Agalsidase-Beta Therapy for Advanced Fabry Disease

  1. Maryam Banikazemi, MD;
  2. Jan Bultas, MD, PhD;
  3. Stephen Waldek, MB, BCh;
  4. William R. Wilcox, MD, PhD;
  5. Chester B. Whitley, PhD, MD;
  6. Marie McDonald, MD;
  7. Richard Finkel, MD;
  8. Seymour Packman, MD;
  9. Daniel G. Bichet, MD;
  10. David G. Warnock, MD;
  11. Robert J. Desnick, PhD, MD; and
  12. for the Fabry Disease Clinical Trial Study Group*
  1. From the Mount Sinai School of Medicine of New York University, New York, New York; University Hospital, Prague, Czech Republic; Hope Hospital and Salford Royal Hospital National Health Service Trust, Manchester, United Kingdom; Medical Genetics Institute and Cedars-Sinai Medical Center, Los Angeles, California; University of Minnesota, Minneapolis, Minnesota; Duke University Medical Center, Durham, North Carolina; The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; University of California, San Francisco, San Francisco, California; University of Montréal, Montréal, Québec, Canada; and University of Alabama at Birmingham, Birmingham, Alabama.
    1. Figure 1.
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      Figure 1. Study flow diagram.
    2. Figure 2.
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      Figure 2. 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).

    3. Figure 3.
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      Figure 3. 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.

    4. Appendix Figure.
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      Appendix Figure. Longitudinal analysis of proteinuria in both groups.Graphic

      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.

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    1. Ann Intern Med January 16, 2007 vol. 146 no. 2 77-86
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