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Abatacept (ORENCIA) for Rheumatoid Arthritis

Abatacept (ORENCIA) for Rheumatoid Arthritis. Biological License Application Arthritis Advisory Committee September 6, 2005. Abatacept. Proposed indications for abatacept:

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Abatacept (ORENCIA) for Rheumatoid Arthritis

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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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