FDA Presentation ODAC Meeting July NDA Applicant: Eli Lilly Evista ® (Raloxifene Hydrochloride)

2 Evista ® Review Team Primary ReviewersTeam Leaders MedicalPatricia CortazarJohn R Johnson Bhupinder S Mann StatisticalKun HeRaji Sridhara Clinical PharmacologyJulie BullockBrian Booth CMCSarah PopeRavi Harapanhalli Project ManagerPatricia Garvey DSILauren 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 Trial Patient population (postmenopausal) Primary Endpoint RUTH High risk of coronary events Major coronary events Invasive breast cancer MOREOsteoporosis Vertebral fracture BMD (lumbar spine & femoral neck) COREOsteoporosis Invasive breast cancer

8 TrialTreatment ArmsExclusion Criteria RUTH Raloxifene 60 mg Placebo H/O myocardial infarction (MI), percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG) within 3 months H/O of venous thromboembolism (VTE) MORE Raloxifene 60 mg Raloxifene 120 mg Placebo Cerebrovascular accident (CVA) within 10 yrs H/O VTE CORE Raloxifene 60 mg Placebo Same as MORE except prior CVA not excluded 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 EventsRaloxifene IR IRPlaceboIRAbsoluteRiskDifference Relative Risk (95% CI) Invasive breast cancer (0.37, 0.84) Clinical Vertebral fractures (0.47, 0.90) Death due to Stroke (0.98, 2.30) Stroke (0.91, 1.32) Deep vein thrombosis (0.94, 1.99) Pulmonary embolism (0.89, 2.49) 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 EventsRaloxifeneIRPlaceboIRAbsoluteRiskDifference Relative Risk (95% CI) Invasive breast cancer (0.13, 0.58) Clinical Vertebral Fractures (0.42, 0.80) Death due to Stroke (0.23, 2.52) Stroke (0.57, 1.14) Deep vein thrombosis (1.27, 6.68) Pulmonary embolism (0.92, 10.85) 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 arm94% – –Raloxifene arm90%

14 EventsRaloxifeneIRPlaceboIRAbsoluteRiskDifference Relative Risk (95% CI) Invasive breast cancer (0.23, 0.89) Clinical vertebral fractures (0.62, 1.53) Death due to Stroke (0.34, 12.9) Stroke (0.92, 2.98) Deep vein thrombosis (0.68, 5.95) Pulmonary embolism NA CORE: Comparison of Safety and Efficacy

15 Summary of Benefits vs. Risks Raloxifene Placebo-controlled Trials RUTH: Benefit equals Risk –Benefit: ARR of 1.16 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 of 3.10 IBC per 1,000 P-Y and osteoporosis prevention and treatment –Risk: smaller increase in thromboembolic AEs IR CORE:Risk outweighs Benefit –Benefit: ARR of 2.98 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 ARR: absolute risk reduction, IBC: invasive breast cancer, P-Y: person-years, AE: adverse events, IR: incidence rate

16 Raloxifene: Risk vs. Benefit Raloxifene 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 (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