Endocrinologic

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Endocrinologic

  1. 1. Endocrinologic & Metabolic Drugs Advisory Committee Replagal BLA 103977 Transkaryotic Therapies, Inc. January 14, 2003 4000.01
  2. 2. REPLAGAL: agalsidase alfa <ul><li>Human  -galactosidase A </li></ul><ul><li>Homodimer comprised of two ~ 50kDa subunits </li></ul><ul><li>Produced in continuous human cell line </li></ul><ul><li>Identical amino acid sequence to endogenous protein </li></ul>4002.03
  3. 3. Clinical Summary: Replagal <ul><li>Improves standard glomerular pathology </li></ul><ul><ul><li>Correlates with renal function </li></ul></ul><ul><li>Stabilizes renal function over 30 months </li></ul><ul><li>Reduces LV mass </li></ul><ul><li>Improves cardiac conduction system function </li></ul><ul><li>Safe and well-tolerated after 2 ½ years of therapy </li></ul>4001.06
  4. 4. TKT Presentations 4778.05 Thomas J. Schuetz, M.D., Ph.D. Vice President, Clinical Affairs, TKT Renal Pathology of Fabry Disease Thomas J. Schuetz, M.D., Ph.D. Replagal Clinical Data Ravi Thadhani, M.D., M.P.H. Assistant Professor of Medicine, Harvard Medical School Director of Clinical Research in Nephrology Massachusetts General Hospital, Boston Fabry Disease Neil Kirby, Ph.D. Vice President, Global Regulatory Affairs, TKT Introduction
  5. 5. Experts <ul><li>Dr. Wilson Colucci </li></ul><ul><ul><li>Chief of Cardiovascular Medicine, Boston Medical Center. </li></ul></ul><ul><ul><li>Director, Myocardial Biology Unit, Boston University School of Medicine. </li></ul></ul><ul><li>Dr. Christoph Kampmann </li></ul><ul><ul><li>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. </li></ul></ul><ul><li>Dr. Edwin Kolodny </li></ul><ul><ul><li>Chairman, Department of Neurology, New York University School of Medicine, New York. </li></ul></ul><ul><li>Dr. Kathleen Lamborn </li></ul><ul><ul><li>Professor of Neurological Surgery (Biostatistics), University of California, San Francisco. </li></ul></ul>4780.06
  6. 6. Experts (cont) <ul><li>Dr. Atul Mehta </li></ul><ul><ul><li>Consultant Hematologist, Royal Free Hospital, London, UK. </li></ul></ul><ul><li>Dr. Ronald Perrone </li></ul><ul><ul><li>Professor of Medicine, Tufts University School of Medicine. </li></ul></ul><ul><ul><li>Associate Chief of New England Medical Center Division of Nephrology. </li></ul></ul><ul><ul><li>Medical Director of Renal Transplantation, Tufts New England Medical Center, Boston. </li></ul></ul><ul><li>Dr. Melvin Schwartz </li></ul><ul><ul><li>Professor, Department of Pathology at Rush-Presbyterian-St Luke’s Medical Center, Chicago. </li></ul></ul>4784.04
  7. 7. TKT Presentations 4546.05 Thomas J. Schuetz, M.D., Ph.D. Vice President, Clinical Affairs, TKT Renal Pathology of Fabry Disease Thomas J. Schuetz, M.D., Ph.D. Replagal Clinical Data Ravi Thadhani, M.D., M.P.H. Assistant Professor of Medicine, Harvard Medical School Director of Clinical Research in Nephrology Massachusetts General Hospital, Boston Fabry Disease Neil Kirby, Ph.D. Vice President, Global Regulatory Affairs, TKT Introduction
