LymphoStat-B TM A Case Study for Endpoints and Trial Design in SLE

1. LymphoStat-BTMA Case Study for Endpoints and Trial Design in SLE Presentation to the Arthritis Drugs Advisory Committee30 September 2003 Bill Freimuth, MD, PhD

2. Agenda • Review BLyS and the pharmacologic rationale, nonclinical and clinical data for LymphoStat-B • Review phase 2 trial design in SLE • Pose questions related to SLE trial design/endpoints to the Committee for discussion

3. BLyS • B-Lymphocyte Stimulator • Identified in a high-throughput proliferation assay • A member of the TNF family • Alternate names: • TALL-1, zTNF4, THANK, BAFF & TNFSF-20 • Biologically active, soluble form is a 51 kd homotrimer • Binds 3 membrane receptors on B lymphocytes • Acts as a survival factor by inhibiting B-cell apoptosis • Stimulates differentiation of B cells to Ig-producing plasma cells

4. Rationale for BLyS Antagonists in SLE • Mouse data links BLyS and autoimmune disease • Transgenic models over-expressing BLyS have autoimmune/SLE-like phenotype • Genetic models of autoimmune disease have elevated levels of circulating BLyS • Soluble BLyS receptors administered in an animal model of SLE ameliorates disease progression and improves survival • Elevated BLyS levels are evident in the serum of SLE and RA patients • BLyS levels positively correlated with serum IgG and autoantibody levels

5. Autoimmune Patients Display Elevated Serum BLyS Concentrations 5 0 Normal vs SLE or RA, p <0.001 4 0 3 0 BLyS concentration (ng/mL) 2 0 1 0 0 Normal SLE1 SLE2 RA RAsf (From Zhang et al, J Immunol, 2001)

6. LymphoStat-B Inhibits BLyS Effects in Mice • Human BLyS administration stimulates increased spleen weight, B220+/ThB+ splenic B cell numbers and serum IgA • LymphoStat-B is a fully human IgG1l monoclonal antibody that specifically recognizes and binds to soluble human BLyS • LymphoStat-B selectively inhibits these BLyS-induced effects

7. LymphoStat-B Inhibits BLyS Induced Serum IgA Increase # 700 # p <0.05 600 # 500 400 Serum IgA (g/mL) # # # # 300 200 100 0 5.0 0.05 0.15 0.5 1.5 5.0 0.05 0.15 0.5 1.5 Naive LymphoStat-B(mg/kg) IgG1 control(mg/kg) Ab Buffer + BLyS Ab Buffer + BLyS Buffer

8. LymphoStat-B: Activity and Safety in Cynomolgus Monkeys • LymphoStat-B was well tolerated at doses up to 50 mg/kg q2 weeks for 6 months and during an 8-month recovery period • No study agent-related infections during treatment or recovery periods • Activity of LymphoStat-B is demonstrated by decreases in B lymphocytes • Flow cytometry, organ weights and histologic findings correlated with effects on B lymphocytes • PK are linear, with a terminal half-life of ~11-14 days • Complete results to be presented at ACR

9. LymphoStat-B Reduces CD20+ Peripheral Blood B-lymphocytes * Statistically significant difference from vehicle control 250 0 mg/kg/dose 5 mg/kg/dose 225 15 mg/kg/dose 200 50 mg/kg/dose 175 150 99% % Baseline CD20+ Cells 125 100 41% 42% 75 * * * 35% * * * * * 50 * * * * 25 0 Week 13 Week 26 Week 33 Week 39 Week 45 Week 52 Week 60 Treatment Recovery Animals per dose group: 12/16 8/10 4 4 4 4 4

10. LymphoStat-B: Clinical Development in SLE • Phase 1 Clinical Trial • 4 IV doses (1, 4, 10 and 20 mg/kg) and placebo evaluated as a single dose or 2 doses 21 days apart • Well tolerated • No drug-related serious adverse events • No increase in adverse events or laboratory abnormalities • No increase in incidence of infection • Linear pharmacokinetics with ~14 day half-life • Biological activity observed • Complete results to be presented at ACR • Fast Track Designation granted

11. LymphoStat-B: Phase 2 SLE Trial Design • Multi-center, randomized, double-blind, placebo-controlled, dose-ranging (1, 4, 10 mg/kg) • Patients with active SLE (SELENA SLEDAI > 4) and on stable medications • 350 patients • IV administration Day 0, 14, 28 then q28 days for 1 year

12. LymphoStat-B: Phase 2 SLE Trial Design • Primary endpoints • SELENA SLEDAI activity at week 24 • Time to first flare (defined by SELENA SLEDAI flare index) over 52 weeks • Sample Size • 80% power,  0.05, to detect in 1 of the active groups • a 25% absolute or 100% relative improvement (e.g., 25% to 50%) in the percent change from baseline score in SELENA SLEDAI at Week 24 and • a reduction in the percent of subjects having their first flare by Week 52 from 65% to 43%

13. LymphoStat-B: Phase 2 SLE Trial Design • Major secondary endpoints • Week 52 SELENA SLEDAI and BILAG scores • Time to first flare (defined by BILAG) over 52 weeks • Reduction in steroid use • AUC of SELENA SLEDAI and BILAG over 52 weeks • Biological markers • Anti-dsDNA, ANA, and C3 and C4 levels • B cells (CD20+, CD27+, CD69+) and plasmacytoid cells (CD138+, CD19/CD27BRIGHT) • Total serum IgG and other subclasses

14. Questions for Committee Discussion • Would an effect in either SELENA SLEDAI at 24 weeks or time to first flare over 52 weeks be an adequate basis to move forward to a confirmatory trial? • Which endpoint is thought to be more clinically meaningful? • Is the magnitude of effect being tested for clinically relevant? Would a lesser effect also be clinically meaningful?

15. Questions for Committee Discussion • Are there other endpoints that would be preferred and considered more clinically meaningful? For example: • Would significant benefit in one or more specific SLE organ system manifestations (as defined in BILAG) be a relevant primary endpoint? • Would a significant steroid-sparing effect with or without a positive trend in disease activity and/or flare be a sufficient primary endpoint? • Which endpoint would be the most compelling as a primary endpoint in a pivotal trial?

16. Questions for Committee Discussion • Several other clinical endpoints and markers of biological activity are being explored • Which are believed to be the more meaningful? • Is there currently sufficient evidence to consider any of these biomarkers reasonably likely to predict clinical benefit?