LymphoStat-BLymphoStat-BTMTM

A Case Study for A Case Study for Endpoints and Trial Endpoints and Trial

Design in SLEDesign in SLE

Presentation to the Arthritis Presentation to the Arthritis Drugs Advisory CommitteeDrugs Advisory Committee

30 September 200330 September 2003

Bill Freimuth, MD, PhDBill Freimuth, MD, PhD

AgendaAgenda

• Review BLyS and the pharmacologic rationale, Review BLyS and the pharmacologic rationale, nonclinical and clinical data for LymphoStat-B nonclinical and clinical data for LymphoStat-B

• Review phase 2 trial design in SLEReview phase 2 trial design in SLE

• Pose questions related to SLE trial design/endpoints to Pose questions related to SLE trial design/endpoints to the Committee for discussionthe Committee for discussion

BLySBLyS

• BB--LyLymphocyte mphocyte SStimulatortimulator

• Identified in a high-throughput proliferation assayIdentified in a high-throughput proliferation assay

• A member of the TNF familyA member of the TNF family

• Alternate names:Alternate names:– TALL-1, zTNF4, THANK, BAFF & TNFSF-20TALL-1, zTNF4, THANK, BAFF & TNFSF-20

• Biologically active, soluble form is a 51 kd homotrimerBiologically active, soluble form is a 51 kd homotrimer

• Binds 3 membrane receptors on B lymphocytesBinds 3 membrane receptors on B lymphocytes

• Acts as a survival factor by inhibiting B-cell apoptosisActs as a survival factor by inhibiting B-cell apoptosis

• Stimulates differentiation of B cells to Ig-producing Stimulates differentiation of B cells to Ig-producing plasma cellsplasma cells

Rationale for BLyS Antagonists in SLERationale for BLyS Antagonists in SLE

• Mouse data links BLyS and autoimmune diseaseMouse data links BLyS and autoimmune disease– Transgenic models over-expressing BLyS have Transgenic models over-expressing BLyS have

autoimmune/SLE-like phenotypeautoimmune/SLE-like phenotype– Genetic models of autoimmune disease have Genetic models of autoimmune disease have

elevated levels of circulating BLySelevated levels of circulating BLyS– Soluble BLyS receptors administered in an animal Soluble BLyS receptors administered in an animal

model of SLE ameliorates disease progression and model of SLE ameliorates disease progression and improves survivalimproves survival

• Elevated BLyS levels are evident in the serum of SLE Elevated BLyS levels are evident in the serum of SLE and RA patientsand RA patients– BLyS levels positively correlated with serum IgG BLyS levels positively correlated with serum IgG

and autoantibody levelsand autoantibody levels

00

1100

2200

3300

4400

5500

NormalNormal SLE1SLE1 SLE2SLE2 RARA RAsfRAsf

Autoimmune Patients Display Elevated Autoimmune Patients Display Elevated Serum BLyS ConcentrationsSerum BLyS Concentrations

Normal vs SLE or RA, p <0.001Normal vs SLE or RA, p <0.001

(From Zhang (From Zhang et alet al, J Immunol, 2001), J Immunol, 2001)

BL

yS c

on

cen

trat

ion

(n

g/m

L)

LymphoStat-B Inhibits BLyS Effects in LymphoStat-B Inhibits BLyS Effects in MiceMice

• Human BLyS administration stimulates increased Human BLyS administration stimulates increased spleen weight, B220spleen weight, B220++/ThB/ThB++ splenic B cell numbers and splenic B cell numbers and serum IgAserum IgA

• LymphoStat-B is a fully human IgG1LymphoStat-B is a fully human IgG1 monoclonal monoclonal antibody that specifically recognizes and binds to antibody that specifically recognizes and binds to soluble human BLySsoluble human BLyS

• LymphoStat-B selectively inhibits these BLyS-induced LymphoStat-B selectively inhibits these BLyS-induced effectseffects

LymphoStat-B Inhibits BLyS Induced LymphoStat-B Inhibits BLyS Induced Serum IgA IncreaseSerum IgA Increase