  8. 8. Fabry Disease <ul><li>X-linked glycosphingolipid lysosomal storage disorder </li></ul><ul><li>Deficiency of  -galactosidase A leading to accumulation of Gb 3 </li></ul><ul><li>Rare: Approximately 1500-2000 patients in USA </li></ul><ul><li>Progressive, multisystem disease </li></ul><ul><ul><li>Renal </li></ul></ul><ul><ul><li>Cardiac </li></ul></ul><ul><ul><li>Cerebrovascular </li></ul></ul><ul><ul><li>Neurologic </li></ul></ul><ul><ul><li>Gastrointestinal </li></ul></ul><ul><ul><li>Metabolic </li></ul></ul><ul><li>Death in 4th or 5th decade of life </li></ul>4003.04
  9. 9. Disease Management <ul><li>No specific treatment </li></ul><ul><li>Patient care generally restricted to palliation: </li></ul><ul><ul><li>Renal failure: dialysis/transplantation </li></ul></ul><ul><ul><li>Heart disease/stroke: standard treatment </li></ul></ul><ul><ul><li>GI disease: antidiarrheals </li></ul></ul><ul><ul><li>Neuropathic pain: </li></ul></ul><ul><ul><ul><li>generally refractory to analgesics and opioids </li></ul></ul></ul><ul><ul><ul><li>empiric use of anticonvulsants has been useful for pain control in some patients </li></ul></ul></ul>4004.01
  10. 10. Pathophysiology 4005.06 Parenchymal cell deposition of Gb 3 leads to multisystem pathology Kidney: Glomerular epithelial cells (podocytes) Glomerular mesangial cells Tubular epithelial cells Renal failure Concentrating defects Cardiomyopathy and cardiac hypertrophy QRS complex widening Heart: Myocytes Conduction system Pain Nerves: Autonomic ganglia
  11. 11. Fabry Disease: Renal Natural History <ul><li>Early manifestations </li></ul><ul><li>Proteinuria </li></ul><ul><li>Renal concentrating defects </li></ul><ul><li>Progressive decline in renal function </li></ul><ul><li>Late manifestations </li></ul><ul><li>Nephrotic syndrome </li></ul><ul><li>Diabetes insipidus </li></ul><ul><li>ESRD </li></ul>4006.04 Progression of Renal Disease
  12. 12. Fabry Disease: Renal Natural History 4782.05 Summary 0 10 20 30 40 50 60 70 80 90 100 110 120 Renal Function (mL/min) Time (years) Chronic Renal Insufficiency Normal ESRD Impaired Renal Function
  13. 13. Fabry Disease: Renal Natural History <ul><li>All patients (n=116) </li></ul><ul><ul><li>Age: 33.6 ± 10.4 years </li></ul></ul><ul><ul><li>Renal function: 48.9 ± 44.9 mL/min </li></ul></ul><ul><li>Patients not in ESRD (n=54) </li></ul><ul><ul><li>Age: 30.7 ± 9.8 years </li></ul></ul><ul><ul><li>Renal function: 85.1 ± 33.8 mL/min </li></ul></ul><ul><li>Patients in ESRD (n=62) </li></ul><ul><ul><li>Age of onset: 36.7 ± 10.1 years </li></ul></ul>4007.03 Age and Renal Function
  14. 14. Fabry Disease: Renal Natural History 4008.08 Decline of Renal Function Over Time * Mean patient age range over the period of the decline of renal function 10.6 35.5 -> 36.8 84 Mean 8.3 35.7 -> 36.2 59 TKT003, TKT005, and TKT010 placebo patients 12.2 39.8 -> 43.1 14 Branton, et al 21 28.8 -> 32.1 11 Individual literature patients Rate of Decline of Renal Function (mL/min/yr) Age* Patients (Number) Patient Population
  15. 15. Fabry Disease: Renal Natural History 4741.04 Predicted Rate of Decline 6 18 Month Creatinine Clearance ( mL /min) 120 100 80 60 40 0 12 24 30 10.6mL/min/yr 21.0mL/min/yr Month ( Predicted Rate of Decline 8.3 mL/min/yr
