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Endocrinologic & Metabolic Drugs Advisory Committee Replagal BLA 103977

Endocrinologic & Metabolic Drugs Advisory Committee Replagal BLA 103977. Transkaryotic Therapies, Inc. January 14, 2003. 4000.01. REPLAGAL: agalsidase alfa. Human -galactosidase A Homodimer comprised of two ~ 50kDa subunits Produced in continuous human cell line

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Endocrinologic & Metabolic Drugs Advisory Committee Replagal BLA 103977

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  1. Endocrinologic & Metabolic Drugs Advisory CommitteeReplagal BLA 103977 Transkaryotic Therapies, Inc. January 14, 2003 4000.01

  2. REPLAGAL: agalsidase alfa • Human -galactosidase A • Homodimer comprised of two ~50kDa subunits • Produced in continuous human cell line • Identical amino acid sequence to endogenous protein 4002.03

  3. Clinical Summary: Replagal • Improves standard glomerular pathology • Correlates with renal function • Stabilizes renal function over 30 months • Reduces LV mass • Improves cardiac conduction system function • Safe and well-tolerated after 2½ years of therapy 4001.06

  4. TKT Presentations 4778.05

  5. Experts Dr. Wilson Colucci Chief of Cardiovascular Medicine, Boston Medical Center. Director, Myocardial Biology Unit, Boston University School of Medicine. Dr. Christoph Kampmann Professor of Pediatrics, Pediatric Cardiology and Neonatology, Director of the Dept. of Pediatric Cardiology, Children’s Heart Center, University Children’s Hospital, Johannes Gutenberg University, Mainz, Germany. Dr. Edwin Kolodny Chairman, Department of Neurology, New York University School of Medicine, New York. Dr. Kathleen Lamborn Professor of Neurological Surgery (Biostatistics), University of California, San Francisco. 4780.06

  6. Experts (cont) Dr. Atul Mehta Consultant Hematologist, Royal Free Hospital, London, UK. Dr. Ronald Perrone Professor of Medicine, Tufts University School of Medicine. Associate Chief of New England Medical Center Division of Nephrology. Medical Director of Renal Transplantation, Tufts New England Medical Center, Boston. Dr. Melvin Schwartz Professor, Department of Pathology at Rush-Presbyterian-St Luke’s Medical Center, Chicago. 4784.04

  7. TKT Presentations 4546.05

  8. Fabry Disease • X-linked glycosphingolipid lysosomal storage disorder • Deficiency of -galactosidase A leading to accumulation of Gb3 • Rare: Approximately 1500-2000 patients in USA • Progressive, multisystem disease • Renal • Cardiac • Cerebrovascular • Neurologic • Gastrointestinal • Metabolic • Death in 4th or 5th decade of life 4003.04

  9. Disease Management • No specific treatment • Patient care generally restricted to palliation: • Renal failure: dialysis/transplantation • Heart disease/stroke: standard treatment • GI disease: antidiarrheals • Neuropathic pain: • generally refractory to analgesics and opioids • empiric use of anticonvulsants has been useful for pain control in some patients 4004.01

  10. Kidney: Glomerular epithelial cells (podocytes) Glomerular mesangial cells Tubular epithelial cells Renal failure Concentrating defects Heart: Myocytes Conduction system Cardiomyopathy and cardiac hypertrophy QRS complex widening Nerves: Autonomic ganglia Pain Pathophysiology Parenchymal cell deposition of Gb3 leads to multisystem pathology 4005.06

  11. Early manifestations Proteinuria Renal concentrating defects Progressive decline in renal function Late manifestations Nephrotic syndrome Diabetes insipidus ESRD Fabry Disease: Renal Natural History Progression of Renal Disease 4006.04

  12. 120 110 Normal 100 90 Impaired Renal Function 80 70 Renal Function (mL/min) 60 50 Chronic Renal Insufficiency 40 30 20 10 ESRD 0 Time (years) Fabry Disease: Renal Natural History Summary 4782.05

  13. Fabry Disease: Renal Natural History Age and Renal Function • All patients (n=116) • Age: 33.6 ± 10.4 years • Renal function: 48.9 ± 44.9 mL/min • Patients not in ESRD (n=54) • Age: 30.7 ± 9.8 years • Renal function: 85.1 ± 33.8 mL/min • Patients in ESRD (n=62) • Age of onset: 36.7 ± 10.1 years 4007.03

