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Clinical Nephrology
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Sustained, Long-Term Renal Stabilization After 54 Months of Agalsidase β Therapy in Patients with Fabry Disease

Dominique P. Germain, Stephen Waldek, Maryam Banikazemi, David A. Bushinsky, Joel Charrow, Robert J. Desnick, Philip Lee, Thomas Loew, Anouk C. Vedder, Rekha Abichandani, William R. Wilcox and Nathalie Guffon
JASN May 2007, 18 (5) 1547-1557; DOI: https://doi.org/10.1681/ASN.2006080816
Dominique P. Germain
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Stephen Waldek
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Maryam Banikazemi
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David A. Bushinsky
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Joel Charrow
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Robert J. Desnick
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Philip Lee
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Thomas Loew
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Anouk C. Vedder
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Rekha Abichandani
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William R. Wilcox
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Nathalie Guffon
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    Figure 1.

    Design of phase III and extension study. All 58 patients from the double-blind phase III trial entered the extension study (registration NCT00074971, clinicaltrials.gov). Kidney and cardiac biopsies that were required by study protocol are indicated by the asterisks at baseline of the phase III study, end of the phase III study, and month 6 of the extension study. Optional kidney and heart biopsies were obtained from eight patients at month 54.

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    Figure 2.

    Globotriaosylceramide (GL-3) clearance from kidney, heart, and skin capillary endothelium in all patients. Histologic specimens that were obtained at pretreatment, month 6, and month 54 (optional for kidney and heart) were evaluated for the presence of GL-3. Results show that for the majority of patients, initial GL-3 clearance (score of 0) seen at month 6 was maintained during the 54-mo treatment period. Numbers above bar graphs represent the number of patients with zero scores out of the total number evaluated. cap. endo., capillary endothelium.

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    Figure 3.

    Agalsidase β therapy reduced GL-3 accumulation to zero at 54 mo in various types of kidney cells. For distal convoluted tubule (DCT)/collecting duct cells, baseline scores were obtained at the beginning of the double-blind trial and at month 54 on a 0 to 3 scale. For all other cell types, pretreatment scores were obtained before agalsidase β treatment as defined in Materials and Methods. Mesangial cells were scored on a scale of 0 to 2, and other cell types were scored on a scale of 0 to 3.

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    Figure 4.

    Long-term agalsidase β therapy decreases GL-3 accumulation in podocytes. (A) Kidney biopsy that was obtained before agalsidase β therapy exhibits dark-staining granules in podocytes. (B) By month 54, fewer GL-3 inclusions are evident from a specimen that was obtained from the same patient. Methylene blue/azure II stain (13). Magnification, ×400.

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    Figure 5.

    Median estimated GFR (eGFR; ml/min per 1.73 m2) over time. Patients in the “as treated” population maintained a stable median eGFR during the 54-mo treatment period, which was observed in both the placebo/agalsidase β and the agalsidase β/agalsidase β treatment groups (left) as well as in the overall, combined population (right).

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    Figure 6.

    High (>1 g/24 h) baseline proteinuria is associated with higher rate of eGFR decline and increased probability of renal events. (A) Subgroup analyses of patients in the “as treated” population who were stratified by baseline proteinuria (≤1 g/24 h versus >1 g/24 h) showed differences in the rate of eGFR decline during the 54-mo treatment period. (B) Increased baseline proteinuria values seem to correlate with the probability of renal event (a 50% increase in serum creatinine from the pretreatment assessment and the increased value was >1.4 mg/dl). Note that baseline proteinuria was determined before entry into the double-blind study for all patients.

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    Figure 7.

    Pretreatment glomerulosclerosis involving ≥50% glomeruli is associated with higher rate of eGFR decline and increased risk for renal events. (A) Subgroup analyses of patients in the “as treated” population show that those with pretreatment glomerulosclerosis (≥50% sclerotic glomeruli) had a higher rate of decline in eGFR compared with patients with <50% sclerotic glomeruli at pretreatment. (B) As pretreatment glomerulosclerosis increases, the likelihood of having a renal event (a 50% increase in serum creatinine over the pretreatment assessment and an increased value >1.4 mg/dl) also increases.

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    Figure 8.

    Seroconversion does not appear to influence incidence of infusion-associated reactions (IAR) over time. Overall, 90% of patients seroconverted, with the majority of patients having seroconverted within 3 mo of the first agalsidase β infusion. The percentage of patients with IAR peaked early in the treatment period and coincided with IgG seroconversion. This overall seroconversion status was maintained over time; nevertheless, the percentage of patients with IAR steadily declined.

