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Abatacept (ORENCIA) for Rheumatoid Arthritis: FDA Overview

Detailed information on Abatacept (ORENCIA) Biological License Application for Rheumatoid Arthritis, including clinical development program, study design, efficacy and safety data presented to the FDA Advisory Committee on September 6, 2005.

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Abatacept (ORENCIA) for Rheumatoid Arthritis: FDA Overview

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  1. Abatacept (ORENCIA)for Rheumatoid Arthritis Biological License Application Arthritis Advisory Committee September 6, 2005

  2. Abatacept • Proposed indications for abatacept: • For use in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more biologic or non-biologic DMARDs • Reducing signs and symptoms • Inducing major clinical response • Inhibiting the progression of structural damage • Improving physical function • Abatacept may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARD therapy

  3. Overview of FDA Presentation • Clinical Development Program and Study Design • Efficacy Data • Improvement of Signs and Symptoms • Improvement of Physical Function • Inhibition of Radiographic Progression • Safety Data • Summary

  4. Abatacept BLA CLINICAL DEVELOPMENT PROGRAM & STUDY DESIGN

  5. Abatacept Clinical TrialsRandomized, Double-Blind, Placebo-Controlled

  6. Study Design-Common Features • Randomized, double-blind, placebo-controlled studies • Major Inclusion Criteria: • Diagnosis of RA (1987 ARA criteria) • Active disease despite DMARD therapy at randomization • ≥ 10 swollen joints (66 joint count) • ≥ 12 tender joints (68 joint count) • CRP ≥ 1 mg/dL • Stable doses of prednisone and NSAIDs allowed • Abatacept Dosing: Week 0, 2, and 4, then Q4 weeks • Weight-based dosing • Weight-Tiered-based dosing • <60kg: Abatacept 500 mg IV • 60 kg to 100 kg: Abatacept 750 mg IV • > 100 kg: Abatacept 1000 mg IV

  7. Study Design-Common Features • Statistical Analyses • Modified ITT efficacy analyses performed for all trials • Sequential testing for co-primary endpoints • Co-primary endpoint tested for significance only if preceding co-primary endpoint was statistically significant • Type I error rate of 5% maintained • Adjustment for multiple doses performed using global testing then pairwise comparisons for individual doses

  8. Study Design-Common Features • Statistical Analyses • ACR and Health Assessment Questionnaire (HAQ) response rates • Categorical Endpoints • Chi-square Test • Non-responder imputation for missing data • Radiographic Progression • Genant-modified Sharp Score • Rank-based nonparametric ANCOVA model • Linear extrapolation for missing data

  9. Study IM101-102: Concomitant MTX Study • 12 month study • Active RA despite MTX therapy • 656 patients randomized 2:1 • Weight-Tiered-dose Abatacept + MTX (n=433) • Placebo + MTX (n=219) • Sequential Co-Primary Endpoints • ACR 20 response at 6 months • Improvement in Physical Function (HAQ) at 12 months • Inhibition of Radiographic Progression at 12 months

  10. 12 month Study Active RA despite MTX therapy 339 patients randomized 1:1:1 Abatacept 10 mg/kg + MTX (n=115) Abatacept 2 mg/kg + MTX (n=105) Placebo + MTX (n=119) Primary Endpoint ACR 20 response at 6 months Study IM101-100: Dose-Ranging Study

  11. Study IM101-029: TNF-Blocker Failure Study • 6 month Study • Active RA despite TNF-blocker therapy ± DMARD • Etanercept or Infliximab • Following drug-washout 393 patients with active RA randomized 2:1 • Weight-Tiered-dose Abatacept + DMARD (n=258) • Placebo + DMARD (n=133) • Co-Primary Endpoints • ACR 20 response at 6 months • Improvement in Physical Function (HAQ) at 6 months

  12. Study IM101-031: Clinical Practice Study • 12 month Study • Active RA despite DMARD therapy • non-biologic and/or biologic DMARDs • Patients with co-morbid conditions permitted • 1441 patients randomized 2:1 • Baseline therapy + Weight-tiered dose Abatacept (n=959) • Baseline therapy + Placebo (n=482) • Primary Objective • Safety • Exploratory Endpoint • Improvement in Physical Function (HAQ) at Day 365

  13. Clinical Studies-Study Conduct • Baseline Patient Demographics (mean): • 52 years of age • 79% Female • 85% White and 4% Black • Baseline Disease Activity (mean): • 10 years RA duration • 21 swollen joints • 31 tender joints • 79% RF(+) • MTX 16 mg Qweek