  14. Fabry Disease: Renal Natural History Decline of Renal Function Over Time 4008.08

  15. Fabry Disease: Renal Natural History Predicted Rate of Decline 120 100 /min) Creatinine Clearance 8.3 mL/min/yr mL 80 ( ( 10.6mL/min/yr 60 21.0mL/min/yr Predicted Rate of Decline 40 0 6 12 18 24 30 Month Month 4741.04

  16. Fabry Disease: Renal Natural History Age at End Stage Renal Disease 4679.06

  17. Fabry Disease: Renal Natural History Progression to ESRD 100 80 60 * Percent of Patients w/o ESRD 40 20 0 0 10 20 30 40 50 60 70 Age (years) * Fabry ESRD Patients All USRDS Patients 4742.02

  18. 120 Early to mid 30’s 110 Normal 100 ~10.6 mL/min/yr 90 Impaired Renal Function 80 70 Renal Function (mL/min) 60 50 Chronic Renal Insufficiency 40 mean age of ESRD ~38 yrs 30 20 10 ESRD 0 ~ 4.3 yrs Time (years) Fabry Disease: Renal Natural History Summary 4009.07

  19. Fabry Disease: Renal Natural History Two Major Conclusions • Beginning at approximately age 30-35 years the rate of decline of renal function is ~10.6 mL/min/year • The mean age at which patients with Fabry disease progress to ESRD is ~38 years 4011.04

  20. Fabry Disease: Heart Disease • Accumulation of Gb3 in myocytes and conduction system • Cardiomyopathy with LV hypertrophy • Progressive increase in LV mass • Significant age-related progression in males and females • Conduction system dysfunction • Widening of QRS complex leading to bundle branch blocks • 20% incidence of cardiac death 4012.07

  21. Other Manifestations • Cerebrovascular system • Stroke • Altered cerebrovascular blood flow • Neuropathic pain • Chronic pain • Refractory to pain medications • Gastrointestinal system • Abdominal pain; diarrhea • Chronic weight loss • Progressive hearing loss • Angiokeratoma; hypohydrosis 4015.02

  22. Fabry Disease: Conclusions • Complex, multisystem disorder • Progressive deterioration of renal function • Progressive increase in LV mass • Major causes of mortality • Progressive renal failure • Progressive cardiac failure 4520.04

  23. TKT Presentations 4547.05

  24. Kidney Pathology: Introduction Intracellular Deposition Disease of the Nephron: • Glomerular epithelial cell Gb3 deposition • Glomerular mesangial widening • Segmental glomerular sclerosis • Obsolescent glomeruli • Tubular epithelial cell deposition • Capillary endothelial cells relatively spared 4016.03

  25. Kidney: Normal Glomeruli PAS Stain Toluidine Blue Stain 4540.04

  26. Kidney: Early Glomerular Disease PAS Stain Toluidine Blue Stain 4017.06

  27. Kidney: Mesangial Widening PAS Stain Toluidine Blue Stain 4018.04

  28. Kidney: Segmental Sclerosis PAS Stain Toluidine Blue Stain 4019.07

  29. Kidney: Obsolescence PAS Stain Toluidine Blue Stain 4020.03

  30. Early Deposition Mesangial Widening Segmental Sclerosis Obsolescence Histopathological Spectrum of Disease Histopathological Progression 4021.03

  31. Replagal Clinical Data 4867.02

  32. Replagal Clinical Studies 4026.02

  33. TKT011 (1 year analysis) TKT003 TKT006 Replagal 6 months (n=14) Replagal (n=25) Replagal (n=24) placebo 6 months (n=12) Replagal: NIH Clinical Studies 4027.05

  34. TKT003: Creatinine Clearance 130 120 110 p=0.051 (Replagal vs placebo) 100 Creatinine Clearance (mL/min) 90 80 TKT003 Replagal (n=14 : mean age = 34.0) 70 TKT003 placebo (n=11 : mean age = 34.4) 60 0 6 Treatment Period (months) 4028.03

