism has far-reaching effects due to the triggering of secondary pathogenic cascades. It appears that many of the consequences of these secondary pathogenic events, while they may improve on treatment, cannot be fully corrected even with long-term exposure to enzyme, thereby supporting the treatment of patients with MPS before the onset of clinical disease. This review examines the data from clinical trials and other studies in human patients to explore the limits of ERT as currently used, then discusses the pathophysiology, fetal tissue studies, animal studies, and sibling reports to explore the question of how early to treat an MPS patient with a firm diagnosis. The review is followed by an expert opinion on the rationale for and the benefits of early treatment. Copyright © 2013 The Author. Published by Elsevier Inc. All rights reserved.

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Enzyme-replacement therapy in a 5-month-old boy with attenuated presymptomatic MPS I: 5-year follow-up.

Orazio Gabrielli, Lorne Clarke, Stefano Bruni … (2010)

Mucopolysaccharidosis type I (MPS I) is a progressive and multisystemic disease, even in its attenuated Hurler-Scheie and Scheie forms. Clinical trials of enzyme-replacement therapy in MPS I have shown clinical benefit in patients with considerable preexisting disease, but no data exist on the effect of beginning enzyme replacement before the onset of significant clinical signs of disease. Here we present the 5-year follow-up of a boy with attenuated MPS I who had laronidase therapy initiated at the age of 5 months and compare his clinical course to that of his older sister, who began treatment at 5 years of age after she had developed typical signs of MPS I. After 5 years of treatment, the younger sibling has not developed any clinical manifestations of MPS I except for mild corneal clouding. In contrast, although many of the older sibling's clinical features have improved after 5 years of treatment, her dysostosis multiplex, cardiac valve involvement, and corneal clouding, although stabilized, have persisted. We suggest that early treatment of attenuated MPS I may significantly delay or prevent the onset of the major clinical signs, substantially modifying the natural history of the disease.

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Systematic review of timed stair tests.

Elizabeth Nightingale, Fereshteh Pourkazemi, Claire Hiller (2014)

Functional testing is particularly useful in the clinic and for making research translatable; however, finding measures relevant across ages and different conditions can be difficult. A systematic review was conducted to investigate timed stair tests as an objective measure of functional abilities and musculoskeletal integrity. Data were analyzed for their ability to differentiate between controls and patient groups and between different patient groups. Literature was reviewed using the Medline, CINAHL, and PubMed databases until February 2012. Data were grouped according to methodology, ages, and medical conditions. Time per step was calculated to allow comparison between studies. Eighty-eight studies were included in this review. Methodologies varied considerably with stair ascent, stair descent, or a combination of the two being used across a wide range of ages and medical conditions. Times increased with age for ascent, descent, and combined and for a variety of medical problems. Timed stair tests appear to be sensitive to medical conditions but further data are required to obtain normative values for this test. We suggest that timed stair tests should follow a more standardized methodology using a combination of ascent and descent and asking participants to complete the stairs as quickly and safely as possible.

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Author and article information

Contributors

Line Borgwardt: +4535455225 , Line.Gutte.Borgwardt@regionh.dk

Journal

Journal ID (nlm-ta): J Inherit Metab Dis

Journal ID (iso-abbrev): J. Inherit. Metab. Dis

Title: Journal of Inherited Metabolic Disease

Publisher: Springer Netherlands (Dordrecht )

ISSN (Print): 0141-8955

ISSN (Electronic): 1573-2665

Publication date (Electronic): 30 May 2018

Publication date PMC-release: 30 May 2018

Publication date (Print): 2018

Volume: 41

Issue: 6

Pages: 1215-1223

Affiliations

[1 ]Department of Paediatrics and Adolescent Medicine, Centre for Inherited Metabolic Diseases, Copenhagen, Denmark

[2 ]ISNI 0000 0004 0646 7373, GRID grid.4973.9, Center for Genomic Medicine, , Copenhagen University Hospital, ; Rigshospitalet, Copenhagen, Denmark

[3 ]GRID grid.414103.3, Centre de Référence des Maladies Héréditaires du Métabolisme, , Hôpital Femme Mère Enfant, ; Lyon, France

[4 ]GRID grid.410607.4, Center for Pediatric and Adolescent Medicine, , University Medical Center Mainz, ; Villa Metabolica, Mainz, Germany

[5 ]ISNI 0000 0004 0626 3303, GRID grid.410566.0, Paediatric Neurology and Metabolism, , Universitair Ziekenhuis, ; Brussel, Belgium

[6 ]ISNI 0000 0001 2183 9102, GRID grid.411901.c, Unidad de Metabolismo e Investigación Pediátrica, Hospital Universitario Reina Sofía, IMIBIC, , Universidad de Córdoba, CIBERObn, ; Córdoba, Spain

[7 ]Department of Pediatric Neurology, Reference Center for Lysosomal Diseases, Trousseau Hospital, APHP, and GRC ConCer-LD, Sorbonne Universities, UPMC University 06, Paris, France

[8 ]ISNI 0000 0004 1761 6733, GRID grid.467287.8, Chiesi Farmaceutici S.p.A, ; Parma, Italy

[9 ]ISNI 0000 0004 0545 6138, GRID grid.476852.a, Zymenex A/S, ; Hillerød, Denmark

[10 ]ISNI 000000040459992X, GRID grid.5645.2, Center for Lysosomal and Metabolic Diseases (Department of Pediatrics), , Erasmus MC University Medical Center – Sophia Children’s Hospital, ; Rotterdam, The Netherlands

[11 ]GRID grid.410607.4, Institute of Human Genetics, , University Medical Center, ; Mainz, Germany

[12 ]GRID grid.498924.a, Manchester Centre for Genomic Medicine, , Central Manchester University Hospitals NHS Foundation Trust, ; Manchester, UK

[13 ]ISNI 0000 0001 2232 2498, GRID grid.413923.e, Department of Paediatric, Nutrition and Metabolic Diseases, , The Children’s Memorial Health Institute, ; Warsaw, Poland

[14 ]ISNI 0000 0004 0646 7373, GRID grid.4973.9, Department of Occupational Therapy and Physiotherapy, , Copenhagen University Hospital, ; Rigshospitalet, Copenhagen, Denmark

[15 ]ISNI 0000 0004 0646 7373, GRID grid.4973.9, Department of Clinical Genetics, Centre for Inherited Metabolic Diseases, , Copenhagen University Hospital, ; Rigshospitalet, Copenhagen, Denmark

Author notes

Communicated by: Carla E. Hollak

Article

Publisher ID: 185

DOI: 10.1007/s10545-018-0185-0

PMC ID: 6326984

PubMed ID: 29846843

SO-VID: 65ac23cc-284b-4e9e-bb7d-7dffb775731f

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 16 June 2017

Date revision received : 27 March 2018

Date accepted : 5 April 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100011259, FP7 International Cooperation;

Award ID: FP7-HEALTH-201-261331

Funded by: Zymenex A/S

Funded by: FundRef http://dx.doi.org/10.13039/100007560, Chiesi Farmaceutici;

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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

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Abstract

Introduction

Methods

Results

Conclusions

Electronic supplementary material

Related collections

Karger: Gastroenterology

Most cited references 12

Early initiation of enzyme replacement therapy for the mucopolysaccharidoses.

Enzyme-replacement therapy in a 5-month-old boy with attenuated presymptomatic MPS I: 5-year follow-up.

Systematic review of timed stair tests.

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