Maryam Banikazemi, MD; Jan Bultas, MD, PhD; Stephen Waldek, MB, BCh; William R. Wilcox, MD, PhD; Chester B. Whitley, PhD, MD; Marie McDonald, MD; Richard Finkel, MD; Seymour Packman, MD; Daniel G. Bichet, MD; David G. Warnock, MD; Robert J. Desnick, PhD, MD; for the Fabry Disease Clinical Trial Study Group*
Disclaimer: The views expressed herein are those of the authors and do not necessarily reflect those of the National Center for Research Resources or the National Institutes of Health.
Acknowledgments: The authors thank the patients, nurses, and hospital staff who participated in the study, as well as Lisa Underhill for writing assistance.
Grant Support: By the National Center for Research Resources of the National Institutes of Health grants to the Mount Sinai School of Medicine (grant 5 M01 RR00071); Cedars-Sinai Medical Center (grant 5 M01 RR00425); University of Minnesota (grant 5 M01 RR00400); The Children's Hospital of Philadelphia (grant 5 M01 RR00240); University of California, San Francisco (grant 5 M01 RR01271); and University of Alabama at Birmingham (grant 5 M01 RR00032). Additional support came from the National Institutes of Health Merit Award 5 R37 DK34045 (Dr. Desnick) and from the Genzyme Corporation.
Potential Financial Conflicts of Interest: Consultancies: J. Bultas (Genzyme Corp.), W.R. Wilcox (Genzyme Corp.), S. Packman (Genzyme Corp.), D.G. Bichet (Genzyme Corp.), D.G. Warnock (Genzyme Corp.), R.J. Desnick (Genzyme Corp., Amicus Therapeutics); Honoraria: M. Banikazemi (Genzyme Corp.), S. Waldek (Genzyme Corp.), W.R. Wilcox (Genzyme Corp.), C.B. Whitley (Genzyme Corp.), M. McDonald (Genzyme Corp.), D.G. Bichet (Genzyme Corp.), D.G. Warnock (Genzyme Corp.); Stock ownership or options (other than mutual funds): M. McDonald (Genzyme Corp.), R.J. Desnick (Amicus Therapeutics); Grants received: S. Waldek (Genzyme Corp., Amicus Therapeutics), W.R. Wilcox (Genzyme Corp.), C.B. Whitley (BioMarin, Genzyme Corp.), M. McDonald (Genzyme Corp.), R. Finkel (Genzyme Corp.), S. Packman (Genzyme Corp.), D.G. Bichet (Genzyme Corp.), D.G. Warnock (Genzyme Corp.), R.J. Desnick (Genzyme Corp.); Grants pending: D.G. Warnock (Genzyme Corp.); Patents received: R.J. Desnick (Mount Sinai School of Medicine to Genzyme Corp. for Fabrazyme); Royalties: R.J. Desnick (Genzyme Corp.).
Requests for Single Reprints: Robert J. Desnick, PhD, MD, Department of Human Genetics, Mount Sinai School of Medicine, Fifth Avenue at 100th Street, Box 1498, New York, NY 10029-6574; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Banikazemi: New York University, 403 East 34th Street, 2nd Floor, New York, NY 10016.
Dr. Bultas: Second Department of Medicine, Charles University, U Nemocnice 2, 128 08 Prague 2, Czech Republic.
Dr. Waldek: Department of Lysosomal Storage Diseases, Hope Hospital, Salford Royal Hospital Trust, Manchester M6 8HD, United Kingdom.
Dr. Wilcox: Division of Medical Genetics, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048.
Dr. Whitley: Gene Therapy Center, Department of Pediatrics, Institute of Human Genetics, 420 Delaware Street SE, MMC 446, Minneapolis, MN 55455.
Dr. McDonald: Division of Medical Genetics, Duke University Medical Center, Box 3528, Durham, NC 27710.
Dr. Finkel: Division of Neurology, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104.
