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Intermitent long-term treatment in a patient with Fabry disease
Clinical Therapeutics
INTERMITENT LONG-TERM TREATMENT IN A PATIENT W I T H FABRY DISEASE
Background: Fabry disease (FD) results from systemic accumulation of unmetabolized glycosphingolipids, primarily globotriaosylceramide (GL-3), due to genetic mutations of the lysosomal hydrolase, c~-galactosidaseA. In the classic Fabry phenotype, clinical symptoms arise in childhood or adolescence, usually involving acroparesthesia and episodic pain crises, and often accompanied by hypohidrosis with exercise intolerance. The quality of life of these young patients is negatively impacted. An open-label study of enzyme replacement therapy in pediatric patients with FD found that Fabrazyme® (recombinant human c~-galactosidase A) effectively cleared GL-3 from the dermal capillary endothelium of skin and normalized GL-3 concentrations in plasma. Most treatment-related adverse events were mild or moderate infusion-associated reactions that had previously been seen in adults. Objective: Reported here are additional results from exploratory quality-ofqife measures based on self-assessments of school attendance, physical activity, general health, and pain that were recorded in an electronic patient diary. Methods: The multisite study enrolled 14 males and 2 females (age range, 8-15 years) with clinical symptoms of FD. A 12-week observation period to collect baseline data preceded the 48-week treatment period during which Fabrazyme (1 mg/kg) was infused intravenously every 2 weeks. Results: From the observation period to treatment weeks 37 to 48, diary entries indicated that the mean percentage of days absent from school due to sickness decreased from 12% to 7% (P = 0.040). Reductions were also documented in the mean percentage of days with difficulty performing low-energy activities (12% vs 3%; P < 0.001) and moderate-energy activities (18% vs 12%; P = 0.325). The mean percentage of days when patients reported good general health increased from 66% to 75% (P = 0.009) from observation to weeks 13 to 24, with similar gains sustained through weeks 37 to 48. Pain medications were not restricted during the study, and most patients reported low pain levels during observation. Nevertheless, between the observation period and weeks 13 to 24, the mean percentage of days with reports of no pain increased from 30% to 44% (P = 0.025) while the percentage of days when patients reported considerable pain decreased from 7% to 2% (P = 0.005), with these improvements maintained through weeks 37 to 48. Conclusions: During Fabrazyme treatment of pediatric patients with FD, significant and consistent improvements in quality-of-life measures were reported.
C. Del Pozo; R. L6pez-Menchero; L. Sfinchez; and M.D. Albero
Nefrologfa, Hospital Virgen de Los Lirios, Alcoy, Spain Background: We describe here our experiences with agalsidase beta (Fabrazyme ®) treatment in a 59-year-old patient with Fabry disease (FD) in whom therapy had to be interrupted because of personal reasons. Case Report: A male patient with FD was diagnosed in June 2001 by demonstration of deficient ct-galactosidase A activity in leukocytes. At that time, the patient presented with renal insufficiency (1.8-mg/dL serum creatinine, 540-mg/24 h proteinuria). We performed a renal biopsy and observed a foamy transformation of gtomerular epithelial cells. Angiokeratoma in the scrotal area were noted, and we detected a moderate left ventricular hypertrophy at echocardiography. Results of the ocular examination, transcranial Doppler imaging, and brain magnetic resonance imaging were normal. We present here results of serum creatinine and modification of diet in renal disease (MDRD) measurements, as well as rates of decline in glomerular filtration rate (GFR), for agalsidase beta treatment periods 1 and 3 (Tables I and II) and period 2 (ie, the period of time during which agalsidase beta treatment had to be interrupted because of the patient's personal reasons [Table III]). Conclusions: Enzyme replacement therapy with agalsidase beta (Fabrazyme) slowed the progression of renal damage, as demonstrated by changes in rates of GFR decline.
W I T H D R A W A L OF ENZYME REPLACEMENT THERAPY IN FABRY DISEASE: INDIRECT EVIDENCE OF TREATMENT BENEFIT?. M. West; and K. Lemoine
Division of Nephrology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada Background: Fabry disease (FD) is an X-linked lysosomal storage disease determined by deficiency of ~-galactosidase A (c~-GalA). This results in premature death due to hypertrophic cardiomyopathy, stroke, or renal failure in severely affected individuals. Treatment with human recombinant ct-Gal A has been shown to remove deposits of the enzyme glycolipid substrate from various tissues and cells. Longterm clinical outcomes of such therapy are uncertain.
Table I. Treatment from December 4, 2001 to March 26, 2003.
Creatinine, mg/dL MDRD, mL/min/1.73
12/4/01
3/5/02
6/5/02
9/9/02
12/4/02
3/19/03
1.8 41.9
1.8 41.9
2 37.1
2.2 33.2
2 37.0
1.9 39.2
m 2 SC
Rate oFGFR decline: -0.18 mL/min/mo.
Table II. Treatment from September 29, 2004 (ongoing).
9/6/04 .
.
.
.
.
.
Creatinine, mg/dL MDRD, mL/min/1.73
.
.
m 2 SC
.
.
2.8 24.9
12/22/04 .
.
.
2.6 27.1
.
3/20/05 7/6/05 9/28/05 1/14/06 4/12/06 .
.
3.1 22.1
.
.
.
2.7 25.9
.
.
.
3.2 21.3
.
.
.
3.2 21.2
.
7/5/06
.
3.1 22.0
3.2 21.2
Rate oFGFR dechne: -0.17 mL/mm/mo.
