1 Romiplostim FDA Overview Oncologic Drugs Advisory Committee Meeting Oncologic Drugs Advisory Committee Meeting Faranak Jamali, MD March 12, 2008

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

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 and Study “105:” Splenectomy Study “212:” Spleen intact + completed 1 prior treatment “e.g., prednisone” 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 Target plt 50 to 200 K/mcL – Dose reduction for > 200K – Dose held for > 400K Weekly Plt ct; regular lab/antibody Weekly Plt ct; regular lab/antibody PRO: ITP Questionnaire PRO: ITP Questionnaire

7 Phase 3 study endpoints 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

8 Disposition Disposition Group Pl Romi- plostim PlRomi-plostim Randomized Discontinued2242 D/C Cause Death Death2--- AE AE-112 Pregnancy Pregnancy--1- Consent w/d Consent w/d-12-

9 Baseline Characteristics Baseline CharacteristicsCx Pl, n = 21 Romi- plastim n = 42 Pl n = 21 Romi- plastim n = 41 Age, med Female (%) Med Plt (10 9 /L) Med Hgb (g/L) Med WBC (10 9 /L)

10 Prior Therapies Prior TherapiesCx Pl, n = 21 Romi-plostim n = 42 Pl n = 21 Romi-plostim n = 41 Subjects w prior ITP Treatment (n) Steroid Anti-D IVIG Vinc/Vinblastin Cyclophos Azathioprine51012 Danazol Rituximab Other

11 Primary Endpoint: Durable Platelet Response Primary Endpoint: Durable Platelet ResponseStudyPlRomi-plostimp-value 105(splenectomy) 0/21 (0%) 16/42 (38%) < (no splenectomy) 1/21 (5%) 25/41 (61%) < 0.01

12 Secondary Endpoints Outcome Study 105 splenectomy Study 212 no splenectomy Pl n = 21 Romi- n = 42 Pl n = 21 Romi- n = 41 Overall Plt Resp n (%) 0 33 (79%) 3 (14%) 36 (88%) Wks w Plt Resp, mean Rescue Med, n (%) 12(57%) 11 (26%) 13 (62%) 7 (17%) Dur Plt Resp & Stable Dose, n (%) 0 13 (31%) 0 21 (51%) All p-values < 0.01

13 Safety Data in Phase 3 Studies Adverse events Specific risks: 1)Reticulin formation and potential for fibrosis 2)Thrombotic events 3)Severe thrombocytopenia after discontinuation of Romiplostim 4)Immunogenicity 5)Neoplasia

14 Adverse Events in Phase 3 Studies, n (%) Adverse event Pl n = 41 Romi- n = 84 Any 39 (95%) 84 (100%) Any serious 8 (20%) 14 (17%) Fatal 3 (7%) 1 (1%) Any bleed 25 (61%) 48 (57%) Any serious bleed 4 (10%) 5 (6%)

15 Adverse Events in Phase 3 Studies (%) TermPl n = 41 Romi- n = 84 Arthralgia20%26% Dizziness017% Insomnia7%16% Myalgia2%14% Extremity pain 5%13% Abdominal pain 011% Shoulder pain 08% Dyspepsia07% Paresthesia06%

16 Specific Safety Risks: Safety Database ITP: n = 271 ≤ 6 months: phase 3 and other studies Extension study 213 & SOC study 131 Median exposure ~ 37 weeks 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 Developed: ITP subjects tested n = 225 “Binding” Abs Romiplostim Romiplostim 23 (10%) TPO TPO 12 (5%) “Neutralizing” Abs Romiplostim Romiplostim1 TPO TPO0

25 5) Neoplasia Subjects with neoplasms, n Pl n = 41 Romi n = 84 Any 52 B cell lymphoma 01 Basal cell ca 01 M myeloma 10 Liver metastasis 10 Benign lung neoplasm 10 Fibroma (arm) 10 Benign ovarian tumor/ Uterine leiomyoma 10 Phase 3 Studies, Pooled

26 Romiplostim in Chronic ITP Summary 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