  14. Abatacept BLA EFFICACY ANALYSES Signs and Symptoms

  15. IM101-102: Concomitant MTX StudySigns & Symptoms:ACR Responses *p<0.001

  16. IM101-102: Concomitant MTX StudySigns & Symptoms:ACR 20 Response Time Course

  17. IM101-102: Concomitant MTX StudySigns & Symptoms:Major Clinical Response

  18. IM101-102: Concomitant MTX StudyMedian %Improvement in ACR Components at Day 169

  19. IM101-102: Concomitant MTX StudyDAS28 Response at Day 365 *p<0.001

  20. IM101-100: Dose-Ranging StudySigns & Symptoms:ACR Responses *p≤0.03

  21. IM101-029: TNF-Blocker Failure Study Signs & Symptoms:ACR Responses at Day 169 *p≤0.003

  22. IM101-029: TNF-Blocker Failure Study Signs & Symptoms:DAS28 Response at Day 169 *p<0.001

  23. Exploratory AnalysisCriteria to Assess Very Low Disease Activity • EULAR-definition of remission is defined as a DAS28<2.6 • However, patients with a EULAR definition of remission can still have several swollen or tender joints • Alternative criterion for very low disease activity DAS28<2.6 AND ≤ 1 swollen and ≤1 tender joint

  24. Criteria to Assess Very Low Disease ActivityIM101-102: Concomitant MTX Study

  25. Criteria to Assess Very Low Disease ActivityIM101-029: TNF-Blocker Failure Study

  26. Exploratory AnalysisWeight-Tiered-Dosing : ACR20 Responders

  27. Abatacept BLA EFFICACY ANALYSES Improvement in Physical Function

  28. IM101-102: Concomitant MTX StudyImprovement in HAQ score ≥ 0.3u at Day 365

  29. IM101-100: Dose-Ranging StudyImprovement in HAQ score ≥ 0.3u at Day 360

  30. IM101-100: Dose-Ranging StudyImprovement in HAQ score ≥ 0.3u Open-Label Study

  31. Abatacept BLA EFFICACY ANALYSES Inhibition of Radiographic Progression

  32. IM101-102: Concomitant MTX StudyMean Change In Genant-Modified Sharp Scores at Day 365

  33. IM101-102: Concomitant MTX StudyMean Change in Genant-Modified Sharp Score Components

  34. Study IM103-002: Monotherapy Study • 3 month study • Active RA despite DMARD therapy • 112 patients randomized • Abatacept (n=90) • 0.5 mg/kg (n=26), 2 mg/kg (n=32), or 10 mg/kg (n=32) • Placebo (n=32) • Primary Endpoint • ACR 20 response at Day 85

  35. Study IM103-002: Monotherapy StudyACR Responses at Day 85

  36. AbataceptEfficacy Analysis • Subset Analyses by: • Baseline Demographics • Age • Sex • Race • Weight • Baseline Disease Activity • Disease Duration • Swollen & Tender Joints • CRP • Genant-modified Sharp Score • HAQ

  37. Abatacept BLA SAFETY ANALYSES

  38. Safety Analyses: Overview • Safety Assessment Based on 5 Studies: • IM101100, IM101101, IM101102, IM101029, IM101031 • Double-Blind Periods: • 1955 Abatacept-treated patients (1688 person-years) • 989 Placebo-treated patients (795 person-years) • Open-Label Periods + Double-Blind Periods: • 2688 Abatacept-treated patients

  39. Cumulative Extent of Exposure

  40. Deaths • 26 total deaths • 16 patients died during the double-blind periods • 10 (0.5%) abatacept-treated patients • 4 died from cardiovascular disorders • 3 found dead at home • 2 died from malignancies • 1 died from infection • 6 (0.6%) placebo-treated patients • 2 died from cardiovascular disorders • 1 found dead at home • 1 died from malignancy • 2 died from infection

  41. Deaths • Analysis of the individual deaths did not suggest a safety signal for any single type of AE • 8 of the deaths in the Abatacept group occurred during a study that permitted enrollment of patients with co-morbidities

  42. Serious Adverse Events • 14% of Abatacept-treated patients had an SAE compared to 12% placebo-treated patients • 3% of Abatacept-treated patients had an infectious SAE compared to 2% placebo-treated patients

  43. Malignancies: Double-Blind Periods

  44. Solid Organ TumorsAbatacept-Treated Patients-Double Blind Periods

  45. Malignancies: Open-Label Periods • 47 patients developed 52 neoplasms • 26 malignancies • 13 solid-organ tumors • 4 lung cancers • 2 ovarian cancers • 2 endometrial cancers • 1 case each of breast, prostate, melanoma, cervical, and rectal cancer • 3 lymphomas

  46. Most Frequently Observed vs. Expected Malignancies

  47. Incidence Rates of Malignancies

  48. Malignancies • 3 potentially concerning malignancies • Lung Cancer • 8 cases of lung cancer in patients receiving abatacept • Breast Cancer and Lymphoma • Pre-clinical studies demonstrated increased rate of mammary tumors and lymphomas in mice that was believed to be secondary to abatacept-induced chronic immunosuppression and MMTV and MLV • Immunosuppression and RA both associated with increased risk of lymphoma

  49. Lung Cancer Incidence

  50. Breast Cancer & Lymphoma • Breast Cancer • 3 (0.1%) cases of breast cancer reported in abatacept-treated patients compared to 2 (0.2%) cases reported in placebo-treated patients • Current evidence does not suggest abatacept increases the rate of breast cancer • Lymphoma • 4 cases of lymphoma reported in patients receiving abatacept • Approximately 4-fold higher than general US population • However, increased rate of lymphoma in RA patients, particularly those with high disease activity

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