Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation

Elizabeth Braunlin,Elise Northrop,Weston P Miller,Bradley S Miller,Ellen Fung,Lynda E Polgreen,Troy C Lund,Chester B Whitley,Julie B Eisengart,Kyle Rudser,Jakub Tolar,Paul J Orchard

doi:10.1038/s41390-019-0541-2

Abstract

BackgroundMucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT.MethodsThis 2-year open-label pilot study of laronidase included ten patients (age 5–13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls.ResultsThe two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients.ConclusionsLaronidase seemed to improve growth in participants <8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made.

Highlights

The mucopolysaccharidoses (MPS) are a group of diseases resulting from specific lysosomal enzyme deficiencies that result in accumulation of glycosaminoglycans
The average age at hematopoietic cell transplantation (HCT) was 15.4 ± 8.2 months in controls and 19.7 ± 12.7 months in the treated group. 39% vs. 50% received Enzyme replacement therapy (ERT) peri-HCT in controls versus treated group, respectively
We found that ERT, 2 or more years after HCT in MPS IH, was safe and tolerable

Summary

Introduction

The mucopolysaccharidoses (MPS) are a group of diseases resulting from specific lysosomal enzyme deficiencies that result in accumulation of glycosaminoglycans. Even in the setting of complete hematopoietic engraftment from enzyme-normal donors, patients with MPS IH treated with HCT are continuing to develop severe orthopedic disease, which may include carpal tunnel syndrome, progressive kyphosis, scoliosis, hip dysplasia, genu valgum, cervical instability, and cord compression, along with cardiomyopathy and valve disease, corneal clouding, sleep disordered breathing, hearing loss, and endocrinological disease.[3,4,5,6,7,8,9] there is an urgent need for augmentative treatments in patients with MPS IH, despite “successful” transplantation. Mucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations.

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