  16. 16. Fabry Disease: Renal Natural History 4679.06 Age at End Stage Renal Disease 39±10 24 Branton (2002) 38±8 93 Ojo (2000) 38 83 Tsakiris (1996) Median ~40 17 Nissenson (1989) 43.3 7 Maizel (1981) † among the 116 patients identified in the literature search there are 62 individual case reports of patients who progressed to ESRD, and the mean age of these patients is 36.7 ± 10.1 years. * age at kidney transplant ~38 363 patients Summary 36.7±10.1 62 Individual case reports in the literature † 39-42 42 Thadhani (2002) 36.7 26 MacDermot (2001) 41* 9 Barnes (1975) Age of ESRD (yrs) Patients (n) References
  17. 17. Fabry Disease: Renal Natural History Fabry ESRD Patients 0 20 40 60 80 100 0 10 20 30 40 50 60 70 Age (years) Percent of Patients w/o ESRD 4742.02 Progression to ESRD * All USRDS Patients *
  18. 18. Fabry Disease: Renal Natural History 4009.07 Summary 0 10 20 30 40 50 60 70 80 90 100 110 120 Renal Function (mL/min) Time (years) Chronic Renal Insufficiency Normal ESRD ~10.6 mL/min/yr mean age of ESRD ~38 yrs Early to mid 30’s ~ 4.3 yrs Impaired Renal Function
  19. 19. Fabry Disease: Renal Natural History <ul><li>Beginning at approximately age 30-35 years the rate of decline of renal function is ~ 10.6 mL/min/year </li></ul><ul><li>The mean age at which patients with Fabry disease progress to ESRD is ~38 years </li></ul>4011.04 Two Major Conclusions
  20. 20. Fabry Disease: Heart Disease <ul><li>Accumulation of Gb 3 in myocytes and conduction system </li></ul><ul><li>Cardiomyopathy with LV hypertrophy </li></ul><ul><ul><li>Progressive increase in LV mass </li></ul></ul><ul><ul><li>Significant age-related progression in males and females </li></ul></ul><ul><li>Conduction system dysfunction </li></ul><ul><ul><li>Widening of QRS complex leading to bundle branch blocks </li></ul></ul><ul><li>20% incidence of cardiac death </li></ul>4012.07
  21. 21. Other Manifestations <ul><li>Cerebrovascular system </li></ul><ul><ul><li>Stroke </li></ul></ul><ul><ul><li>Altered cerebrovascular blood flow </li></ul></ul><ul><li>Neuropathic pain </li></ul><ul><ul><li>Chronic pain </li></ul></ul><ul><ul><li>Refractory to pain medications </li></ul></ul><ul><li>Gastrointestinal system </li></ul><ul><ul><li>Abdominal pain; diarrhea </li></ul></ul><ul><ul><li>Chronic weight loss </li></ul></ul><ul><li>Progressive hearing loss </li></ul><ul><li>Angiokeratoma; hypohydrosis </li></ul>4015.02
  22. 22. Fabry Disease: Conclusions <ul><li>Complex, multisystem disorder </li></ul><ul><li>Progressive deterioration of renal function </li></ul><ul><li>Progressive increase in LV mass </li></ul><ul><li>Major causes of mortality </li></ul><ul><ul><li>Progressive renal failure </li></ul></ul><ul><ul><li>Progressive cardiac failure </li></ul></ul>4520.04
  23. 23. TKT Presentations 4547.05 Thomas J. Schuetz, M.D., Ph.D. Vice President, Clinical Affairs, TKT Renal Pathology of Fabry Disease Thomas J. Schuetz, M.D., Ph.D. Replagal Clinical Data Ravi Thadhani, M.D., M.P.H. Assistant Professor of Medicine, Harvard Medical School Director of Clinical Research in Nephrology Massachusetts General Hospital, Boston Fabry Disease Neil Kirby, Ph.D. Vice President, Global Regulatory Affairs, TKT Introduction
