- Email: [email protected]
Fabrazyme® therapy in pediatric patients with Fabry disease: Improvements in quality-of-life measures
Poster Abstracts
Conclusions: Agalsidase beta significantly improved the function of unmyelinated C-fibers and thinly myelinated A-deha fibers in Fabry neuropathy.
IMPACT OF T R E A T M E N T W I T H AGALSIDASE BETA O N HEALTH-RELATED QUALITY OF LIFE IN PATIENTS W I T H FABRY DISEASE X. Badial; P. Perezl; M. Layolal; D. Checa2; A. Tutor3; A. Mvarez3; R. Torra4; J. TorrasS; G. de Arriba6; C. Garcia-Monc67; J.M. PuigS; and V. Torregrosa9
1Health Outcomes Research Europe (IMS Health): 2Hospital Insular de Las Palmas; ~Hospital Vlrgen de la Salud, Toledo; 4Fundacidn Puigvert, Barcelona; SHospital de Bellvitge, Barcelona; OHospital General de Guadalajara: 7Hospital de Galddcano; SHospital del Mar, Barcelona; and 9Hospital Clinico de Barcelona, Spain Background: Fabry disease (FD) is caused by the lack of ~-galactosidase A, or by faulty transcription of this enzyme, which is involved in lipid metabolism. Agalsidase alfa and beta are enzyme therapies that have been increasingly used in FD treatment. Nevertheless, their effects on health-related quality of life (HRQOL) have not previously been analyzed. Objective: The study objective was to assess the effects of agalsidase beta treatment on HRQOL. The therapeutic objectives of treatment included maintenance of HRQOL. Methods: A prospective, observational, multicenter study was performed. Patients were followed up for a maximum period of 24 months, with visits every 3 months. The study was performed by 8 specialists (from the fields of nephrology, neurology, and internal medicine). Seventeen patients with FD beginning or already receiving treatment with agalsidase beta were included in the study, but only 14 (included in final analysis) completed the follow-up period. Treatment effectiveness was assessed in terms of clinical measures and HRQOL, using the EuroQol 5-dimension (EQ-SD) questionnaire. Due to the relatively low number of patients, only descriptive statistical measures were used. Results: Of the included patients, 87.5% were male, with a mean (SD) age of 36.6 (12.1) years; 64.3% of the patients had a positive family history. The mean (SD) time between onset of symptoms and study enrollment was 10.3 (10.9) years. Thirty-six percent of included patients had received agalsidase beta therapy before enrollment (mean [SD] treatment duration, 168.2 1145.6I days). During the follow-up period, the percentage of patients with pain/discomfort problems decreased from 57.1% at baseline to 14.3% at 24 months. Other EQ-5D dimensions remained without important changes. Slight improvement of HRQOL was also shown in EQ-5D visual analog scale scores, which increased from 74.4 (17.0) at baseline to 83.1 (12.3) at month 24. In terms of clinical variables, patients were stable during the study's follow-up period. Conclusions: Despite the relatively small number of patients included in the study, the results provide information about the effects of agalsidase beta on HRQOL of patients with FD. We demonstrated a slight improvement in HRQOL during a follow-up of 24 months.
LONG-TERM AGALSIDASE BETA THERAPY IS ASSOCIATED W I T H IMPROVEMENTS IN PAIN A N D QUALITY OF LIFE A M O N G PATIENTS W I T H FABRY DISEASE N. Guffonl; D.P. Germain2; S. Waldek3; M. Banikazemi4; D.A. BushinskyS: J. Charrow6; E LeeT; T. LoewS; A.C. Vedderg; and W.R. Wilcox 1° 2007
t Hdpital Edouard Herriot, Lyon, France; 2Hdpital Europden Georges Pompidou, Paris, France: ~Hope Hospital, Manchester, United Kingdom; 4Mount Sinat School of Medtcme, New York, New York; ~University of Rochester School of Medicine, Rochester, New York; 6Children's Memorial Hospital, Chicago, Illinois; 7National Hospital for Neurology and Neurosurgery, London, United Kingdom: SUniversity of Iowa Hospital & Clinics, Iowa City, Iowa; ')Academisch Medisch Centrum, Amsterdam, The Netherlands: and WCedars-Sinat Medwal Center, Los Angeles, California Background: Fabry disease (FD) results from a mutation in the gene encoding c~-galactosidase A, causing progressive intralysosomal accumulation of globotriaosylceramide (GL-3) and premature death. Patient quality of life (QOL) is impaired, often secondary to pain in the extremities (acroparesthesia), which may be increased by physical exertion, stress, and warm temperatures. In a Phase II1 extension study, human recombinant c~-galactosidase A (agalsidase beta) was associated with maintained clearance of GL-3 in the kidney, heart, and skin; normalized plasma GL-3; and stabilized normal renal function for most patients. Most adverse events were mild and unrelated to treatment. Objective: The goal of this study was to assess changes in pain and QOL factors among patients with FD who received agalsidase beta during a 54-month Phase III extension study. Methods: All 58 patients with FD who successfully completed a 20-week, double-blind, placebo-controlled Phase III study of agalsidase beta transitioned to an extension trial and