Table of Contents
Endocrinologic & Metabolic Drugs Advisory Committee Replagal BLA 103977
REPLAGAL: agalsidase alfa
Clinical Summary: Replagal
TKT Presentations
Experts
Experts (cont)
TKT Presentations
Fabry Disease
Disease Management
Pathophysiology
Fabry Disease: Renal Natural History
Fabry Disease: Renal Natural History
Fabry Disease: Renal Natural History
Fabry Disease: Renal Natural History
Fabry Disease: Renal Natural History
Fabry Disease: Renal Natural History
Fabry Disease: Renal Natural History
Fabry Disease: Renal Natural History
Fabry Disease: Renal Natural History
Fabry Disease: Heart Disease
Other Manifestations
Fabry Disease: Conclusions
TKT Presentations
Kidney Pathology: Introduction
Kidney: Normal Glomeruli
Kidney: Early Glomerular Disease
Kidney: Mesangial Widening
Kidney: Segmental Sclerosis
Kidney: Obsolescence
Histopathological Spectrum of Disease
Replagal Clinical Data
Replagal Clinical Studies
Replagal: NIH Clinical Studies
TKT003: Creatinine Clearance
TKT003: Creatinine Clearance
TKT003: Glomerular Filtration Rate (GFR)
TKT010: Glomerular Filtration Rate (GFR)
NIH Clinical Trials: Creatinine Clearance
NIH Clinical Trials: GFR
Renal Function: 2 years of Replagal
Progression of Renal Disease: NIH Replagal Patients vs. Historical Controls
Individual Patient Data: Creatinine Clearance
Progression to ESRD: Age Range of Replagal-Treated Patients vs. Literature
Histopathological Spectrum of Disease
TKT003: Kidney Pathology
TKT003: Kidney Pathology Procedures
TKT003: Kidney Pathology
Mean Baseline Creatinine Clearance vs Normal Glomeruli (%)
Mean Baseline Creatinine Clearance vs Segmental Sclerosis and Obsolescent Glomeruli (%)
Renal Efficacy of Replagal: Conclusions
Effect of Replagal on Cardiomyopathy: Study TKT005
TKT005: LV Mass by MRI
Effect of Replagal on Cardiomyopathy: NIH Studies (TKT003/TKT006)
LV Mass: TKT003/TKT006
Replagal Reduces LV Mass in Female Patients (Study TKT014)
TKT014: LV Mass Response to Replagal
TKT014: LV Mass Index – Long Term Therapy with Replagal
Cardiac Efficacy of Replagal: Conclusions
Replagal: Metabolic Effects
Safety Experience: Adverse Events
Safety Experience: Infusion Reactions
TKT003/TKT006: Infusion Reactions and IgG Antibodies
Antibody Response to Replagal Therapy
Study TKT011: Plasma Gb3 Results
Study TKT011: Creatinine Clearance Results
Study TKT011: LV Mass Results
Antibody Response to Replagal Therapy: Conclusions
Conclusions: Replagal
TKT Q&A Slides
Figure 12A: GFR vs the Fraction of Glomeruli with Mesangial Widening (%): Scatter Plot
Reversal of Proteinuria
Effect of Replagal on Glomerular Endocapillary Gb3 Deposition
Change of Creatinine Clearance vs Change of Normal (%) and Mesangial Widening
TKT003 – Creatinine Clearance Over/Under Collections
GFR in Study TKT003
Replagal Liver Biodistribution vs. Dose in Humans (75 Kg patient, 2 hours after infusion)
Choice of Recommended Human Dose (0.2 mg/kg)
TKT003: Two Interpretations of Placebo Arm
Figure 23A: GFR vs Plasma Gb3
Table 20: Effect of Replagal on Interstitial Vascular Endothelial Gb3 Deposition
Figure 9: TKT003 Kidney Pathology Results
Branton, et al – Decline in Renal Function
Table 21: Reduction of Interstitial Capillary Endothelial Cell Gb3 by Agalsidase Beta (Fabrazyme™, Genzyme Corporation)
Effect of Replagal on Gb3 Storage in the Kidney: Peritubular Capillaries
Figure 6: Fabry Disease: Heart Biopsy (Toluidine Blue Stain: 40x)
FOS - Fabry Outcome Survey A database on medical outcomes of patients with Fabry disease
Number of Patients on Agalsidase Alfa
Number of Involved Organ Systems
Clinical Manifestations in Obligate Carrier Females: MacDermot, 2001
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