Romiplostim FDA Overview

1. RomiplostimFDA Overview Oncologic Drugs Advisory Committee Meeting Faranak Jamali, MD March 12, 2008

2. FDA Overview Chronic ITP efficacy and safety Faranak Jamali, MD Exploratory study in MDS Steven Lemery, MD Risk management considerations Suzanne Berkman, PharmD

3. Proposed indication …for the treatment of thrombocytopenia in adult patients with chronic ITP: • who are non-splenectomized and have an insufficient response or are intolerant to corticosteroids and/or immunoglobulins. • who are splenectomized and have an insufficient response to splenectomy.

4. Romiplostim Database • 14 Studies supply data • Healthy subjects: 2 studies • ITP: 2 phase 3 studies, 8 supportive • MDS: 1 study • CIT: 1 study • Ongoing studies in ITP, MDS, CIT • Romiplostim exposure in BLA: • n = 271 in ITP • n = 121 in other settings

5. Phase 3: Studies 20030105 and 20030212 • Study “105:” Splenectomy • Study “212:” Spleen intact + completed 1 prior treatment “e.g., prednisone” • Study “213:” an open label extension

6. Phase 3 Design Features • R (2:1), DB, PC, 24 week treatment period with 12 wk f/u (off med) • R stratified by con meds (yes/no) • Starting dose 1 mcg/kg, SC; max 15 mcg/kg • Target plt 50 to 200 K/mcL • Dose reduction for > 200K • Dose held for > 400K • Weekly Plt ct; regular lab/antibody • PRO: ITP Questionnaire

7. Primary endpoint: Durable plt response Weekly plt ct ≥ 50 K/mcL for ≥ 6 weeks of the last 8 weeks Secondary endpoints: Overall platelet response Number of weekly platelet responses Patients requiring rescue medication Durable plt response on stable dose Multiple other supportive endpoints Phase 3 study endpoints

8. Disposition

9. Baseline Characteristics

10. Prior Therapies

11. Primary Endpoint: Durable Platelet Response

12. Secondary Endpoints All p-values < 0.01

13. Safety Data in Phase 3 Studies Adverse events Specific risks: Reticulin formation and potential for fibrosis Thrombotic events Severe thrombocytopenia after discontinuation of Romiplostim Immunogenicity Neoplasia

14. Adverse Events in Phase 3 Studies, n (%)

15. Adverse Events in Phase 3 Studies (%)

16. Specific Safety Risks: Safety Database • ITP: n = 271 • ≤ 6 months: phase 3 and other studies • Extension study 213 & SOC study 131 • Median exposure ~ 37weeks • 36 subjects exposed for 2 years • Healthy: n = 56 • MDS: n = 44 • CIT: n = 21

17. 1) Reticulin Formation and Risk for Fibrosis • Reticulin in marrow: “reticulin fibrosis” • identified with silver stain • associated with benign and malignant conditions • thought to be reversible • Collagen in marrow: “collagen fibrosis” • identified with trichrome stain • “less likely” reversible • myelofibrosis/cytopenias • Could long term Romiplostim exposure result in marrow fibrosis/cytopenia?

18. Romiplostim and Reticulin Formation • Repeat Romiplostim dose studies in rats: • marrow fibrosis on H and E stains • reversible after drug discontinuation • Prior study in rats with a TPO (Yanagida): • repeat dose resulted in myelofibrosis • predominance of reticulin • marrow TGFß content paralleled reticulin • suggested megakarycocyte TGFß may stimulate reticulin formation

19. “Increased Reticulin” in ITP Studies • Phase 3 (controlled) studies: • One Romiplostim group/none Placebo • Uncontrolled studies: • Nine patients • Follow-up information: • 2 patients had marrows “improved” with Romiplostim discontinuation; 2 others “stable” • 2 remained on Romiplostim or dose interrupted • Not available or pending as of 120 day update

20. Patient Features from Detailed Review of Six AE with “Increased Reticulin” • All had nucleated RBC in peripheral blood • All had undergone splenectomy • All received “high” doses: 7 to 18 mcg/kg • 5 had no collagen on trichrome; 1 had “localized collagen” assessed as “inconsistent with chronic idiopathic myelofibrosis”

21. Aplastic Anemia • 75 y o female with ITP, DM, CAD & breast cancer history • Six months Romiplostim • Marrow at time of AA diagnosis: “…only focal erythropoiesis and myelopoiesis…convincing marrow megakaryocytes not identified” • No JAK2 V617F point mutation detected • Con meds: azathioprine, carvedilol, amlodipine, losartan, acyclovir, ezetimibe and fenfibrate • Died 54 days later

22. 2) Thrombotic Events • Phase 3 (controlled) studies: • Placebo group: PE • Romi group: CVA and arterial embolus • Other studies: 12 patients • DVT (3), PE (3) • MI (2), Portal V thrombosis (2), Superficial thrombophlebitis (2), Thrombosis (2)

23. 3) Severe Thrombocytopenia after Romiplostim Discontinuation • Potential risk: suppression of TPO • Early phase studies: • 4/57 patients experienced decreased plts • Approximated baseline within 14 days • Notable case: • 80 y o male received six months Romiplostim • CVA 3 days after Romiplostim discontinuation (plt count 107K/mcL), aspirin therapy • 7 days later ICH (plt ct 5K/mcL) • Plt transfusion and died next day

24. 4) Immunogenicity

25. 5) Neoplasia Phase 3 Studies, Pooled

26. Romiplostim in Chronic ITPSummary • Increases and sustains platelet counts in patients who have failed prior therapies • Long term safety data limited: • marrow events/reticulin/potential fibrosis • thrombotic events • severe thrombocytopenia after discontinuation • immunogenicity • neoplasia