  24. 24. Kidney Pathology: Introduction <ul><li>Glomerular epithelial cell Gb 3 deposition </li></ul><ul><li>Glomerular mesangial widening </li></ul><ul><li>Segmental glomerular sclerosis </li></ul><ul><li>Obsolescent glomeruli </li></ul><ul><li>Tubular epithelial cell deposition </li></ul><ul><li>Capillary endothelial cells relatively spared </li></ul>Intracellular Deposition Disease of the Nephron: 4016.03
  25. 25. Kidney: Normal Glomeruli 4540.04 PAS Stain Toluidine Blue Stain
  26. 26. Kidney: Early Glomerular Disease 4017.06 Toluidine Blue Stain PAS Stain
  27. 27. Kidney: Mesangial Widening 4018.04 Toluidine Blue Stain PAS Stain
  28. 28. Kidney: Segmental Sclerosis 4019.07 Toluidine Blue Stain PAS Stain
  29. 29. Kidney: Obsolescence 4020.03 Toluidine Blue Stain PAS Stain
  30. 30. Histopathological Spectrum of Disease Histopathological Progression 4021.03 Early Deposition Mesangial Widening Segmental Sclerosis Obsolescence
  31. 31. Replagal Clinical Data 4867.02
  32. 32. Replagal Clinical Studies 4026.02 > 2½ yrs 56 Multidose Studies TOTAL 3 – 12 months 15 Open label safety and efficacy trial in females TKT014 University of Mainz Clinical Study 6 months 15 Randomized, double blind, placebo controlled TKT005 RFH Clinical Study 1 yr interim analysis 24 Open label maintenance study for patients completing TKT006 TKT011 1 yr 25 Open label maintenance study for patients completing TKT003 TKT006 6 months 26 Randomized, double blind, placebo controlled TKT003 single dose 10 Open label, dose escalation safety study TKT001 NIH Clinical Study Duration # Pts Design Study
  33. 33. Replagal: NIH Clinical Studies 4027.05 Replagal (n=24) Replagal (n=25) Replagal 6 months (n=14) placebo 6 months (n=12) TKT003 TKT011 (1 year analysis) TKT006
  34. 34. TKT003: Creatinine Clearance 4028.03 p=0.051 (Replagal vs placebo) 60 70 80 90 100 110 120 130 0 6 TKT003 Replagal (n=14 : mean age = 34.0) TKT003 placebo (n=11 : mean age = 34.4) Creatinine Clearance (mL/min) Treatment Period (months)
  35. 35. TKT003: Creatinine Clearance 0 9 17 23/24 4683b.04 p=0.045 (Replagal vs placebo)
  36. 36. TKT003: Glomerular Filtration Rate (GFR) 0 23/24 4683c.05 p=0.25 (Replagal vs placebo)
  37. 37. TKT010: Glomerular Filtration Rate (GFR) 4869.01 p=0.74 (Replagal vs placebo)
  38. 38. NIH Clinical Trials: Creatinine Clearance 4029.05 60 70 80 90 100 110 120 130 0 6 12 18 24 30 Creatinine Clearance (mL/min) Treatment Period (months) Study TKT003 Replagal – Study TKT006/TKT011 Replagal (n=13) Study TKT003 placebo – Study TKT006/TKT011 Replagal (n=12) TKT011 TKT003 TKT006
  39. 39. NIH Clinical Trials: GFR 4744.02 60 70 80 90 100 110 120 130 0 6 12 18 24 30 GFR (mL/min/ 1.73m 2 ) Treatment Period (months) Study TKT003 Replagal – Study TKT006/TKT011 Replagal Study TKT003 placebo – Study TKT006/TKT011 Replagal TKT011 TKT003 TKT006
  40. 40. Renal Function: 2 years of Replagal TKT011 TKT006 4031.02 GFR Creatinine clearance
  41. 41. Progression of Renal Disease: NIH Replagal Patients vs. Historical Controls 4034.03 6 18 TKT003, TKT006, TKT011 Patients Month Creatinine Clearance ( mL /min) 120 100 80 60 40 0 12 24 30 10.6 mL/min/yr 21.0 mL/min/yr Month ( Predicted Rate of Decline 8.3 mL/min/yr TKT003, TKT006, TKT011 Patients
