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Progress in lupus trial design

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  • 1. Progress in Lupus Trial Design Contact: Mark.Abrahams@ig-b.com
  • 2. Patients Trial design Interventions Endpoints ⏏ ⏏ 3 key design factors determine the fate of clinical trials
  • 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. 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. Some nomenclature: SLEDAI
  • 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. Abatacept failed P2 trial An easy-to-fail endpoint and aggressive background meds
  • 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. 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. BLISS (belimumab-P3) trial design incorporated learnings from previous studies Success
  • 11. Epratuzumab P2 trials also used novel/refined trial design approaches Success BICLA: BILAG-based Combined Lupus Assessment
  • 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. 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. Thank You