LymphoStat-B™(belimumab)

A human monoclonal antibody to B-lymphocyte stimulator

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Physiology of BLySTM

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LymphoStat-B

Medical needAutoimmune diseases:• Systemic lupus erythematosus• Rheumatoid arthritis• Idiopathic thrombocytopenic purpura• Sjogren’s syndrome

B-cell neoplasia

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B-cell

Myeloid Cells

Neutralizing Ab against BLyS

ProliferationIg Production

TACI

BCMA

BLyS

X

Neutralizing Antibodies Against BLyS

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LymphoStat-BStatus

Fast Track and Pilot 2 status granted for SLE by U.S. FDA Phase 2 SLE trial completePhase 3 SLE program design agreement reached with regulatory authorities• End of Phase 2 meetings completed• SPA filed

Phase 3 implementation in progress

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Phase 2 Data Demonstrate Across Multiple Measures, LymphoStat-B Improves or Stabilizes Disease Activity

In serologically active patients, statistically significant improvements in SLE disease activity were observed• SELENA SLEDAI• PGA• SF-36• Combined Response Rate (SS/PGA/BILAG)

Significant reduction in proportion of patients experiencing BILAG flares for neurological and musculoskeletal organ domains• Favorable trends noted for the cardiovascular-respiratory, renal,

and general domainsReduction in frequency of subjects transitioning from low dose prednisone (≤7.5 mg/day to >7.5 mg/day)

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LymphoStat-B

Rationale for subgroup analysisAll known prior to unblinding• Phase 2 was exploratory for interactions between

> Drug effect> Target population> Endpoints

• Frequency of “seronegatives” meeting inclusion criteria was unexpected

• LymphoStat-B drug effect more robust in “seropositive”(rheumatoid factor) RA patients

• Circulating BLyS levels correlate with seropositivity• Meaningful (70%) subpopulation

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“Serologically Active”• HEp-2 ANA >1:80 and/or anti-dsDNA >30 IU at baseline• 72% patients in study

29% reduction in SELENA SLEDAI score in seropositive patients

Significant Reduction in Disease Activity for ANA+/anti-dsDNA+ Patients

* p=0.044 at week 52

**

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PGA Scores Significantly Improved with LymphoStat-B as Early as Week 4

* p<0.05 ** p<0.01p=0.0011 at week 52

*

*

** **

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Significant Improvements in QOL (SF-36) Evident Early in Treatment with LymphoStat-B

* p<0.05p=0.041 at week 52

** * *

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Percent of Patients with Worsening* BILAG Score

Musculoskeletal**p=0.0076

Neurological*p=0.0355

* Worsening is defined as shift from BILAG (B,C,D, or E) at baseline to BILAG (A) at week 52 or a shift from BILAG (C,D, or E) at baseline to BILAG (B) at Week 52; No significant difference in composite numerical BILAG scores

LymphoStat-B Reduced BILAG Organ Domain Flares

Favorable trends observed in• Cardiovascular-respiratory (p=0.06)• General and Renal (both p<0.15)

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SELENA SLEDAI Score Improved for a Greater Proportion of Patients Treated with LymphoStat-B

* p<0.05

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PGA Score Improved for a Greater Proportion of LymphoStat-B Treated Patients

** p<0.01 *** p<0.001

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Smaller Proportion of LymphoStat-B Patients Increased from ≤7.5 mg/day Prednisone at Baseline to >7.5 mg/day

** ** ** **

* p<0.05; ≤ 7.5 mg/day prednisone at baseline: 36/86 placebo and 110/235 LymphoStat-B

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Combined Response Endpoint for SLE

Responder index composed of multiple measures• >4 point improvement in SS score• No BILAG worsening (new A or 2 B flares)• No worsening in PGA (<0.3 point increase)

Addresses• Clinician interest in good outcome for individual patient• Regulatory need for demonstration of no off-setting

worsening in multi-organ disease• Biological response modification profile of LymphoStat-B

