FDA Presentation ODAC Meeting July 24 2007

1. FDA PresentationODAC Meeting July 24 2007 NDA 22042 Applicant: Eli Lilly Evista® (Raloxifene Hydrochloride)

2. Evista® Review Team Primary Reviewers Team Leaders Medical Patricia Cortazar John R Johnson Bhupinder S Mann Statistical Kun He Raji Sridhara Clinical Pharmacology Julie Bullock Brian Booth CMC Sarah Pope Ravi Harapanhalli Project Manager Patricia Garvey DSI Lauren Iacono-ConnorsLeslie Ball

3. Raloxifene Proposed New Indication:Women with Osteoporosis • “The reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis” • Supporting trials: • RUTH, MORE and CORE

4. Raloxifene Proposed New Indication:Women at High Risk for Breast Cancer • “The reduction in risk of invasive breast cancer in postmenopausal women at high risk for breast cancer” • Supporting trial: • STAR

5. Issues to Consider before Approval • Safety and efficacy of raloxifene • Clinical Benefit: • Reduction in the incidence of invasive breast cancer • Risks: • Adverse events associated with raloxifene exposure • Deep vein thrombosis • Pulmonary embolism • Death due to stroke

6. Approved Drug: Nolvadex (Tamoxifen Citrate) • “NOLVADEX is indicated to reduce the incidence of breast cancer in women at high risk for breast cancer.” • NSABP BCPT P-1 Eligibility: • Age 35 to 59 years with projected 5-year risk of invasive breast cancer ≥ 1.66% • Age ≥ 60 years • Lobular Carcinoma in situ

7. Raloxifene: Placebo-controlled Trials

8. Raloxifene Placebo-controlled Trials: Treatment Arms & Exclusion Criteria

9. RUTH: Invasive Breast Cancers • Invasive breast cancers: • Raloxifene 40 (N = 5,044) • IR per 1,000 person-years 1.50 • Placebo 70 (N = 5,057) • IR per 1,000 person-years 2.66 • Absolute risk difference 1.16 • Breast cancers diagnosed at stage ≤ II A • Placebo 92% • Raloxifene 83% IR: Incidence Rate

10. RUTH: Comparison of Safety and Efficacy

11. MORE: Invasive Breast Cancers • Invasive breast cancers: • Raloxifene 11 (N = 2,576) • IR per 1,000 person-years 1.26 • Placebo 38 (N = 2,557) • IR per 1000 person-years 4.36 • Absolute risk difference 3.10 • Breast cancers diagnosed at stage ≤ II A • Placebo 96% • Raloxifene 90%

12. MORE: Comparison of Safety and Efficacy

13. CORE: Invasive Breast Cancers • Invasive breast cancers: • Raloxifene 19 (N = 2,716) • IR per 1,000 person-years 2.43 • Placebo 20 (N = 1,274) • IR per 1000 person-years 5.41 • Absolute risk difference 2.98 • Breast cancers diagnosed at stage ≤ II A • Placebo arm 94% • Raloxifene arm 90%

14. CORE: Comparison of Safety and Efficacy

15. Summary of Benefits vs. RisksRaloxifene Placebo-controlled Trials • RUTH:Benefit equals Risk • Benefit: ARR of1.16 IBC per 1,000 P-Y and osteoporosis prevention and treatment • Risk: equal increase in thromboembolic AEs IR • MORE: Benefit more than Risk • Benefit: ARR of3.10 IBC per 1,000 P-Y and osteoporosis prevention and treatment • Risk: smaller increase in thromboembolic AEs IR • CORE: Risk outweighs Benefit • Benefit: ARR of2.98 IBC per 1,000 P-Y and osteoporosis prevention and treatment • Risk: larger increase in thromboembolic AEs IR ARR: absolute risk reduction, IBC: invasive breast cancer, P-Y: person-years, AE: adverse events, IR: incidence rate

16. Raloxifene: Risk vs. BenefitRaloxifene Placebo-controlled Trials • Reduced risk of invasive breast cancers • Variability of raloxifene effect size: • Number of women needed to treat (NNT) for one year to prevent one invasive breast cancer: • RUTH 862 (Women with ≥4 CV risk score) • MORE 323 (Women with osteoporosis) • CORE 335 (Women with osteoporosis) • NSABP P-1 300 (Women ≥35 y old, at high risk) • Increased risk of thromboembolic adverse events • Comparison of Risk vs.Benefit: • Reduction in invasive breast cancer incidence and osteoporosis prevention and treatment benefit vs. increased risk of thromboembolic AEs