1. LymphoStat-BTM A Case Study for Endpoints and Trial Design in SLE
Presentation to the Arthritis Drugs Advisory Committee 30 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 Concentrations5
Normal vs SLE or RA, p <0.001 4 3
BLyS concentration (ng/mL) 2 1
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
0.05
0.15
0.5
1.5
5.0
0.05
0.15
0.5
1.5
5.0
Naive
IgG1 control (mg/kg)
LymphoStat-B (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
225
5 mg/kg/dose
15 mg/kg/dose
200
50 mg/kg/dose
175
150
99%
% Baseline CD20+ Cells
125
100
41%
42% 75 *
35% * * * * * 50 * * * * * * 25
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?