Ab

Bu

ffe

r +

BL

yS

Ab

Bu

ffe

r +

BL

yS

Ab

Bu

ffe

r +

BL

yS

Bu

ffe

rA

b B

uff

er

+ B

Ly

S B

uff

er00

500500

600600

700700

IgG1 controlIgG1 control(mg/kg)(mg/kg)

LymphoStat-BLymphoStat-B(mg/kg)(mg/kg)

Na

ive

Na

ive

Ser

um

IgA

(S

eru

m Ig

A ( g

/mL

)g

/mL

)

0.0

50

.05

5.05.0

0.1

50

.15

0.50.5

1.51.5

0.0

50

.05

5.05.0

0.1

50

.15

0.50.5

1.51.5

400400

300300

200200

100100

##

## ## ## ##

# p <0.05# p <0.05##

LymphoStat-B: Activity and Safety in LymphoStat-B: Activity and Safety in Cynomolgus MonkeysCynomolgus Monkeys

• LymphoStat-B was well tolerated at doses up to 50 LymphoStat-B was well tolerated at doses up to 50 mg/kg q2 weeks for 6 months and during an 8-month mg/kg q2 weeks for 6 months and during an 8-month recovery periodrecovery period– No study agent-related infections during treatment No study agent-related infections during treatment

or recovery periodsor recovery periods

• Activity of LymphoStat-B is demonstrated by decreases Activity of LymphoStat-B is demonstrated by decreases in B lymphocytesin B lymphocytes

• Flow cytometry, organ weights and histologic findings Flow cytometry, organ weights and histologic findings correlated with effects on B lymphocytescorrelated with effects on B lymphocytes

• PK are linear, with a terminal half-life of ~11-14 daysPK are linear, with a terminal half-life of ~11-14 days

• Complete results to be presented at ACRComplete results to be presented at ACR

LymphoStat-B Reduces CD20LymphoStat-B Reduces CD20++ Peripheral Peripheral Blood B-lymphocytesBlood B-lymphocytes

Week 13Week 13 Week 26Week 26 Week 33Week 33 Week 39Week 39 Week 45Week 45 Week 52Week 52 Week 60Week 6000

2525

5050

7575

100100

125125

150150

175175

200200

225225

2502500 mg/kg/dose0 mg/kg/dose

5 mg/kg/dose5 mg/kg/dose

15 mg/kg/dose15 mg/kg/dose

50 mg/kg/dose50 mg/kg/dose

% B

asel

ine

CD

20%

Bas

elin

e C

D20

+ + C

ells

Cel

ls

99%99%

41%41%42%42%

35%35%

Animals per Animals per dose group:dose group: 12/1612/16 8/108/10 44 44 44 44 44

** Statistically significant difference Statistically significant difference

from vehicle controlfrom vehicle control

** ** ** ** ****

**

****

**

** **

TreatmentTreatment RecoveryRecovery

LymphoStat-B: Clinical Development in LymphoStat-B: Clinical Development in SLESLE

• Phase 1 Clinical Trial Phase 1 Clinical Trial – 4 IV doses (1, 4, 10 and 20 mg/kg) and placebo 4 IV doses (1, 4, 10 and 20 mg/kg) and placebo

evaluated as a single dose or 2 doses 21 days apartevaluated as a single dose or 2 doses 21 days apart– Well toleratedWell tolerated

• No drug-related serious adverse eventsNo drug-related serious adverse events• No increase in adverse events or laboratory abnormalitiesNo increase in adverse events or laboratory abnormalities• No increase in incidence of infectionNo increase in incidence of infection

– Linear pharmacokinetics with ~14 day half-lifeLinear pharmacokinetics with ~14 day half-life– Biological activity observedBiological activity observed– Complete results to be presented at ACRComplete results to be presented at ACR

• Fast Track Designation grantedFast Track Designation granted

LymphoStat-B: Phase 2 SLE Trial Design LymphoStat-B: Phase 2 SLE Trial Design

• Multi-center, randomized, double-blind, placebo-Multi-center, randomized, double-blind, placebo-controlled, dose-ranging (1, 4, 10 mg/kg) controlled, dose-ranging (1, 4, 10 mg/kg)

• Patients with active SLE (SELENA SLEDAI Patients with active SLE (SELENA SLEDAI >> 4) and on 4) and on stable medicationsstable medications

