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Biologic License Application: anakinra (KINERET) for rheumatoid arthritis

Biologic License Application: anakinra (KINERET) for rheumatoid arthritis. Arthritis Advisory Committee August 16, 2001. Anakinra: Proposed Indication.

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Biologic License Application: anakinra (KINERET) for rheumatoid arthritis

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  1. Biologic License Application:anakinra (KINERET) for rheumatoid arthritis Arthritis Advisory Committee August 16, 2001

  2. Anakinra: Proposed Indication • Kineret is indicated for the reduction in signs and symptoms of moderately to severely active rheumatoid arthritis, in patients 18 years of age or older who have failed 1 or more disease modifying antirheumatic drugs (DMARDs). Kineret can be used alone or in combination with other disease‑modifying antirheumatic drugs (DMARDs).

  3. Anakinra: Background • The agency accepted a BLA filing in December, 1999, that contained the results of 2 randomized trials in RA • At the time of BLA filing, the agency recommended that Amgen begin additional studies to address issues not covered by existing data

  4. Background (cont.) • Amgen began several additional clinical trials in RA in 2000: • 1 year trial of radiographic progression • 6 month randomized safety study with long-term open-label extension • JRA • Combination with TNF antagonists

  5. Kineret BLA • Upon review of the originally submitted data, the agency informed Amgen that the data were suggestive of biologic activity, but that additional safety and efficacy data would be needed • Amgen responded to agency request with data from 3 additional trials

  6. Trials of Anakinra

  7. Study 990145 • 10 radiographic EP: 1 yr • 10 clinical EP: 6 mo • Interim analysis of 506 subjects randomized as of May 18, 2000 • Study remains blinded

  8. 990145: Study Design • Patients with active RA,  1 bony erosion, on stable dose MTX • 1:1 randomization to anakinra 100 mg sc qd or placebo • Independent blinded joint assessors • 10 EP: ACR20 at 6 mo

  9. 990145: Study Conduct

  10. 990145: Baseline Disease Activity

  11. 990145: Disease Activity (cont.)

  12. 990145: ACR Responses

  13. 990145: Time Course

  14. 990145: ACR Components

  15. 990145: Subset Analysis • Similar clinical response seen in patient populations subsetted by: • Male vs. female • Ethnicity • Disease duration < 15 yrs (upper quartile) • TJC > 30 (upper quartile)

  16. 990145: Subset by Age

  17. 990145: Subset by RF Status

  18. 990145: Subset by ESR

  19. Additional Efficacy Trials • Study 560 and 960180: phase 2, 2/3 randomized, double-blind, placebo-controlled trials of anakinra • Both studies: • Active RA by ACR criteria • Stable NSAIDs and prednisone • 6 months blinded therapy • Study 560 also assessed radiographic progression

  20. Studies 560 & 960180

  21. Study 560: Patient Population • Similar baseline characteristics to 990145 with respect to: age, gender, corticosteroid use, RF+, baseline ESR • Differences noted in 560: • > 98% caucasian • Shorter duration of RA: 4 yrs vs. 11

  22. 560: Clinical Responses

  23. Study 960180 • Similar baseline characteristics to 990145 with respect to: age, gender, RF+, baseline disease activity, ESR • Differences noted in 960180: • Higher corticosteroid use: 64% vs. 53% • Shorter duration of RA: 7 years vs. 11

  24. 960180: Clinical Responses Test for dose response: p=0.004 at 6 mo

  25. 960180: Sustained Responses

  26. Signs & Symptoms: Summary • Three randomized trials show a higher proportion of ACR20 responses in anakinra-treated subjects than placebo • Responses seen within weeks and maintained to 6 months • Effects seen on all components of ACR criteria • Consistent effects across subsets of baseline demographics and baseline disease states

  27. Radiographic Progression: RA Guidance Document • A claim of inhibition of structural damage may be based on: • A demonstration of efficacy for signs & symptoms, and • A 1 year study showing a decrease in structural damage based on a validated index

  28. 560: Radiographic Assessment • Hand, wrist x-rays obtained at baseline and 6 months • Analyses: • Change in Larsen score pre-specified • Change in Sharp scores measured in post-hoc re-analysis • Baseline and follow-up x-rays available for 74% of subjects (347 of 472)

  29. 560: Larsen Scores

  30. FDA Analysis of Larsen Scores, Non-Parametric Analysis a Wilcoxon test

  31. 560: Sharp Scores • Amgen conducted an analysis of the Sharp scores, which suggested differences between study arms • Limitations of analysis: • Post-hoc, exploratory • 133 fewer subjects included in Sharp readings compared to Larsen readings

