Enzyme replacement therapy with agalsidase alfa in patients with Fabry's disease: an analysis of registry data

doi:10.1016/S0140-6736(09)61493-8

The Lancet

Volume 374, Issue 9706, 12–18 December 2009, Pages 1986-1996

https://doi.org/10.1016/S0140-6736(09)61493-8 Get rights and content

Summary

Background

We analysed 5-year treatment with agalsidase alfa enzyme replacement therapy in patients with Fabry's disease who were enrolled in the Fabry Outcome Survey observational database (FOS).

Methods

Baseline and 5-year data were available for up to 181 adults (126 men) in FOS. Serial data for cardiac mass and function, renal function, pain, and quality of life were assessed. Safety and sensitivity analyses were done in patients with baseline and at least one relevant follow-up measurement during the 5 years (n=555 and n=475, respectively).

Findings

In patients with baseline cardiac hypertrophy, treatment resulted in a sustained reduction in left ventricular mass (LVM) index after 5 years (from 71·4 [SD 22·5] g/m^2·7 to 64·1 [18·7] g/m^2·7, p=0·0111) and a significant increase in midwall fractional shortening (MFS) from 14·3% (2·3) to 16·0% (3·8) after 3 years (p=0·02). In patients without baseline hypertrophy, LVM index and MFS remained stable. Mean yearly fall in estimated glomerular filtration rate versus baseline after 5 years of enzyme replacement therapy was −3·17 mL/min per 1·73 m² for men and −0·89 mL/min per 1·73 m² for women. Average pain, measured by Brief Pain Inventory score, improved significantly, from 3·7 (2·3) at baseline to 2·5 (2·4) after 5 years (p=0·0023). Quality of life, measured by deviation scores from normal EuroQol values, improved significantly, from −0·24 (0·3) at baseline to −0·17 (0·3) after 5 years (p=0·0483). Findings were confirmed by sensitivity analysis. No unexpected safety concerns were identified.

Interpretation

By comparison with historical natural history data for patients with Fabry's disease who were not treated with enzyme replacement therapy, long-term treatment with agalsidase alfa leads to substantial and sustained clinical benefits.

Funding

Shire Human Genetic Therapies AB.

Introduction

Fabry's disease is a rare progressive multisystem disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A. Renal failure, cardiomyopathy, and cerebrovascular disease are the main causes of morbidity and premature death.¹ During the past 8 years, results of randomised controlled trials and clinical studies of the two preparations of enzyme replacement therapy, agalsidase alfa (Shire Human Genetic Therapies [HGT]) and agalsidase beta (Genzyme Corporation), have shown the safety and efficacy of treatment in small groups of adults and children with Fabry's disease.2, 3, 4, 5, 6, 7 Two observational databases, the Fabry Outcome Survey (FOS) and the Fabry Registry, follow the treatment of patients receiving agalsidase alfa and agalsidase beta, respectively. Data from these registries extend our knowledge of the natural history of the disease and its response to enzyme replacement therapy.1, 8, 9, 10, 11 We report FOS data for the effects of 5 years of treatment with agalsidase alfa on cardiac mass and function, renal function, pain, and quality of life.

Section snippets

Patients

FOS was approved by ethics institution review boards of participating centres. Patients gave written informed consent and were either receiving or not receiving enzyme replacement therapy with agalsidase alfa. No patient received agalsidase beta during the study. Every patient's medical history was documented by a physician or nurse specialist, including year of diagnosis, signs and symptoms, treatment, demographic details, and family history. Results of routine clinical assessments or

Results

At the time of analysis (database locked October, 2007), FOS contained data for 1428 patients from 19 countries, of whom 692 (607 adults) were receiving agalsidase alfa. 5-year longitudinal data were not available for most patients because therapy was continuing. Baseline and 5-year follow-up data were available for 181 adults (mean age 39·2 [12·3] years; 126 men; 176 (97·2%) Caucasian). Mutation data were available for 152 patients (102 men): 75 missense mutations (52 men), 35 non-sense

Discussion

We report long-term data for the effects of enzyme replacement therapy with agalsidase alfa on cardiac mass and function, renal function, pain, and quality of life in a large group of patients enrolled in FOS. Our results show sustained benefits of agalsidase alfa during 5 years of treatment. Patients with LVH at baseline had a clinically significant reduction in LVH during the 5 years and an improvement in myocardial contractility during the first 3 years of treatment. In patients with normal

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ArticlesEnzyme replacement therapy with agalsidase alfa in patients with Fabry's disease: an analysis of registry data

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Patients

Results

Discussion

Am J Cardiol

J Am Soc Echocardiogr

J Pain

Lancet Neurol

Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey

Eur J Clin Invest

Enzyme replacement therapy in Fabry disease: a randomized controlled trial

JAMA

Safety and efficacy of recombinant human alpha-galactosidase A-replacement therapy in Fabry's disease

N Engl J Med

Effects of enzyme replacement therapy on the cardiomyopathy of Anderson–Fabry disease: a randomised, double-blind, placebo-controlled clinical trial of agalsidase alfa

Heart

Agalsidase-beta therapy for advanced Fabry disease: a randomized trial

Ann Intern Med

Enzyme replacement therapy with agalsidase alfa in children with Fabry disease

Acta Paediatr