  42. 42. Individual Patient Data: Creatinine Clearance Patients 4777.04
  43. 43. Progression to ESRD: Age Range of Replagal-Treated Patients vs. Literature 4032.06 Percent of Patients not in ESRD Age (years) 0 10 20 30 40 50 60 70 100 80 60 40 20 0 Source: Literature Patients TKT003/006/011 Replagal Patients
  44. 44. Histopathological Spectrum of Disease Histopathological Progression 4868.01 Early Deposition Mesangial Widening Segmental Sclerosis Obsolescence
  45. 45. TKT003: Kidney Pathology <ul><li>Patients underwent Baseline and Month 6 renal biopsies </li></ul><ul><li>Outcomes </li></ul><ul><ul><li>Lipid deposition (ALDS) </li></ul></ul><ul><ul><li>Chronic damage (CDS) </li></ul></ul><ul><ul><li>Standard histopathology </li></ul></ul><ul><ul><ul><li>Normal glomeruli </li></ul></ul></ul><ul><ul><ul><li>Mesangial widening </li></ul></ul></ul><ul><ul><ul><li>Segmental sclerosis </li></ul></ul></ul><ul><ul><ul><li>Obsolescence </li></ul></ul></ul><ul><li>Mean of 24.3 glomeruli examined per biopsy </li></ul>4035.02
  46. 46. TKT003: Kidney Pathology Procedures <ul><li>Biopsies performed at baseline and week 24 </li></ul><ul><li>Biopsy cores fixed and embedded </li></ul><ul><li>All blocks assigned random numbers </li></ul><ul><li>Blocks sectioned and stained </li></ul><ul><li>Investigators amended planned analysis to include assessment of standard glomerular histopathology </li></ul><ul><li>Slides read in one batch by 2 AFIP pathologists – consensus reached </li></ul>4922.01
  47. 47. TKT003: Kidney Pathology 4036.03 Normal glomeruli Mesangial widening Segmental sclerosis Obsolescence p=0.012 p=0.010 p=0.048 p=0.870 0 10 20 30 40 50 60 70 80 Percent Replagal placebo Replagal placebo Replagal placebo Replagal placebo 0 6 m 0 6 m 0 6 m 0 6 m 0 6 m 0 6 m 0 6 m 0 6 m
  48. 48. Mean Baseline Creatinine Clearance vs Normal Glomeruli (%) 4748.01 Normal Glomeruli (%) 100 80 60 40 20 0 0 20 40 60 80 100 120 140 180 200 160 Creatinine Clearance r = 0.76
  49. 49. Mean Baseline Creatinine Clearance vs Segmental Sclerosis and Obsolescent Glomeruli (%) 4749.01 Segmental Sclerosis and Obsolescent Glomeruli (%) 100 80 60 40 20 0 0 20 40 60 80 100 120 140 180 200 160 Creatinine Clearance r = -0.68
  50. 50. Renal Efficacy of Replagal: Conclusions <ul><li>Replagal stabilizes renal function </li></ul><ul><li>Replagal may delay progression to ESRD compared with historical controls </li></ul><ul><li>Replagal therapy significantly improves the renal pathology of Fabry Disease </li></ul><ul><li>Standard renal glomerular histopathology is reasonably likely to predict clinical benefit </li></ul>4039.08
  51. 51. Effect of Replagal on Cardiomyopathy: Study TKT005 <ul><li>Randomized, double-blind, placebo controlled study of 15 patients over six months </li></ul><ul><ul><li>Males with LVH by Echo (mean LV mass = 262 g) </li></ul></ul><ul><li>Reduction in cardiac Gb 3 favoring Replagal, but not statistically significant </li></ul><ul><li>Statistically significant reduction in LV mass (MRI) </li></ul><ul><ul><li>Placebo: 8.8% LV mass increase </li></ul></ul><ul><ul><li>Replagal: 4.2% LV mass decrease </li></ul></ul><ul><ul><li>p-value = 0.041 </li></ul></ul>4040.03
