1 / 49

FDA Review of Clinical Data Agalsidase alfa for treatment of Fabry Disease

FDA Review of Clinical Data Agalsidase alfa for treatment of Fabry Disease Transkaryotic Therapies, Inc. FDA/Center for Biologics Evaluation and Research. Agalsidase alfa Introduction.

xaviera-vaughan
Download Presentation

FDA Review of Clinical Data Agalsidase alfa for treatment of Fabry Disease

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. FDA Review of Clinical Data Agalsidase alfa for treatment of Fabry Disease Transkaryotic Therapies, Inc. FDA/Center for Biologics Evaluation and Research

  2. Agalsidase alfa Introduction • Proposed indication: “Replagal is indicated for long-term enzyme replacement therapy for patients with Fabry Disease (-galactosidase A deficiency)” • Proposed dose: 0.2 mg/kg IV every 2 weeks

  3. Agalsidase alfa Overview of Studies • Studies submitted to BLA:

  4. Agalsidase alfa Overview • Notable observations: • Pain outcomes • Renal function • Renal histopathology • Cardiac outcomes • Weight changes • Antibody formation • Safety findings

  5. Agalsidase alfa Study 003 Design • Study 003 design: • Single center, randomized, double-blind, placebo-controlled, six months • 26 Men with neuropathic pain • Evaluations • Pain scores, renal biopsy, cardiac data • Primary EP: “Worst Pain” score while “off pain medication” • Many 2⁰ and 3⁰ EP

  6. Agalsidase alfa Study 003 Design • Analytic Plan • Primary endpoint: T-test comparison of area under the curve of pain score change from baseline for the four “off pain medication” assessments • Numerous exploratory analyses: • Repeated measures analysis • Analyses of all pain assessments (on and off pain medication; RM & AUC) • Missing value imputations

  7. Agalsidase alfa Study 003 Results • Primary endpoint result: • P-value 0.20

  8. Agalsidase alfa Study 003 Results • Limitations to “off medication” analyses: • Inability to verify medication use status at the time of pain score assessment • Definition of “pain medication” highly problematic • Distinguished between types of analgesics • Common analgesics (e.g. NSAID, opiates) treated as ineffective on Fabry pain

  9. Agalsidase alfa Study 003 Results • Additional pain outcomes and exploratory analyses Other prospective planned analytic methods (repeated measures) and analyses of all pain assessments (mixed on and “off” medication; AUC or RM analyses) generally provide no support for a finding of efficacy in the reduction of pain.

  10. Agalsidase alfa Study 003 Results • Study 003 Pain endpoint findings: Primary endpoint data cannot be interpreted due to inability to verify pain medication usage and a problematic definition of “pain medication.” Exploratory and additional pain data analyses also provide no evidence for a treatment effect.

  11. Agalsidase alfa Renal Function Study 003 Average Cr Cl Change (mL/min)

  12. Agalsidase alfa Renal Function Study 003 Serum Cr (mg/dL) & Cr Cl (mL/min)

  13. Agalsidase alfa Renal Function Creatinine clearance

  14. Agalsidase alfa Renal Function Average GFR Change (mL/min)

  15. Agalsidase alfa Renal Function GFR

  16. Agalsidase alfa Renal Function Renal function in noncontrolled studies show no change in: • Cr Cl • GFR

  17. Agalsidase alfa Renal Function Historical Assessment of Renal Deterioration • Average age of 38 years for onset of ESRD from • literature review of 363 subjects • Average age of 34.5 at enrollment in Study 003

  18. Agalsidase alfa Renal Function • Limitations ofHistorical Assessment of Renal Deterioration: • Small sample size • Published data are from subjects with marked renal insufficiency at baseline

  19. Agalsidase alfa Histopathology • Renal histopathology: • Data: • Paired samples for 21 subjects • Missing samples for 5 subjects: Agalsidase n = 2, Placebo n = 3 • Analyses: • Acute Lipid Damage Score (ALDS) • Chronic Damage Score (CDS) • Standard Histopathology

  20. Agalsidase alfa Histopathology Average ALDS score

  21. Agalsidase alfa Histopathology ALDS Components

  22. Agalsidase alfa Histopathology Standard Histopathology

  23. Agalsidase alfa Histopathology Renal histopathology limitations: • Unclear clinical correlation • Limited rigor: • Criteria for “severity” of deposition • Criteria for glomerular category • Training of pathologists • Number of slides/stains/glomeruli reviewed • Source documents unavailable

  24. Agalsidase alfa Cardiac Outcomes • Study 005 design: • Single center, randomized, double-blind, placebo-controlled, six months • 15 men with left ventricular enlargement on echo • Cardiac biopsy, MRI, echo, EKG • Primary endpoint: Cardiac Gb3

