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