S32
Volume 29 Supplement A
INTERMITENT LONG-TERM TREATMENT IN A PATIENT W I T H FABRY DISEASE
Background: Fabry disease (FD) results from systemic accumulation of unmetabolized glycosphingolipids, primarily globotriaosylceramide (GL-3), due to genetic mutations of the lysosomal hydrolase, c~-galactosidaseA. In the classic Fabry phenotype, clinical symptoms arise in childhood or adolescence, usually involving acroparesthesia and episodic pain crises, and often accompanied by hypohidrosis with exercise intolerance. The quality of life of these young patients is negatively impacted. An open-label study of enzyme replacement therapy in pediatric patients with FD found that Fabrazyme® (recombinant human c~-galactosidase A) effectively cleared GL-3 from the dermal capillary endothelium of skin and normalized GL-3 concentrations in plasma. Most treatment-related adverse events were mild or moderate infusion-associated reactions that had previously been seen in adults. Objective: Reported here are additional results from exploratory quality-ofqife measures based on self-assessments of school attendance, physical activity, general health, and pain that were recorded in an electronic patient diary. Methods: The multisite study enrolled 14 males and 2 females (age range, 8-15 years) with clinical symptoms of FD. A 12-week observation period to collect baseline data preceded the 48-week treatment period during which Fabrazyme (1 mg/kg) was infused intravenously every 2 weeks. Results: From the observation period to treatment weeks 37 to 48, diary entries indicated that the mean percentage of days absent from school due to sickness decreased from 12% to 7% (P = 0.040). Reductions were also documented in the mean percentage of days with difficulty performing low-energy activities (12% vs 3%; P < 0.001) and moderate-energy activities (18% vs 12%; P = 0.325). The mean percentage of days when patients reported good general health increased from 66% to 75% (P = 0.009) from observation to weeks 13 to 24, with similar gains sustained through weeks 37 to 48. Pain medications were not restricted during the study, and most patients reported low pain levels during observation. Nevertheless, between the observation period and weeks 13 to 24, the mean percentage of days with reports of no pain increased from 30% to 44% (P = 0.025) while the percentage of days when patients reported considerable pain decreased from 7% to 2% (P = 0.005), with these improvements maintained through weeks 37 to 48. Conclusions: During Fabrazyme treatment of pediatric patients with FD, significant and consistent improvements in quality-of-life measures were reported.
C. Del Pozo; R. L6pez-Menchero; L. Sfinchez; and M.D. Albero
Nefrologfa, Hospital Virgen de Los Lirios, Alcoy, Spain Background: We describe here our experiences with agalsidase beta (Fabrazyme ®) treatment in a 59-year-old patient with Fabry disease (FD) in whom therapy had to be interrupted because of personal reasons. Case Report: A male patient with FD was diagnosed in June 2001 by demonstration of deficient ct-galactosidase A activity in leukocytes. At that time, the patient presented with renal insufficiency (1.8-mg/dL serum creatinine, 540-mg/24 h proteinuria). We performed a renal biopsy and observed a foamy transformation of gtomerular epithelial cells. Angiokeratoma in the scrotal area were noted, and we detected a moderate left ventricular hypertrophy at echocardiography. Results of the ocular examination, transcranial Doppler imaging, and brain magnetic resonance imaging were normal. We present here results of serum creatinine and modification of diet in renal disease (MDRD) measurements, as well as rates of decline in glomerular filtration rate (GFR), for agalsidase beta treatment periods 1 and 3 (Tables I and II) and period 2 (ie, the period of time during which agalsidase beta treatment had to be interrupted because of the patient's personal reasons [Table III]). Conclusions: Enzyme replacement therapy with agalsidase beta (Fabrazyme) slowed the progression of renal damage, as demonstrated by changes in rates of GFR decline.
W I T H D R A W A L OF ENZYME REPLACEMENT THERAPY IN FABRY DISEASE: INDIRECT EVIDENCE OF TREATMENT BENEFIT?. M. West; and K. Lemoine
Division of Nephrology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada Background: Fabry disease (FD) is an X-linked lysosomal storage disease determined by deficiency of ~-galactosidase A (c~-GalA). This results in premature death due to hypertrophic cardiomyopathy, stroke, or renal failure in severely affected individuals. Treatment with human recombinant ct-Gal A has been shown to remove deposits of the enzyme glycolipid substrate from various tissues and cells. Longterm clinical outcomes of such therapy are uncertain.
Table I. Treatment from December 4, 2001 to March 26, 2003.
Creatinine, mg/dL MDRD, mL/min/1.73
12/4/01
3/5/02
6/5/02
9/9/02
12/4/02
3/19/03
1.8 41.9
1.8 41.9
2 37.1
2.2 33.2
2 37.0
1.9 39.2
m 2 SC
Rate oFGFR decline: -0.18 mL/min/mo.
Table II. Treatment from September 29, 2004 (ongoing).
9/6/04 .
.
.
.
.
.
Creatinine, mg/dL MDRD, mL/min/1.73
.
.
m 2 SC
.
.
2.8 24.9
12/22/04 .
.
.
2.6 27.1
.
3/20/05 7/6/05 9/28/05 1/14/06 4/12/06 .
.
3.1 22.1
.
.
.
2.7 25.9
.
.
.
3.2 21.3
.
.
.
3.2 21.2
.
7/5/06
.
3.1 22.0
3.2 21.2
Rate oFGFR dechne: -0.17 mL/mm/mo.
S32
Volume 29 Supplement A