  25. Agalsidase alfa Cardiac Outcomes • Study 005 primary endpoint: Change from baseline in cardiac Gb3 content (nmol/mcg protein)

  26. Agalsidase alfa Cardiac Outcomes Other cardiac outcomes: LV mass by MRI and Echo Electrocardiographic changes Study 005 Study 003 Noncontrolled studies

  27. Agalsidase alfa Cardiac Outcomes • MRI LV Mass, Study 005, Change:

  28. Agalsidase alfa Cardiac Outcomes • Echo LV Mass, Study 005, Change :

  29. Agalsidase alfa Cardiac Outcomes • LV mass findings, Study 003, Change : • Similar findings in subset of subjects • with LV enlargement, • Agalsidase n = 7, Placebo n = 6

  30. Agalsidase alfa Cardiac Outcomes

  31. Agalsidase alfa Cardiac Outcomes • QRS duration in Study 005: • QRS duration in Study 003: *one subject with intermittent BBB, baseline = 150 or 103 msec

  32. Agalsidase alfa Cardiac Outcomes QRS Changes in Noncontrolled Studies

  33. Agalsidase alfa Weight • Weight changes in controlled studies:

  34. Agalsidase alfa Weight Weight changes in noncontrolled studies: Two years of follow-up, Study 006 & 011: Prior Agalsidase group ~ 2.1 kg (n = 12) Prior Placebo group ~ 2.7 kg (n = 9) Six months follow-up in Study 014: Weight gain of ~ 0.9 kg (n = 11)

  35. Agalsidase alfa Weight • Limitations of weight data: • Concomitant medication • steroids • diuretics • Unclear nutritional status • Average baseline weights in controlled studies ~ 70 kg

  36. Agalsidase alfa Antibody • Antibody formation in Study 003: • 50% to 64%, depending on assay (ELISA, immunoprecipitation, neutralization) • Antibody formation (ELISA) during 003, 006, 011 time periods: • 13/25 (52%) positive at some point • 3/13 had reversion to baseline levels • 10 had persistently positive levels -- 7 had increasing magnitude

  37. Agalsidase alfa Antibody Impact Plasma Gb3 Concentration Among Subjects Completing Study 011 Interim

  38. Agalsidase alfa Antibody Impact Urine Gb3 Content Among Subjects Completing Study 011 Interim

  39. Agalsidase alfa Safety Safety findings No anaphylaxis Infusion reactions ~ 60 % in 003 ~ 40 % in 006 ~ 25 % in 011 Two infusion reaction SAE

  40. Agalsidase alfa Overall Summary • Multi-dose studies: • 47 Adult Fabry Disease subjects infused with Agalsidase at 0.2 mg/kg on alternate weeks

  41. Agalsidase alfa Overall Summary • Controlled studies: • Study 003 (pain) • 1 endpoint uninterpretable • Renal, cardiac, safety data • Study 005 (cardiac) • 1 endpoint: no statistical difference between treatment groups in cardiac Gb3 content • Renal, safety data

  42. Agalsidase alfa Overall Summary • Major observations from studies: • Renal function • Renal histopathology • Cardiac outcomes • Weight changes • Antibody formation • Infusion reactions

  43. Agalsidase alfa Overall Summary • Renal Function in controlled studies: • Cr Cl: • Study 003—Wk 23/24 inconsistent • Study 005—uninterpretable • GFR: • Study 003—no difference • Study 005—no difference

  44. Agalsidase alfa Overall Summary • Renal function in noncontrolled studies: • GFR and CC generally unchanged over 0.5 – 2.5 years • Limitations in historical review of renal function changes over time preclude meaningful comparisons to noncontrolled clinical findings

  45. Agalsidase alfa Overall Summary • Renal histopathology: • Vascular Gb3 deposition • Standard histopathology: • Agalsidase : fraction normal glomeruli fraction glomeruli with mesangial widening • Placebo : fraction glomeruli with segmental sclerosis

  46. Agalsidase alfa Overall Summary LV Mass in Controlled Studies • Cardiac outcomes:

  47. Agalsidase alfa Overall Summary • Cardiac outcomes: QRS Changes in Controlled Studies

  48. Agalsidase alfa Overall Summary • Weight changes: • Study 003: • Agalsidase group gain, p = 0.03 • Study 005: • No statistical difference • Study 006 & 011: • Gain of 2.1 – 2.7 kg over 2 yrs

  49. Agalsidase alfa Overall Summary • Infusion reactions: • ~ 60% in Study 003, lower in subsequent studies • Most mild – moderate severity • Antibody formation: • ~ 30% have persistent antibody formation • Antibodies impact biomarkers

More Related