16 * p=0.0058; Phase 2 SLE Results in Serologically Active Patients

**

LymphoStat-B Significantly Improved Response Rate

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LymphoStat-B

Interpretation of results for program• Hypothesis generated that LymphoStat-B is

clinically effective in SLE• Phase 3 study relative to Phase 2

> Target population refined> Primary endpoint modified> Dose optimization still necessary

►Risk mitigated due to improved knowledge of patient population, drug activity, and safety

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LymphoStat-B Development Strategy

Extensive consultation with clinical experts, GSK, and regulatory authorities• All agree with decision to conduct definitive

Phase 3 trial> Phase 2 data in seropositive patients were

compelling> Patient need for new options> Simply stated – need to duplicate Phase 2

sub-population results to have a positive clinical outcome

Met all our criteria for moving into Phase 3

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LymphoStat-B

Phase 3 program• 2 randomized double blind, placebo controlled superiority

trials: BLISS-52 (52 weeks) and BLISS-76 (76 weeks)• Seropositive SLE patients with SELENA SLEDAI activity

>6 on stable medications• 2 active doses (1 mg/kg or 10 mg/kg) versus placebo for

12 or 18 months• Primary endpoint: combined response at 12 months

> >4 point improvement in SS score> No BILAG worsening (new A or 2 B flares)> No worsening in PGA (<0.3 point increase)

• 810 patients each

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LymphoStat-BNext Steps

Obtain approval of SPAInitiate Phase 3 trialsData presentations at ACR (November 14)

LymphoStat-B™(belimumab)

A human monoclonal antibody to B-lymphocyte stimulator

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LymphoStat-B: Large, Underserved Patient Population

Lupus and Related Conditions (U.S. Only)Up to 1.5MM

Moderate / Severe Systemic Lupus320K

Non-Systemic Lupus /Other Conditions

Skin / Joint Involvement Only

200K

Organ Involvement120K

Initial Candidates for Biologics80K

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Sustained efficacy not well establishedLong term safety concerns

Competitive LandscapeSubstantial and Persistent Unmet Need

SteroidsImmunosuppressants

Multiple products in development• Randomized data

required to draw conclusions

Need for multiple options• Induction• Maintenance

Current Future

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Induction vs. Maintenance: Key Product Attributes

Self-administration

Convenience

Maintenance of B cell immunity

Avoidance of steroidimmunosuppressant AE’s

Safety–Duration of response

Speed of response

Efficacy

MaintenanceInduction

Very ImportantImportantLess Important

– Not Important

• High dose steroids, immunosuppressants

• Rituxan?• CellCept?• Riquent?

• LymphoStat-B

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Would ConsiderWould Use% Patients

Preference for LymphoStat-B

40% improvement in response rate vs. background therapy at 52 weeksNo significant increase in AE’sImprovement in Biomarkers• Anti-dsDNA• Complement• B cell sub-populations

Monthly IV infusion (30-60 minute)

Base Case Product Profile Preference Share

Skin / Joint Organ

20

60

40

4%

16% 24%

40%

0

* Source: HGS Rheumatology Market Research, February 2006

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PrednisoneReduction

FlareReduction

Sub-Q Self Injection• Skin / Joint +53%• Organ +27%

% Patients

20

40

60

S/J S/JOrgan Organ

Base Case

LSB: Upside Potential

Would ConsiderWould Use

S/J Organ

Preference Share

* Source: HGS Rheumatology Market Research, February 2006

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Summary of LymphoStat-B Potential

Patients in need of safe and effective treatmentsMultiple options required• Induction• Maintenance

LymphoStat-B may offer differentiated profile for maintenance treatmentPositive perceptions among LSB-experienced physicians and patients

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Complementary Lead Products

High probability of technical success

• Established treatment modality• Established trial endpoints

Formidable incumbent competitorsStrong basis for Phase 3Attractive specialty marketWorld class partner

High unmet patient needs• Few new treatments• Ample room for differentiated

productsDisease, endpoints less predictableStrong basis for Phase 3Attractive specialty marketWorld class partner

Albuferon LymphoStat-B

LymphoStat-B™Q&A

David Stump and Barry Labinger