received biweekly 1-mg/kg agalsidase beta for up to 54 months. Pain was evaluated with the Short Form of the McGill Pain Questionnaire and included a visual analog scale (VAS; range, 0-10 [worst pain]) and a present pain intensity (PPI) scale (range, 0-5 lintense pain]). Changes in QOL were evaluated with the SF-36 Health Survey. Results: Generally, pain scores at baseline and during the study were low, possibly due to unrestricted use of pain medications. Slight improvements were observed in all pain scores. For patients with pain before treatment, changes in mean PPI and VAS scores through month 54 were -0.63 (P < 0.017) and -1.09 (P < 0.007), respectively. Mean changes through month 54 for the SF-36 Health Survey components of physical functioning, role emotional, body pain, and standardized physical component scale (for patients with suboptimal scores lie, <100] before treatment) were significant (P < 0.015, 0.032, 0.003, and 0.007, respectively) for the overall population. Conclusions: Significant improvements m pain assessments were observed among patients with FD receiving agalsidase beta who had pain before their first treatment. Patients experienced a mean improvement in QOL assessments after long-term treatment with agalsidase beta, with significant improvements in several SF-36 Health Survey components for those with suboptimal scores before treatment.
FABRAZYME ® THERAPY IN PEDIATRIC PATIENTS W I T H FABRY DISEASE: IMPROVEMENTS IN QUALITY-OF-LIFE MEASURES A. Tylki-Szymanskal; D.P. Germain2;J.E. Wraith3; N. Guffon4; Y.H. LienS; M. Tsimaratos6; and A. Vellodi7 tKlinika Chorob Metabolicznych, Warsaw, Poland: 2H6pital Europeen Georges Pompidou, Paris, France; 3Royal Manchester Chddren's Hospital, Manchester, United Kmgdom: 4H6pital Edouard Herriot, Lyon, France; ~University of Arizona, Tucson, Artzona; 6H6pital de la Timone Enfants, Marseille, France; and 7Great Ormond Street Hospital for Sick Children, London, United Kingdom $31
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
Conclusions: Agalsidase beta significantly improved the function of unmyelinated C-fibers and thinly myelinated A-deha fibers in Fabry neuropathy.
IMPACT OF T R E A T M E N T W I T H AGALSIDASE BETA O N HEALTH-RELATED QUALITY OF LIFE IN PATIENTS W I T H FABRY DISEASE X. Badial; P. Perezl; M. Layolal; D. Checa2; A. Tutor3; A. Mvarez3; R. Torra4; J. TorrasS; G. de Arriba6; C. Garcia-Monc67; J.M. PuigS; and V. Torregrosa9
1Health Outcomes Research Europe (IMS Health): 2Hospital Insular de Las Palmas; ~Hospital Vlrgen de la Salud, Toledo; 4Fundacidn Puigvert, Barcelona; SHospital de Bellvitge, Barcelona; OHospital General de Guadalajara: 7Hospital de Galddcano; SHospital del Mar, Barcelona; and 9Hospital Clinico de Barcelona, Spain Background: Fabry disease (FD) is caused by the lack of ~-galactosidase A, or by faulty transcription of this enzyme, which is involved in lipid metabolism. Agalsidase alfa and beta are enzyme therapies that have been increasingly used in FD treatment. Nevertheless, their effects on health-related quality of life (HRQOL) have not previously been analyzed. Objective: The study objective was to assess the effects of agalsidase beta treatment on HRQOL. The therapeutic objectives of treatment included maintenance of HRQOL. Methods: A prospective, observational, multicenter study was performed. Patients were followed up for a maximum period of 24 months, with visits every 3 months. The study was performed by 8 specialists (from the fields of nephrology, neurology, and internal medicine). Seventeen patients with FD beginning or already receiving treatment with agalsidase beta were included in the study, but only 14 (included in final analysis) completed the follow-up period. Treatment effectiveness was assessed in terms of clinical measures and HRQOL, using the EuroQol 5-dimension (EQ-SD) questionnaire. Due to the relatively low number of patients, only descriptive statistical measures were used. Results: Of the included patients, 87.5% were male, with a mean (SD) age of 36.6 (12.1) years; 64.3% of the patients had a positive family history. The mean (SD) time between onset of symptoms and study enrollment was 10.3 (10.9) years. Thirty-six percent of included patients had received agalsidase beta therapy before enrollment (mean [SD] treatment duration, 168.2 1145.6I days). During the follow-up period, the percentage of patients with pain/discomfort problems decreased from 57.1% at baseline to 14.3% at 24 months. Other EQ-5D dimensions remained without important changes. Slight improvement of HRQOL was also shown in EQ-5D visual analog scale scores, which increased from 74.4 (17.0) at baseline to 83.1 (12.3) at month 24. In terms of clinical variables, patients were stable during the study's follow-up period. Conclusions: Despite the relatively small number of patients included in the study, the results provide information about the effects of agalsidase beta on HRQOL of patients with FD. We demonstrated a slight improvement in HRQOL during a follow-up of 24 months.
