Long-term safety and clinical outcomes of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency: two-year results

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Abstract

Background

Olipudase alfa is a recombinant human acid sphingomyelinase (ASM) enzyme replacement therapy (ERT) for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). We report 2-year cumulative safety and efficacy data after olipudase alfa treatment in 20 children (four adolescents [12–17 year], nine children [6–11 year], and seven infants/early child [1–5 year]) with baseline splenomegaly and growth deficits who completed the 1-year ASCEND-Peds clinical trial (NCT02292654) and who continue to receive olipudase alfa in a long-term study (NCT02004704). Efficacy endpoints include spleen and liver volumes, diffusing capacity of the lung for carbon monoxide (DL _CO), high-resolution computed tomography (HRCT) lung imaging, lipid profiles, liver function tests, and height Z-scores.

Results

All 20 former ASCEND-Peds patients completed at least 2 years of olipudase alfa treatment. No patient discontinued and no new safety issue arose during the second year of treatment; 99% of adverse events were mild or moderate. During year 2, one patient had two treatment-related serious events of hypersensitivity that resolved. Mean reductions from baseline in spleen and liver volumes were 61% and 49%, respectively ( p < 0.0001) and mean percent-predicted-DL _CO increased by 46.6% ( p < 0.0001) in nine patients who performed the test at baseline. Lipid profiles and elevated liver transaminase levels that improved or normalized by 1 year remained stable. Mean height Z-scores improved in all age groups (mean change from baseline 1.17, P < 0.0001).

Conclusion

Olipudase alfa was generally well-tolerated during 2 years of treatment. Improvements in clinically relevant disease endpoints observed during the first year of treatment were maintained or augmented in the second year.

Trial registration NCT02004704 registered 26 Nov 2013, https://clinicaltrials.gov/ct2/show/record/NCT02004704.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13023-022-02587-0.

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Most cited references 32

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Types A and B Niemann-Pick disease.

Edward Schuchman, Robert J Desnick (2017)

The eponym Niemann-Pick disease (NPD) refers to a group of patients who present with varying degrees of lipid storage and foam cell infiltration in tissues, as well as overlapping clinical features including hepatosplenomegaly, pulmonary insufficiency and/or central nervous system (CNS) involvement. Due to the pioneering work of Roscoe Brady and co-workers, we now know that there are two distinct metabolic abnormalities that account for NPD. The first is due to the deficient activity of the enzyme acid sphingomyelinase (ASM; "types A & B" NPD), and the second is due to defective function in cholesterol transport ("type C" NPD). Herein only types A and B NPD will be discussed. Type A NPD patients exhibit hepatosplenomegaly in infancy and profound CNS involvement. They rarely survive beyond 2-3years of age. Type B patients also have hepatosplenomegaly and pathologic alterations of their lungs, but there are usually no CNS signs. The age of onset and rate of disease progression varies greatly among type B patients, and they frequently live into adulthood. Intermediate patients also have been reported with mild to moderate neurological findings. All patients with types A and B NPD have mutations in the gene encoding ASM (SMPD1), and thus the disease is more accurately referred to as ASM deficiency (ASMD). Herein we will review the clinical, pathological, biochemical, and genetic findings in types A and B NPD, and emphasize the seminal contributions of Dr. Brady to this disease. We will also discuss the current status of therapy for this disorder.

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A prospective, cross-sectional survey study of the natural history of Niemann-Pick disease type B.

Robert J Desnick, David Mendelson, Eleanor F Cox … (2008)

