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Progress in lupus trial design


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Progress in lupus trial design

  1. 1. Progress in Lupus Trial Design Contact:
  2. 2. Patients Trial design Interventions Endpoints ⏏ ⏏ 3 key design factors determine the fate of clinical trials
  3. 3. Challenges in SLE trial design We are learning as we go Patients • Lupus is a heterogenous disease • Patients must be sick enough to see treatment effect • Active disease vs inactive disease? • Impact on endpoint (index vs flare) • Trial length: flare trials (in inactive dz pts) take several years longer; Difficult to keep pts on same background Interventions • Unethical to randomize patients with active disese to placebo alone • Background treatments muddy the picture Endpoints • Disease activity indices a work in progress • Difficult to correlate biomarkers with clinical outcome (in nonrenal SLE) • Length of study: longer trials may be needed to see efficacy in joint/organ damage
  4. 4. Some nomenclature: BILAGBasedontheprincipleofphysician’sintentiontotreat BILAG B: Moderate disease activity requiring any of the below: • Systemic low dose oral glucocorticoids (equivalent to prednisolone ≤ 20 mg/day • Intramuscular or intra-articular or soft tissue glucocorticoids injection (equivalent to methylprednisolone < 500mg) • Topical glucocorticoids • Topical immunomodulators • Antimalarials or thalidomide or prasterone or acitretin • Symptomatic therapy (eg: NSAIDs for inflammatory arthritis) BILAG A: Severe disease activity requiring any of the below: • Systemic high dose oral glucocorticoids (equivalent to prednisolone > 20 mg/day) • Intravenous pulse glucocorticoids (equivalent to pulse methylprednisolone ≥ 500 mg) • Systemic immunomodulators (biologics, immunoglobulins and plasmapheresis) • Therapeutic high dose anticoagulation in the presence of high dose steroids or immunomodulators (eg: warfarin with target INR 3 – 4) BILAG C: Mild disease BILAG E: System never involved BILAG D: Inactive disease but previously affected
  5. 5. Some nomenclature: SLEDAI
  6. 6. Rituximab failed P3 trials Much literature documents rituximab efficacy in severe refractory SLE A review in 188 SLE patients from 35 studies (mostly open-label) reported efficacy rates ~90% However, two large randomized trials were unexpectedly negative EXPLORER: RTX for non-renal SLE •Patients: moderate-to-severe active disease (at least one BILAG A or two BILAG B) •Intervention: background of single immunosuppressant, (AZT, MMF, or MTX), plus steroids •Endpoint: Major clinical response (MCR) - BILAG C in all organ systems without new flares •Results: No significant difference between groups, however, sub-group analysis showed benefit in African Americans, hispanics, anti-dsDNA and complement LUNAR: RTX in lupus nephritis •Intervention: Background of steroids, Cytoxan and/or MMF. •Endpoint: Creatinine, proteinuria, and urine sediment •Results: no significant difference between groups, however, • African American and Hispanic subgroups with better response (not statistically significant) Why might a beneficial effect have been missed? • Easy-fo-fail endpoint: BILAG (mild flare) • Most EXPLORER patients had mild disease; patients with severe disease were under represented • Patients received high doses of background steroids and immunosuppressants • EXPLORER lasted 52 weeks. Open-label studies have shown maximal benefit out to 18 months An easy-to-fail endpoint and aggressive background meds
  7. 7. Abatacept failed P2 trial An easy-to-fail endpoint and aggressive background meds
  8. 8. Belimumab failed P2 trial Design • Patients: Clinically active disease as defined by SLE-DAI≥4; no serologic requirements • Intervention: Standard of care (steroids and immunosuppressants) in addition to belimumab • Endpoint: Co-primary endpoints included percentage change in the SELENA SLEDAI, and time to flare [defined by SELENA–SLEDAI flare index (SFI)] • Results: No significant difference between groups, however, Benefits were seen in the seropositive sub-group. Significant improvements in B cell counts, immunoglobulin levels, anti-dsDNA antibody levels, and complement Why might a beneficial effect have been missed? • Seronegative patients included in the study (some chronic disease features may have been misinterpreted as active inflammation) • Unlimited changes in corticosteroid doses and immunosuppressants, confounding the disease activity assessments. • Disease indices perhaps not sensitive enough An easy-to-fail endpoint and aggressive background meds
  9. 9. What would’ve happened had they used different endpoints? BILAG A flares are a more sensitive endpoint than BILAG B or C flares • Significant benefit for both rituximab and abatacept patients (post hoc reanalysis) • Using BILAG A (severe flare) as the primary endpoint • Vs the mild-moderate C or B flare definitions used in the actual P2 studies • Use caution interpreting post hoc analyses Reduced risk of BILAG A flare HR=0.61 P=0.052 Reduced risk of BILAG A flare HR=0.61 P=0.052 Rituximab results - different flare definitions Abatacept results - different flare definitions
  10. 10. BLISS (belimumab-P3) trial design incorporated learnings from previous studies Success
  11. 11. Epratuzumab P2 trials also used novel/refined trial design approaches Success BICLA: BILAG-based Combined Lupus Assessment
  12. 12. • Measuring efficacy in terms of joint/organ protection or steroid sparing effects will require substantially longer trials (3-5 years) Evolution of trial design in SLE
  13. 13. Ongoing late stage trials All are baking the same cake, but each recipe is slightly different Patients Intervention Endpoints LY2127399 (ILLUMINATE) P3 Active disease: SLEDAI≥6, ANA+ SOC (“with some restrictions in dose adjustments”) SRI epratuzumab (EMBODY2) P3 Active mod-severe SLE via BILAG and SLEDAI SOC BICLA and no  in background meds atacicept (APRIL SLE) P3 BILAG A or B SOC BILAG A or B flare abatacept (ACCESS) P2 Lupus nephritis Abatacept + Cytoxan + AZT vs Cytoxan + AZT GFR, proteinuria, creatinine
  14. 14. Thank You