LONG-TERM AGALSIDASE BETA THERAPY IS ASSOCIATED W I T H IMPROVEMENTS IN PAIN A N D QUALITY OF LIFE A M O N G PATIENTS W I T H FABRY DISEASE N. Guffonl; D.P. Germain2; S. Waldek3; M. Banikazemi4; D.A. BushinskyS: J. Charrow6; E LeeT; T. LoewS; A.C. Vedderg; and W.R. Wilcox 1° 2007
t Hdpital Edouard Herriot, Lyon, France; 2Hdpital Europden Georges Pompidou, Paris, France: ~Hope Hospital, Manchester, United Kingdom; 4Mount Sinat School of Medtcme, New York, New York; ~University of Rochester School of Medicine, Rochester, New York; 6Children's Memorial Hospital, Chicago, Illinois; 7National Hospital for Neurology and Neurosurgery, London, United Kingdom: SUniversity of Iowa Hospital & Clinics, Iowa City, Iowa; ')Academisch Medisch Centrum, Amsterdam, The Netherlands: and WCedars-Sinat Medwal Center, Los Angeles, California Background: Fabry disease (FD) results from a mutation in the gene encoding c~-galactosidase A, causing progressive intralysosomal accumulation of globotriaosylceramide (GL-3) and premature death. Patient quality of life (QOL) is impaired, often secondary to pain in the extremities (acroparesthesia), which may be increased by physical exertion, stress, and warm temperatures. In a Phase II1 extension study, human recombinant c~-galactosidase A (agalsidase beta) was associated with maintained clearance of GL-3 in the kidney, heart, and skin; normalized plasma GL-3; and stabilized normal renal function for most patients. Most adverse events were mild and unrelated to treatment. Objective: The goal of this study was to assess changes in pain and QOL factors among patients with FD who received agalsidase beta during a 54-month Phase III extension study. Methods: All 58 patients with FD who successfully completed a 20-week, double-blind, placebo-controlled Phase III study of agalsidase beta transitioned to an extension trial and received biweekly 1-mg/kg agalsidase beta for up to 54 months. Pain was evaluated with the Short Form of the McGill Pain Questionnaire and included a visual analog scale (VAS; range, 0-10 [worst pain]) and a present pain intensity (PPI) scale (range, 0-5 lintense pain]). Changes in QOL were evaluated with the SF-36 Health Survey. Results: Generally, pain scores at baseline and during the study were low, possibly due to unrestricted use of pain medications. Slight improvements were observed in all pain scores. For patients with pain before treatment, changes in mean PPI and VAS scores through month 54 were -0.63 (P < 0.017) and -1.09 (P < 0.007), respectively. Mean changes through month 54 for the SF-36 Health Survey components of physical functioning, role emotional, body pain, and standardized physical component scale (for patients with suboptimal scores lie, <100] before treatment) were significant (P < 0.015, 0.032, 0.003, and 0.007, respectively) for the overall population. Conclusions: Significant improvements m pain assessments were observed among patients with FD receiving agalsidase beta who had pain before their first treatment. Patients experienced a mean improvement in QOL assessments after long-term treatment with agalsidase beta, with significant improvements in several SF-36 Health Survey components for those with suboptimal scores before treatment.
FABRAZYME ® THERAPY IN PEDIATRIC PATIENTS W I T H FABRY DISEASE: IMPROVEMENTS IN QUALITY-OF-LIFE MEASURES A. Tylki-Szymanskal; D.P. Germain2;J.E. Wraith3; N. Guffon4; Y.H. LienS; M. Tsimaratos6; and A. Vellodi7 tKlinika Chorob Metabolicznych, Warsaw, Poland: 2H6pital Europeen Georges Pompidou, Paris, France; 3Royal Manchester Chddren's Hospital, Manchester, United Kmgdom: 4H6pital Edouard Herriot, Lyon, France; ~University of Arizona, Tucson, Artzona; 6H6pital de la Timone Enfants, Marseille, France; and 7Great Ormond Street Hospital for Sick Children, London, United Kingdom $31
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