The objective of this study was to characterize the clinical features of patients with Niemann-Pick disease type B and to identify efficacy end points for future clinical trials of enzyme-replacement therapy. Fifty-nine patients who had Niemann-Pick disease type B, were at least 6 years of age, and manifested at least 2 disease symptoms participated in this multicenter, multinational, cross-sectional survey study. Medical histories; physical examinations; assessments of cardiorespiratory function, clinical laboratory data, and liver and spleen volumes; radiographic evaluation of the lungs and bone age; and quality-of-life assessments were obtained during a 2- to 3-day period. Fifty-three percent of the patients were male, 92% were white, and the median age was 17.6 years. The R608del mutation accounted for 25% of all disease alleles. Most patients initially presented with splenomegaly (78%) or hepatomegaly (73%). Frequent symptoms included bleeding (49%), pulmonary infections and shortness of breath (42% each), and joint/limb pain (39%). Growth was markedly delayed during adolescence. Patients commonly had low levels of platelets and high-density lipoprotein, elevated levels of low-density lipoprotein, very-low-density lipoprotein, triglycerides, leukocyte sphingomyelin, and serum chitotriosidase, and abnormal liver function test results. Nearly all patients had documented splenomegaly and hepatomegaly and interstitial lung disease. Patients commonly showed restrictive lung disease physiology with impaired pulmonary gas exchange and decreased maximal exercise tolerance. Quality of life was only mildly decreased by standardized questionnaires. The degree of splenomegaly correlated with most aspects of disease, including hepatomegaly, growth, lipid profile, hematologic parameters, and pulmonary function. This study documents the multisystem involvement and clinical variability of Niemann-Pick B disease. Several efficacy end points were identified for future clinical treatment studies. Because of its correlation with disease severity, spleen volume may be a useful surrogate end point in treatment trials, whereas biomarkers such as chitotriosidase also may play a role in monitoring patient treatment responses.

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Author and article information

Contributors

George A. Diaz:

ORCID: http://orcid.org/0000-0001-5688-9062

george.diaz@mssm.edu

Journal

Journal ID (nlm-ta): Orphanet J Rare Dis

Journal ID (iso-abbrev): Orphanet J Rare Dis

Title: Orphanet Journal of Rare Diseases

Publisher: BioMed Central (London )

ISSN (Electronic): 1750-1172

Publication date (Electronic): 14 December 2022

Publication date PMC-release: 14 December 2022

Publication date Collection: 2022

Volume: 17

Electronic Location Identifier: 437

Affiliations

[1 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, Department of Genetics and Genomic Sciences, , Icahn School of Medicine at Mount Sinai, ; 1 Gustave L. Levy Place, New York, NY 10029 USA

[2 ]Medical Genetics Service HCPA, Department of Genetics UFRGS, DASA and Casa dos Raros, Porto Alegre, Brazil

[3 ]GRID grid.413852.9, ISNI 0000 0001 2163 3825, Reference Centre of Inherited Metabolic Disease in Femme Mère Enfant Hospital, , Hospices Civils of Lyon, ; Lyon, France

[4 ]GRID grid.416523.7, ISNI 0000 0004 0641 2620, Manchester University National Health Service Trust, , St Mary’s Hospital, ; Manchester, UK

[5 ]Institute of Clinical Science for Lysosomal Storage Disorders, SphinCS GmbH, Mainz, Germany

[6 ]GRID grid.411492.b, University Hospital of Udine, ; Udine, Italy

[7 ]GRID grid.410569.f, ISNI 0000 0004 0626 3338, University Hospitals Leuven, ; Leuven, Belgium

[8 ]GRID grid.417555.7, ISNI 0000 0000 8814 392X, Sanofi, ; Bridgewater, NJ USA

[9 ]GRID grid.417555.7, ISNI 0000 0000 8814 392X, Sanofi, ; Cambridge, MA USA

[10 ]GRID grid.417924.d, Sanofi, ; Paris, France

Author information

George A. Diaz http://orcid.org/0000-0001-5688-9062

Article

Publisher ID: 2587

DOI: 10.1186/s13023-022-02587-0

PMC ID: 9749157

PubMed ID: 36517856

SO-VID: f3e3337c-a6ab-4427-8767-9e835b29914f

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 27 June 2022

Date accepted : 22 November 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100004339, Sanofi;

Custom metadata

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: recombinant human acid sphingomyelinase,dose escalation,organomegaly,lung diffusing capacity,acid sphingomyelinase deficiency,niemann–pick type b

Data availability:

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: recombinant human acid sphingomyelinase, dose escalation, organomegaly, lung diffusing capacity, acid sphingomyelinase deficiency, niemann–pick type b

Long-term safety and clinical outcomes of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency: two-year results

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Most cited references 32

Interpretative strategies for lung function tests.

Types A and B Niemann-Pick disease.

A prospective, cross-sectional survey study of the natural history of Niemann-Pick disease type B.

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