Endocrinologic & Metabolic Drugs Advisory Committee Replagal BLA 103977

2/6/03


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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

Author: Susan Presley