  32. Radiographic Assessments: Summary • Prespecified analysis showed trends towards improved radiographic outcomes, but not statistically significant • Post-hoc analyses also suggest activity of Kineret in inhibiting radiographic progression at 6 months, but firm conclusions cannot be reached due to limitations of analysis

  33. Safety: Overall Exposure

  34. 560 & 960180: Deaths and SAEs • Deaths: None occurred on blinded portion of trials • Incidence of SAEs similar between placebo and anakinra arms • Incidence of serious infections: • 17/1240 on anakinra (1%) vs. 1/243 on placebo (<1%)

  35. 990145: Deaths and SAEs • 1 death: 80 year old man, worsening of underlying chronic lung disease • SAE: 12 on anakinra; 8 on placebo • 3 infectious SAEs on anakinra; 1 on placebo • No malignancies in anakinra arm

  36. Abnormal Lab Values • Leukopenia and mild increase in eosinophil counts only lab abnormalities noted • Leukopenia seen in 12% (85/696) with anakinra vs. 4% with placebo (10/195) in studies 560 & 960180 • 8/696 (1%) discontinued for leukopenia (<3500/mm3) • 1/3 in first 100 days; 1/3 in after >200 days

  37. Leukopenia • Most leukopenia was an increase of 1 grade (e.g. above 4400/mm3 to 3300-4400 range) • 11/696 (2%) patients went from normal to grade 2 (e.g. >4400/mm3 to 2200-3300) • In only 1 case was leukopenia associated with an infection: a non-serious UTI that resolved • ANC at time of withdrawal: 1,800/mm3

  38. AEs Occurring at a Higher Frequency with Anakinra

  39. 990757: Randomized Safety Study • Double-blind, randomized, multicenter trial of safety of adding anakinra 100 mg sc qd to background anti-rheumatic medications • US, Europe and Australia, 169 sites • 1414 subjects: 4:1 randomization • 6 months controlled, then 3 years open-label

  40. 990757: Study Design • Patient population: • Active RA • Stable DMARD regimen for at least 3 months • No uncontrolled medical conditions or recent malignancies • DMARDs allowed as monotherapy or combination • TNF antagonists not permitted • Changes in NSAIDs, corticosteroids, DMARDs allowed as clinically indicated

  41. 990757: Patient Population • Similar demographic characteristics to other RA trials • DMARDs • 52% receiving MTX • 16% on MTX + another DMARD (175/1116) • 6% receiving MTX + 2 or more DMARDs (67/1116) • 57% receiving corticosteroids • No imbalances noted in baseline disease activity or demographics • COPD, h/o pneumonia, asthma, CAD, DM were each present in 5-10% of subjects

  42. 990757: Study conduct • 80% completed 6 months of blinded therapy • Withdrawal for AEs more common in anakinra arm: 12% vs. 6% • Most common AE leading to withdrawal with anakinra was ISRs: 7% • Withdrawal for disease progression more common with placebo 2% vs. 1%

  43. 990757: Deaths and SAEs • 4 deaths on anakinra and 1 on placebo (both <1%) • Similar rate of SAEs overall • More SAEs in GI system: 2% (20/1116) vs. <1% (1/283) • No predominant pattern • More pulmonary SAEs: 2% (18/1116) vs. <1% (1/283) • Difference related to infections

  44. 990757: Serious Infections • Overall infection rate similar between study arms: 41% on anakinra vs. 44% on placebo • Serious infection rate higher on anakinra than on placebo: • 2% on anakinra (23/1116) vs. <1% on placebo (1/283) • Most common: pneumonia, cellulitis, osteomyelitis

  45. Serious Infections • None of the serious infections were fatal • All resolved except one case of osteomyelitis • Atypical infections uncommon: • 1 patient developed MAI 1 mo after discontinuation • 1 patient developed legionella • None associated with leukopenia

  46. Serious Infections: Risk Factors

  47. Study 2000125 (0125): Enbrel Combination • Open-label pilot study of safety • 58 patient with active RA • Patients previously on Enbrel for  3 mo, but no other DMARDs • Anakinra 1 mg/kg sc qd for 6 mo

  48. Study 0125 • 36% withdrew before 6 months (21/58) • 11 for AEs (19%), 8 for withdrawal of consent (14%) • No deaths • 7 SAEs • 4 infectious (7% of subjects) • 2 pneumonia, 2 cellulitis

  49. 0125: Lab Abnormalities • 5 lab toxicities ( in grade of 2 or more) • 2 WBC, 2 lymphs • 2 of the cases of leukopenia occurred in subjects who also developed serious infections: • Cellulitis • Pneumonia

  50. Leukopenia and Serious Infections

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