• 350 patients350 patients

• IV administration Day 0, 14, 28 then q28 days for 1 yearIV administration Day 0, 14, 28 then q28 days for 1 year

LymphoStat-B: Phase 2 SLE Trial DesignLymphoStat-B: Phase 2 SLE Trial Design

• Primary endpointsPrimary endpoints– SELENA SLEDAI activity at week 24SELENA SLEDAI activity at week 24– Time to first flare (defined by SELENA SLEDAI flare Time to first flare (defined by SELENA SLEDAI flare

index) over 52 weeksindex) over 52 weeks

• Sample SizeSample Size– 80% power, 80% power, 0.05, to detect in 1 of the active 0.05, to detect in 1 of the active

groupsgroups• a 25% absolute or 100% relative improvement (e.g., 25% to a 25% absolute or 100% relative improvement (e.g., 25% to

50%) in the percent change from baseline score in SELENA 50%) in the percent change from baseline score in SELENA SLEDAI at Week 24 and SLEDAI at Week 24 and

• a reduction in the percent of subjects having their first flare a reduction in the percent of subjects having their first flare by Week 52 from 65% to 43%by Week 52 from 65% to 43%

LymphoStat-B: Phase 2 SLE Trial Design LymphoStat-B: Phase 2 SLE Trial Design

• Major secondary endpointsMajor secondary endpoints– Week 52 SELENA SLEDAI and BILAG scoresWeek 52 SELENA SLEDAI and BILAG scores– Time to first flare (defined by BILAG) over 52 weeksTime to first flare (defined by BILAG) over 52 weeks– Reduction in steroid useReduction in steroid use– AUC of SELENA SLEDAI and BILAG over 52 weeksAUC of SELENA SLEDAI and BILAG over 52 weeks

• Biological markersBiological markers– Anti-dsDNA, ANA, and C3 and C4 levels Anti-dsDNA, ANA, and C3 and C4 levels – B cells (CD20B cells (CD20++, CD27, CD27++, CD69, CD69++) and plasmacytoid ) and plasmacytoid

cells (CD138cells (CD138++, CD19/CD27, CD19/CD27BRIGHTBRIGHT) ) – Total serum IgG and other subclassesTotal serum IgG and other subclasses

Questions for Committee DiscussionQuestions for Committee Discussion

1.1. Would an effect in either SELENA SLEDAI at 24 weeks Would an effect in either SELENA SLEDAI at 24 weeks or time to first flare over 52 weeks be an adequate or time to first flare over 52 weeks be an adequate basis to move forward to a confirmatory trial?basis to move forward to a confirmatory trial?

2.2. Which endpoint is thought to be more clinically Which endpoint is thought to be more clinically meaningful?meaningful?

3.3. Is the magnitude of effect being tested for clinically Is the magnitude of effect being tested for clinically relevant? Would a lesser effect also be clinically relevant? Would a lesser effect also be clinically meaningful?meaningful?

Questions for Committee DiscussionQuestions for Committee Discussion

4.4. Are there other endpoints that would be preferred and Are there other endpoints that would be preferred and considered more clinically meaningful? For example:considered more clinically meaningful? For example:– Would significant benefit in one or more specific Would significant benefit in one or more specific

SLE organ system manifestations SLE organ system manifestations (as defined in BILAG) be a relevant primary (as defined in BILAG) be a relevant primary endpoint?endpoint?

– Would a significant steroid-sparing effect with or Would a significant steroid-sparing effect with or without a positive trend in disease activity and/or without a positive trend in disease activity and/or flare be a sufficient primary endpoint?flare be a sufficient primary endpoint?

5.5. Which endpoint would be the most compelling as a Which endpoint would be the most compelling as a primary endpoint in a pivotal trial?primary endpoint in a pivotal trial?

Questions for Committee DiscussionQuestions for Committee Discussion

6.6. Several other clinical endpoints and markers of Several other clinical endpoints and markers of biological activity are being exploredbiological activity are being explored– Which are believed to be the more meaningful?Which are believed to be the more meaningful?– Is there currently sufficient evidence to consider Is there currently sufficient evidence to consider

any of these biomarkers reasonably likely to any of these biomarkers reasonably likely to predict clinical benefit?predict clinical benefit?