  52. 52. TKT005: LV Mass by MRI p=0.041 4750.02
  53. 53. Effect of Replagal on Cardiomyopathy: NIH Studies (TKT003/TKT006) <ul><li>No selection criteria for cardiomyopathy (mean cardiac mass = 219 g) </li></ul><ul><li>Statistically significant decline in LV mass compared to baseline </li></ul><ul><ul><li>LV mass declined in 13 of the 16 patients with elevated LV mass </li></ul></ul><ul><ul><li>LV mass declined to the normal range after 12 to 18 months in 8 of the 16 patients </li></ul></ul><ul><li>Significant decline in QRS complex duration in Replagal treated patients compared with placebo (p = 0.047) </li></ul><ul><ul><li>Replagal: 94.1 – 91.7 msec </li></ul></ul><ul><ul><li>Placebo: 94.0 – 97.6 msec </li></ul></ul>4041.08
  54. 54. LV Mass: TKT003/TKT006 4751.03 p=0.006 p=0.023
  55. 55. Replagal Reduces LV Mass in Female Patients (Study TKT014) <ul><li>Mean LV mass at Baseline: 254 g </li></ul><ul><ul><li>38.5 g decline from baseline at Week 27 (p = 0.003) </li></ul></ul><ul><ul><li>42.7 g decline from baseline at Week 41 (p = 0.039) </li></ul></ul><ul><li>Statistically significant declines in cardiac mass index and wall thicknesses </li></ul><ul><ul><li>LV mass declined in all 12 patients with elevated LV mass, and normalized in 4 of the 12 patients </li></ul></ul><ul><li>Statistically significant improvement in QRS complex duration (p = 0.007) </li></ul>4042.05
  56. 56. TKT014: LV Mass Response to Replagal 4752.03 p=0.29 p=0.04 p=0.003
  57. 57. TKT014: LV Mass Index – Long Term Therapy with Replagal 4753.05 p=0.025 Upper limit of Normal (n=13) (n=13) (n=13)
  58. 58. Cardiac Efficacy of Replagal: Conclusions <ul><li>Initiation of the reversal of cardiomyopathy </li></ul><ul><ul><li>Regression of LVH </li></ul></ul><ul><ul><li>Normalization of LV mass in many patients </li></ul></ul><ul><li>Improved cardiac conduction system function with significantly decreased QRS duration </li></ul>4043.03
  59. 59. Replagal: Metabolic Effects <ul><li>Statistically significant change in body weight in Study TKT003 </li></ul><ul><ul><li>Placebo patients: 1.85 kg weight loss </li></ul></ul><ul><ul><li>Replagal patients: 1.55 kg weight gain </li></ul></ul><ul><ul><li>Long term effects confirmed in study TKT006 </li></ul></ul><ul><li>Gb 3 declines </li></ul><ul><ul><li>Plasma: ~ 50% statistically significant decline in Studies TKT003 and TKT005 </li></ul></ul><ul><ul><li>Urine Sediment: 40-60% statistically significant decline in Studies TKT003 and TKT005 </li></ul></ul><ul><ul><li>Tissue: Trends favoring Replagal in kidney and heart tissue </li></ul></ul>4047.05 p = 0.025
  60. 60. Safety Experience: Adverse Events <ul><li>Over 300 patients treated with Replagal </li></ul><ul><li>The most common adverse events were consistent with the natural history of Fabry Disease </li></ul><ul><li>No withdrawals due to adverse events </li></ul><ul><li>Most events mild to moderate in severity </li></ul><ul><li>Most assessed as ‘not related’ to study drug </li></ul>4049.03