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    Table 1.

    Patient demographics (“as treated” population)a

    CharacteristicNo. of Patients
    N58
    Age (yr)b
        mean31.1
        range17 to 62
    Gender (male:female)56:2
    Race (n [%])
        white53 (91)
        nonwhite5 (9)
    ACEI/ARB use23 (40)
    • ↵a ACEI/ARB, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers.

    • ↵b At entry into the extension study.

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    Table 2.

    Improved or sustained GL-3 clearance from renal cells of patients who had Fabry disease and underwent long-term agalsidase β therapya

    Renal Cell TypeNo. Evaluated at Month 6No. (%) with Score of 0No. Evaluated at Month 54bNo. (%) with Score of 0
    Capillary endothelial cells4947 (96)88 (100)
    Glomerular endothelial cells3535 (100)55 (100)
    Mesangial cells3534 (97)55 (100)
    Interstitial cells4843 (90)75 (71)
    Noncapillary endothelial cells4440 (91)66 (100)
    Noncapillary smooth muscle cells430 (0)60 (0)
    • ↵a Patients with data at both pretreatment and month 6 or pretreatment and month 54 are summarized. GL-3, globotriaosylceramide.

    • ↵b Of the extension study.

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    Table 3.

    Adverse events that were related to agalsidase β therapy and occurred in at least 10% of patients overalla

    Body SystemAdverse Eventn (%)
    Body as a whole, general disordersRigors34 (59)
    Temperature-change sensation22 (38)
    Fever21 (36)
    Chest pain12 (21)
    Central and peripheral nervous system disordersHeadache17 (29)
    Tremor8 (14)
    Gastrointestinal system disordersNausea16 (28)
    Vomiting12 (21)
    Abdominal pain10 (17)
    Cardiovascular disorders, generalHypertension7 (12)
    Respiratory system disordersDyspnea10 (17)
    Rhinitis10 (17)
    Skin and appendages disordersPruritus10 (17)
    Vascular (extracardiac) disordersFlushing11 (19)
    Secondary termsFabry pain/acroparesthesia12 (21)
    Musculoskeletal system disordersMyalgia8 (14)
    Psychiatric disordersSomnolence8 (14)
    • ↵a Percentages are based on the total number of patients; a patient who experienced more than one adverse event was counted once.

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Journal of the American Society of Nephrology: 18 (5)
Journal of the American Society of Nephrology
Vol. 18, Issue 5
May 2007
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Sustained, Long-Term Renal Stabilization After 54 Months of Agalsidase β Therapy in Patients with Fabry Disease
Dominique P. Germain, Stephen Waldek, Maryam Banikazemi, David A. Bushinsky, Joel Charrow, Robert J. Desnick, Philip Lee, Thomas Loew, Anouk C. Vedder, Rekha Abichandani, William R. Wilcox, Nathalie Guffon
JASN May 2007, 18 (5) 1547-1557; DOI: 10.1681/ASN.2006080816

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Sustained, Long-Term Renal Stabilization After 54 Months of Agalsidase β Therapy in Patients with Fabry Disease
Dominique P. Germain, Stephen Waldek, Maryam Banikazemi, David A. Bushinsky, Joel Charrow, Robert J. Desnick, Philip Lee, Thomas Loew, Anouk C. Vedder, Rekha Abichandani, William R. Wilcox, Nathalie Guffon
JASN May 2007, 18 (5) 1547-1557; DOI: 10.1681/ASN.2006080816
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  • Reduction of podocyte globotriaosylceramide content in adult male patients with Fabry disease with amenable GLA mutations following 6 months of migalastat treatment
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  • Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease
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  • Fabry Disease: Dose Matters
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  • Screening patients with hypertrophic cardiomyopathy for Fabry disease using a filter-paper test: the FOCUS study
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  • Prognostic Indicators of Renal Disease Progression in Adults with Fabry Disease: Natural History Data from the Fabry Registry
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  • High Incidence of the Cardiac Variant of Fabry Disease Revealed by Newborn Screening in the Taiwan Chinese Population
  • National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Follow-Up Testing for Metabolic Disease Identified by Expanded Newborn Screening Using Tandem Mass Spectrometry; Executive Summary
  • Natural course of Fabry disease: changing pattern of causes of death in FOS - Fabry Outcome Survey
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  • Antiproteinuric Therapy and Fabry Nephropathy: Sustained Reduction of Proteinuria in Patients Receiving Enzyme Replacement Therapy with Agalsidase-beta
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