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Agalsidase Beta

A Review of its Use in the Management of Fabry Disease

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Summary

Abstract

Agalsidase beta (Fabrazyme®) is a recombinant human α-galactosidase A enzyme approved for intravenous use in the treatment of Fabry disease. Fabry disease is a progressive, multisystemic, potentially life threatening disorder caused by a deficiency of α-galactosidase A. This deficiency results in accumulation of glycosphingolipids, particularly globotriaosylceramide (GL-3), in the lysosomes of various tissues. This accumulation is the underlying driver of disease progression. Agalsidase beta provides an exogenous source of α-galactosidase A.

Intravenous agalsidase beta is effective and well tolerated in patients with Fabry disease. In a phase III trial, agalsidase beta was shown to clear GL-3 from various target cells and, in a subsequent extension of this trial, prevent GL-3 reaccumulation. In a post-approval trial, agalsidase beta was shown to provide significant clinical benefit by reducing the risk of a major clinical event. Thus, agalsidase beta represents an important advance in the treatment of Fabry disease, and agalsidase beta therapy should be strongly considered in patients with Fabry disease who are suitable candidates.

Pharmacological Properties

The amino acid sequence of agalsidase beta is the same as that of native α-galactosidase A. Agalsidase beta is taken up (via receptor-mediated endocytosis) by vascular endothelial and parenchymal cells into lysosomes, where it catalyses the hydrolysis of GL-3 (and other glycosphingolipids) to ceramide dihexoside and galactose. Intravenous agalsidase beta reduced plasma GL-3 levels (measured by ELISA) in a rapid, dose-dependent manner in a dose-ranging study in 15 men with classic Fabry disease. Two of three patients receiving agalsidase beta 1 mg/kg every other week (i.e. bi-weekly) [the recommended regimen] had undetectable GL-3 levels (i.e. <1.2 ng/μL) after the first infusion. GL-3 clearance from tissues was generally also dose dependent.

Mean plasma concentrations reached 80% of the peak concentration 90 minutes into the infusion with intravenous agalsidase beta 1 mg/kg with an area under the plasma concentration-time curve of =500 μg · min/mL. Agalsidase beta is thought to be metabolically degraded via peptide hydrolysis and is cleared from the circulation by both saturable and nonsaturable pathways. The terminal elimination half-life was 45–102 minutes.

Therapeutic Efficacy

The efficacy of intravenous agalsidase beta 1 mg/kg bi-weekly has been evaluated in Fabry disease in randomised, double-blind, placebo-controlled, multicentre, phase III (n = 58) and post-approval (n = 82) trials.

Agalsidase beta cleared GL-3 from the renal microvascular endothelium in patients with classic Fabry disease in the pivotal phase III trial. Kidney specimens revealed that at week 20, significantly more agalsidase beta than placebo recipients were free of microvascular endothelial GL-3 deposits (69% vs 0% had a score of 0) [primary endpoint]. Heart and skin specimens were free of microvascular endothelial GL-3 deposits in 72% and 100% of agalsidase beta recipients versus 3% and 3% of placebo recipients. At week 20, significant improvements from baseline in the McGill Pain Questionnaire score and aspects of health-related quality of life (HR-QOL) were seen in both agalsidase beta and placebo recipients.

At the end of the 20-week double-blind treatment period, patients continued in an extension phase during which all patients received intravenous agalsidase beta 1 mg/kg bi-weekly. Agalsidase beta further reduced GL-3 deposits, and prevented their reaccumulation, in the longer term. Renal function was stable throughout 54 months of open-label treatment with agalsidase beta in all but six patients.

In the pivotal post-approval trial, the risk of a clinically significant renal, cardiac or cerebrovascular event or death (primary endpoint) in the per-protocol analysis (n = 74) was significantly reduced by 61%, after adjustment for baseline proteinuria, with intravenous agalsidase beta 1 mg/kg bi-weekly versus placebo (median duration of treatment 18.5 months; patients had advanced Fabry disease and mild to moderate renal impairment at baseline). Indeed, the extent of proteinuria at baseline appeared to predict the risk of patients experiencing a clinically significant event.

Clinical benefits were also seen with agalsidase beta therapy in several noncomparative trials in patients with Fabry disease. Agalsidase beta was effective in paediatric patients and Japanese patients with Fabry disease, improved left ventricular (LV) hypertrophy and aspects of LV function in patients with Fabry cardiomyopathy, and improved small nerve fibre function in patients with Fabry neuropathy. In addition, renal function remained stable, gastrointestinal and other symptoms were ameliorated and improvements in HR-QOL were seen.

Tolerability

Intravenous agalsidase beta 1 mg/kg bi-weekly was reasonably well tolerated in patients with Fabry disease in the well designed phase III and post-approval trials. In the post-approval trial, mild to moderate infusion-related reactions (most commonly rigors and fever) occurred in 55% of agalsidase beta recipients and 23% of placebo recipients. In the phase III trial, transient infusion-related reactions of mild to moderate intensity occurred in 59% of patients during the double-blind and initial 6-month open-label treatment periods; these reactions were controlled by reducing the infusion rate and/or administering preventive medications. The initial infusion reaction often coincided with seroconversion and the frequency of infusion reactions decreased with continued use of agalsidase beta. During the 20-week double-blind treatment period of the phase III trial, agalsidase beta recipients were significantly more likely than placebo recipients to experience treatment-related rigors and fever. By month 54 of the extension study, IgG seroconversion had occurred in 90% of agalsidase beta recipients. Over time, nine patients who seroconverted tolerised, and antibody titres decreased at least 4-fold in 32 patients. Seroconversion did not appear to have an impact on efficacy in the pivotal phase III trial or during the 54-month open-label extension phase.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Authors and Affiliations

  1. Wolters Kluwer Health / Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 1311, New Zealand

    Gillian M. Keating & Dene Simpson

  2. Wolters Kluwer Health, Conshohocken, Pennsylvania, USA

    Gillian M. Keating & Dene Simpson

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  1. Gillian M. Keating
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  2. Dene Simpson
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Correspondence to Gillian M. Keating.

Additional information

Various sections of the manuscript reviewed by: F. Breunig, University Hospital, Department of Medicine/Nephrology, Würzburg, Germany; G.A. Grabowski, The Children’s Hospital Research Foundation, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA; P.J. Lee, Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, England; G.E. Linthorst, Department of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands; R. Mignani, Renal Unit, Infermi Hospital, Rimini, Italy; S. Waldek, Manchester Lysosomal Storage Disease Centre, Hope Hospital, Salford, England; W.R. Wilcox, Division of Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘agalsidase beta’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE search terms were ‘agalsidase beta’ or ‘alpha-galactosidase genzyme’. EMBASE and AdisBase search terms were ‘agalsidase-beta’. Searches were last updated 12 February 2006.

Selection: Studies in patients with Fabry disease who received agalsidase beta. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Agalsidase beta, Fabry disease, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Keating, G.M., Simpson, D. Agalsidase Beta. Drugs 67, 435–456 (2007). https://doi.org/10.2165/00003495-200767030-00007

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