Dr. Packman: Division of Medical Genetics, Department of Pediatrics, University of California, San Francisco, 533 Parnassus Avenue, Room U-585K, San Francisco, CA 94143-0748.
Dr. Bichet: Université de Montréal, Hôpital du Sacré-Coeur de Montréal, 5400, boul. Gouin Ouest, Montréal H4J 1C5, Québec, Canada.
Dr. Warnock: Division of Nephrology, University of Alabama, 1530 3rd Avenue South, THT 647, Birmingham, AL 35233.
Dr. Desnick: Department of Human Genetics, Mount Sinai School of Medicine, Fifth Avenue at 100th Street, Box 1498, New York, NY 10029-6574.
Author Contributions: Conception and design: M. Banikazemi, S. Packman, D.G. Bichet, R.J. Desnick.
Analysis and interpretation of the data: W.R. Wilcox, C.B. Whitley, R. Finkel, S. Packman, D.G. Bichet, D.G. Warnock, R.J. Desnick.
Drafting of the article: M. Banikazemi, S. Packman, D.G. Warnock, R.J. Desnick.
Critical revision of the article for important intellectual content: M. Banikazemi, J. Bultas, S. Waldek, W.R. Wilcox, C.B. Whitley, R. Finkel, S. Packman, D.G. Bichet, D.G. Warnock, R.J. Desnick.
Final approval of the article: M. Banikazemi, J. Bultas, S. Waldek, W.R. Wilcox, C.B. Whitley, M. McDonald, R. Finkel, S. Packman, D.G. Bichet, D.G. Warnock, R.J. Desnick.
Provision of study materials or patients: J. Bultas, S. Waldek, W.R. Wilcox, C.B. Whitley, M. McDonald, R. Finkel, S. Packman, D.G. Bichet, D.G. Warnock.
Administrative, technical, or logistic support: C.B. Whitley.
Collection and assembly of data: W.R. Wilcox, C.B. Whitley, S. Packman, D.G. Bichet.
Fabry disease (α-galactosidase A deficiency) is a rare, X-linked lysosomal storage disorder that can cause early death from renal, cardiac, and cerebrovascular involvement.
To see whether agalsidase beta delays the onset of a composite clinical outcome of renal, cardiovascular, and cerebrovascular events and death in patients with advanced Fabry disease.
Randomized (2:1 treatment-to-placebo randomization), double-blind, placebo-controlled trial.
41 referral centers in 9 countries.
82 adults with mild to moderate kidney disease; 74 of whom were protocol-adherent.
Intravenous infusion of agalsidase beta (1 mg per kg of body weight) or placebo every 2 weeks for up to 35 months (median, 18.5 months).
The primary end point was the time to first clinical event (renal, cardiac, or cerebrovascular event or death). Six patients withdrew before reaching an end point: 3 to receive commercial therapy and 3 due to positive or inconclusive serum IgE or skin test results. Three patients assigned to agalsidase beta elected to transition to open-label treatment before reaching an end point.
Thirteen (42%) of the 31 patients in the placebo group and 14 (27%) of the 51 patients in the agalsidase-beta group experienced clinical events. Primary intention-to-treat analysis that adjusted for an imbalance in baseline proteinuria showed that, compared with placebo, agalsidase beta delayed the time to first clinical event (hazard ratio, 0.47 [95% CI, 0.21 to 1.03]; P = 0.06). Secondary analyses of protocol-adherent patients showed similar results (hazard ratio, 0.39 [CI, 0.16 to 0.93]; P = 0.034). Ancillary subgroup analyses found larger treatment effects in patients with baseline estimated glomerular filtration rates greater than 55 mL/min per 1.73 m2 (hazard ratio, 0.19 [CI, 0.05 to 0.82]; P = 0.025) compared with 55 mL/min per 1.73 m2 or less (hazard ratio, 0.85 [CI, 0.32 to 2.3]; P = 0.75) (formal test for interaction, P = 0.09). Most treatment-related adverse events were mild or moderate infusion-associated reactions, reported by 55% of patients in the agalsidase-beta group and 23% of patients in the placebo group.