  35. TKT003: Creatinine Clearance p=0.045 (Replagal vs placebo) 0 9 17 23/24 4683b.04

  36. TKT003: Glomerular Filtration Rate (GFR) p=0.25 (Replagal vs placebo) 0 23/24 4683c.05

  37. TKT010: Glomerular Filtration Rate (GFR) p=0.74 (Replagal vs placebo) 4869.01

  38. Study TKT003 Replagal – Study TKT006/TKT011 Replagal (n=13) Study TKT003 placebo – Study TKT006/TKT011 Replagal (n=12) 130 120 110 100 Creatinine Clearance (mL/min) 90 80 70 TKT006 TKT003 TKT011 60 0 6 12 18 24 30 Treatment Period (months) NIH Clinical Trials: Creatinine Clearance 4029.05

  39. NIH Clinical Trials: GFR Study TKT003 Replagal – Study TKT006/TKT011 Replagal Study TKT003 placebo – Study TKT006/TKT011 Replagal 130 TKT003 TKT011 TKT006 120 110 100 GFR (mL/min/ 1.73m2) 90 80 70 60 0 6 12 18 24 30 Treatment Period (months) 4744.02

  40. Renal Function: 2 years of Replagal TKT006 TKT011 Creatinine clearance GFR 4031.02

  41. 120 100 /min) Creatinine Clearance 8.3 mL/min/yr mL 80 ( ( 10.6 mL/min/yr 60 TKT003, TKT006, TKT011 Patients TKT003, TKT006, TKT011 Patients 21.0 mL/min/yr Predicted Rate of Decline 40 0 6 12 18 24 30 Month Month Progression of Renal Disease: NIH Replagal Patients vs. Historical Controls 4034.03

  42. Individual Patient Data: Creatinine Clearance Patients 4777.04

  43. 100 80 60 40 20 0 0 10 20 30 40 50 60 70 Age (years) Literature Patients TKT003/006/011 Replagal Patients Source: Progression to ESRD: Age Range of Replagal-Treated Patients vs. Literature Percent of Patients not in ESRD 4032.06

  44. Early Deposition Mesangial Widening Segmental Sclerosis Obsolescence Histopathological Spectrum of Disease Histopathological Progression 4868.01

  45. TKT003: Kidney Pathology • Patients underwent Baseline and Month 6 renal biopsies • Outcomes • Lipid deposition (ALDS) • Chronic damage (CDS) • Standard histopathology • Normal glomeruli • Mesangial widening • Segmental sclerosis • Obsolescence • Mean of 24.3 glomeruli examined per biopsy 4035.02

  46. TKT003: Kidney Pathology Procedures • Biopsies performed at baseline and week 24 • Biopsy cores fixed and embedded • All blocks assigned random numbers • Blocks sectioned and stained • Investigators amended planned analysis to include assessment of standard glomerular histopathology • Slides read in one batch by 2 AFIP pathologists – consensus reached 4922.01

  47. 80 Normal glomeruli Mesangial widening Segmental sclerosis Obsolescence p=0.012 p=0.010 p=0.048 p=0.870 70 60 50 Percent 40 30 20 10 0 0 0 0 0 0 0 0 6 m 6 m 6 m 6 m 6 m 6 m 6 m 6 m 0 Replagal placebo Replagal placebo Replagal placebo Replagal placebo TKT003: Kidney Pathology 4036.03

  48. 200 r = 0.76 180 160 140 120 Creatinine Clearance 100 80 60 40 20 0 0 20 40 60 80 100 Normal Glomeruli (%) Mean Baseline Creatinine Clearance vs Normal Glomeruli (%) 4748.01

  49. 200 r = -0.68 180 160 140 120 Creatinine Clearance 100 80 60 40 20 0 0 20 40 60 80 100 Segmental Sclerosis and Obsolescent Glomeruli (%) Mean Baseline Creatinine Clearance vs Segmental Sclerosis and Obsolescent Glomeruli (%) 4749.01

  50. Renal Efficacy of Replagal: Conclusions • Replagal stabilizes renal function • Replagal may delay progression to ESRD compared with historical controls • Replagal therapy significantly improves the renal pathology of Fabry Disease • Standard renal glomerular histopathology is reasonably likely to predict clinical benefit 4039.08

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