  61. 61. Safety Experience: Infusion Reactions <ul><li>Routine use of premedications not required </li></ul><ul><li>Mild infusion reactions (~10% patients) with recommended infusion over 40 minutes </li></ul><ul><ul><li>Chills </li></ul></ul><ul><ul><li>Facial flushing </li></ul></ul><ul><ul><li>No apparent association with antibodies </li></ul></ul><ul><li>Infusion reactions easily managed </li></ul><ul><li>Infusion reactions generally disappear over time </li></ul>4050.03
  62. 62. TKT003/TKT006: Infusion Reactions and IgG Antibodies 4754.01 25 15 10 15 11 4 – 10 4 6 + Antibody – + Infusion Reaction
  63. 63. Antibody Response to Replagal Therapy <ul><li>Patients originally enrolled in Studies TKT003 and TKT005 </li></ul><ul><ul><li>40 male patients followed for up to 2.5 years </li></ul></ul><ul><ul><li>Persistent IgG antibodies observed in 12/40 patients (30%) </li></ul></ul><ul><ul><li>No patients were positive for IgE, IgA, or IgM antibodies </li></ul></ul><ul><ul><li>Most patients positive at 1:50 or 1:100 dilution; 1 positive at 1:2,500 </li></ul></ul><ul><li>Patients enrolled in Study TKT014 </li></ul><ul><ul><li>15 female patients followed for 3 to 12 months </li></ul></ul><ul><ul><li>No patients positive for IgG, IgE, IgA or IgM antibodies </li></ul></ul>4791.03
  64. 64. Study TKT011: Plasma Gb 3 Results 4793.04
  65. 65. Study TKT011: Creatinine Clearance Results 4796.03
  66. 66. Study TKT011: LV Mass Results 4800.03
  67. 67. Antibody Response to Replagal Therapy: Conclusions <ul><li>Persistent IgG antibodies may occur in approximately 30% of treated patients </li></ul><ul><li>No IgE antibodies or hypersensitivity </li></ul><ul><ul><li>Fully human glycosylation pattern </li></ul></ul><ul><li>No clear correlation of IgG antibody with infusion reactions </li></ul><ul><li>Mean reductions in plasma and urine Gb 3 are lower for subset of patients with persistent antibodies </li></ul><ul><ul><li>Gb 3 levels remain below baseline after 2-2.5 years of therapy </li></ul></ul><ul><li>No effect of IgG antibody formation on renal function or cardiac mass </li></ul><ul><li>No evidence of immune complex deposition </li></ul>4051.03
  68. 68. Conclusions: Replagal <ul><li>Improves glomerular pathology </li></ul><ul><li>Stabilizes renal function over 30 months </li></ul><ul><li>Delay in time to ESRD </li></ul><ul><li>Reduces LV mass </li></ul><ul><li>Improves cardiac conduction system function </li></ul><ul><li>Concomitant metabolic improvements </li></ul><ul><li>Safe and well-tolerated </li></ul>4052.04
  69. 69. TKT Q&A Slides
  70. 70. Figure 12A: GFR vs the Fraction of Glomeruli with Mesangial Widening (%): Scatter Plot 4532.02 Mesangial Widening (%) 100 80 60 40 20 0 0 20 40 60 80 100 120 140 180 200 160 GFR
  71. 71. Reversal of Proteinuria 4280.03 Upper Limit Normal  Albuminuria (mg/d)  Proteinuria (mg/d)
  72. 72. Effect of Replagal on Glomerular Endocapillary Gb 3 Deposition 4787.02
  73. 73. Change of Creatinine Clearance vs Change of Normal (%) and Mesangial Widening 4815.01 Replagal Patients Only Baseline Normal (%) and Mesangial Widening (%) Normal Mesangial Widening -40 -30 -20 -10 0 10 20 30 40 50 Change of Creatinine Clearance 30 20 10 0 -10 -20 -30 -40 -50