The study sample was small. Only one third of the patients experienced clinical events, and some patients withdrew before experiencing any event.
Agalsidase-beta therapy slowed progression to the composite clinical outcome of renal, cardiac, and cerebrovascular complications and death compared with placebo in patients with advanced Fabry disease. Therapeutic intervention before irreversible organ damage may provide greater clinical benefit.
*For a list of members of the Fabry Disease Clinical Trial Study Group, see the Appendix.
ClinicalTrials.gov identifier: NCT00074984.
Fabry disease is an X-linked storage disorder characterized by deficient lysosomal enzyme activity and excessive deposition of glycosphingolipids in vascular endothelial cells.
In this double-blind multicenter trial, 82 adults with kidney dysfunction from Fabry disease were randomly assigned to infusions of enzyme replacement with agalsidase beta or placebo every 2 weeks for up to 35 months. Agalsidase beta reduced the frequency of and delayed the time to clinical events (composite outcome of renal, cardiac, and cerebrovascular events and death) and caused infusion reactions more often than placebo.
Most clinical events in the small trial were worsening kidney function.
Agalsidase beta may slow disease progression in patients with advanced Fabry disease.
Study flow diagram.
Table 1. Baseline Characteristics*
Table 2. Primary End Point Events in the Intention-to-Treat Population*
Analyses of time to first clinical outcome.
Dashed lines show Kaplan–Meier estimates of time to any clinical event (composite outcome). Solid lines show curves with adjustment for baseline proteinuria (urine protein–creatinine ratio), derived from a Cox regression analysis with baseline proteinuria added as a covariate to the regression equation (22, 23). Top. The time-to-event analyses for the composite end point for both treatment groups in the intention-to-treat population are shown. The unadjusted treatment-related hazard ratio associated with agalsidase beta was 0.57 (95% CI, 27.0 to 1.22; P = 0.14). With adjustment for baseline proteinuria, the hazard ratio was 0.47 (CI, 0.21 to 1.03; P = 0.06). Bottom. The time-to-event analyses for the composite end point for both treatment groups in the per-protocol population are shown. The unadjusted treatment-related hazard ratio associated with agalsidase beta was 0.54 (CI, 0.25 to 1.19; P = 0.12). With adjustment for baseline proteinuria, the hazard ratio was 0.39 (CI, 0.16 to 0.93; P = 0.034).
Hazard ratios for the primary end point stratified by median baseline serum creatinine level, estimated glomerular filtration rate (eGFR), and proteinuria.
Proteinuria denotes the urine protein–creatinine ratio. The P values for formal tests for treatment interaction were as follows: baseline serum creatinine level, P = 0.16; baseline eGFR, P = 0.09; and baseline proteinuria, P = 0.54.
Longitudinal analysis of proteinuria in both groups.
Data are shown as increases or decreases from baseline proteinuria (urinary protein–urinary creatinine ratio) for the placebo group (solid line) and the agalsidase-beta group (dashed line). A mixed model with fixed effects for treatment group, time, and treatment-by-time interactions, as well as random intercepts and slopes, for each patient over time was fit. The overall P value for treatment effect is 0.32.
Appendix Table. Adverse Events That Occurred without Regard to Causality in at Least 10% of Patients in the Agalsidase-Beta Group
Table 3. Summary of Adverse Events
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Banikazemi M, Bultas J, Waldek S, Wilcox WR, Whitley CB, McDonald M, et al. Agalsidase-Beta Therapy for Advanced Fabry Disease: A Randomized Trial. Ann Intern Med. ;146:77–86. doi: 10.7326/0003-4819-146-2-200701160-00148
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Published: Ann Intern Med. 2007;146(2):77-86.
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