  74. 74. TKT003 – Creatinine Clearance Over/Under Collections 4808.03 <ul><li>TKT003 creatinine clearance (6 collections) </li></ul><ul><ul><li>Over/under collections defined by 35% difference </li></ul></ul><ul><ul><li>2.7% of creatinine clearance measurements were over/under collections </li></ul></ul>36.5 12.9 11.0 14.1 Urine Creatinine Body Weight (mg/kg) 19.4 25.0 17.6 22.2 Urine Creatinine Body Weight (mg/kg) 3.19 1.67 W9 Replagal 0.86 1.67 W24 Placebo 0.94 1.50 W24 Placebo 0.85 1.32 W23 Placebo Visit Urine Creatinine (g) Mean Urine Creatinine (g) (n=5) Visit
  75. 75. GFR in Study TKT003 4939.01
  76. 76. Replagal Liver Biodistribution vs. Dose in Humans (75 Kg patient, 2 hours after infusion) 4823.01
  77. 77. Choice of Recommended Human Dose (0.2 mg/kg) <ul><li>Phase I single (escalating) dose study </li></ul><ul><li>Rodent biodistribution data </li></ul><ul><li>Gb 3 clearance in a knockout mouse model for Fabry disease </li></ul><ul><li>Comparative pharmacokinetics </li></ul>4816.01
  78. 78. TKT003: Two Interpretations of Placebo Arm 4783.02
  79. 79. Figure 23A: GFR vs Plasma Gb 3 4854.02 Plasma Gb 3 20 15 10 5 0 20 40 60 80 100 120 140 180 200 160 GFR r = -0.17
  80. 80. Table 20: Effect of Replagal on Interstitial Vascular Endothelial Gb 3 Deposition 4570.01
  81. 81. Figure 9: TKT003 Kidney Pathology Results 4712.01 Normal glomeruli Mesangial widening Segmental sclerosis Obsolescence p=0.012 p=0.010 p=0.048 p=0.870 0 10 20 30 40 50 60 70 80 Percent Replagal placebo Replagal placebo Replagal placebo Replagal placebo 0 6 m 0 6 m 0 6 m 0 6 m 0 6 m 0 6 m 0 6 m 0 6 m
  82. 82. Branton, et al – Decline in Renal Function Branton et al, Medicine 2002 4916.01
  83. 83. Table 21: Reduction of Interstitial Capillary Endothelial Cell Gb 3 by Agalsidase Beta (Fabrazyme™, Genzyme Corporation) 4571.01
  84. 84. Effect of Replagal on Gb 3 Storage in the Kidney: Peritubular Capillaries <ul><li>TC4000 </li></ul>Baseline Week 24 330x 4914.02
  85. 85. Figure 6: Fabry Disease: Heart Biopsy (Toluidine Blue Stain: 40x) 4581.01
  86. 86. FOS - Fabry Outcome Survey A database on medical outcomes of patients with Fabry disease Dr. Atul Mehta Consultant Hematologist, Royal Free Hospital, London, UK 5001.02
  87. 87. Number of Patients on Agalsidase Alfa 65.8 % n=217 34.2% n=119 Untreated Treated 5005.02
  88. 88. Number of Involved Organ Systems Females Males Number of organ systems Age at FOS entry 5008.01
  89. 89. Clinical Manifestations in Obligate Carrier Females: MacDermot, 2001 <ul><li>Most frequent symptoms included: </li></ul><ul><ul><li>Neuropathic pain (70%); fatigue (66%) </li></ul></ul><ul><ul><li>GI symptoms (58%); chest pain/palpitations (53%) </li></ul></ul><ul><ul><li>Heart valve abnormalities (48%) </li></ul></ul><ul><ul><li>Angiokeratoma and abnormal renal function (35%) </li></ul></ul><ul><ul><li>Arrhythmia and hypohidrosis (33%); </li></ul></ul><ul><ul><li>Tinnitus (25%); hearing loss (23%); </li></ul></ul><ul><ul><li>TIA or CVA (22%) </li></ul></ul><ul><ul><li>LVH (19%) </li></ul></ul>4669.02

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