1. Arthritis Advisory Committee July 29, 2008 Actemra (tocilizumab) for Rheumatoid Arthritis FDA Perspective Sarah Okada, M.D. Division of Anesthesia, Analgesia, and Rheumatology Products Sarah Okada, M.D. Division of Anesthesia, Analgesia, and Rheumatology Products

2. Arthritis Advisory Committee July 29, 2008 2 Overview Brief background on RA clinical development programs and claims Overview of tocilizumab (TCZ) pivotal trials –Very brief recap of efficacy –Summary of safety Brief background on RA clinical development programs and claims Overview of tocilizumab (TCZ) pivotal trials –Very brief recap of efficacy –Summary of safety

3. Arthritis Advisory Committee July 29, 2008 3 “Typical” Drug Development for RA Phase 1, phase 2 –Including initial study of safety in combination with MTX –3 mo RCT for proof of concept using ACR 20 Phase 3 –Large RCTs at least 3 mo in duration –Characterize monotherapy and combination w other DMARD’s, especially MTX –May include large “clinical practice” trial – assess safety of add-on therapy w prevalent DMARD regimens Phase 4 –Early RA, 1 st line treatment –Juvenile Idiopathic Arthritis (JIA) –Comparative studies –Long-term (e.g. 5 year) safety studies –Study of impact of treatment on immunization response Phase 1, phase 2 –Including initial study of safety in combination with MTX –3 mo RCT for proof of concept using ACR 20 Phase 3 –Large RCTs at least 3 mo in duration –Characterize monotherapy and combination w other DMARD’s, especially MTX –May include large “clinical practice” trial – assess safety of add-on therapy w prevalent DMARD regimens Phase 4 –Early RA, 1 st line treatment –Juvenile Idiopathic Arthritis (JIA) –Comparative studies –Long-term (e.g. 5 year) safety studies –Study of impact of treatment on immunization response

4. Arthritis Advisory Committee July 29, 2008 4 Currently Recognized Claims Signs & symptoms –ACR20, primary endpoint >3 mos Inhibition of progression of structural damage –Change from baseline in radiographic score, e.g. Total Sharp Score –Controlled period >6 mos, total >1yr Improvement in physical function –Improvement in HAQ-DI >0.22 units at end of controlled period, >3 mos; maintained in open-label Major clinical response –ACR70 for >6 continuous months Complete clinical response/remission –ACR remission + radiographic arrest >6 months Signs & symptoms –ACR20, primary endpoint >3 mos Inhibition of progression of structural damage –Change from baseline in radiographic score, e.g. Total Sharp Score –Controlled period >6 mos, total >1yr Improvement in physical function –Improvement in HAQ-DI >0.22 units at end of controlled period, >3 mos; maintained in open-label Major clinical response –ACR70 for >6 continuous months Complete clinical response/remission –ACR remission + radiographic arrest >6 months

5. Arthritis Advisory Committee July 29, 2008 5 Tocilizumab Biologics License Application (BLA) Intended to seek initial claim of reducing signs and symptoms of moderately to severely active RA 24 week data from 5 pivotal studies –Covers the range of RA patients, from early RA to more refractory –Includes data for monotherapy, concomitant MTX and other non-biologic DMARDs Open-label Long-Term Extensions (LTE) –Patients completing the core studies were allowed to enroll into LTE upon completion –Planned for total of 5 years –Interim data submitted; close to 1500 patients have received tocilizumab for up to 18 months Intended to seek initial claim of reducing signs and symptoms of moderately to severely active RA 24 week data from 5 pivotal studies –Covers the range of RA patients, from early RA to more refractory –Includes data for monotherapy, concomitant MTX and other non-biologic DMARDs Open-label Long-Term Extensions (LTE) –Patients completing the core studies were allowed to enroll into LTE upon completion –Planned for total of 5 years –Interim data submitted; close to 1500 patients have received tocilizumab for up to 18 months

6. Arthritis Advisory Committee July 29, 2008 6 EfficacyEfficacy

7. Arthritis Advisory Committee July 29, 2008 7 Summary of ACR Responders at Week 24 ITT = Intent to Treat

8. Arthritis Advisory Committee July 29, 2008 8 Subgroup Analyses: By Demographics and Geographic Region 8

9. Arthritis Advisory Committee July 29, 2008 9 Subgroup Analyses: By Disease Characteristics 9

10. Arthritis Advisory Committee July 29, 2008 10 Sensitivity Analyses

11. Arthritis Advisory Committee July 29, 2008 11 SafetySafety

12. Arthritis Advisory Committee July 29, 2008 12 ExposureExposure

13. Arthritis Advisory Committee July 29, 2008 13 Overview of Adverse Events and Deaths

14. Arthritis Advisory Committee July 29, 2008 14 Exposure-Adjusted Incidence Rates Background rates for RA patients: 2.4-2.5 deaths/100 pt-yrs Background rates for RA patients: 1.3-1.4 malignancies/100 pt-yrs Background rates for RA patients: 5-6 SIE/100 pt-yrs for TNF inhibitors, 2-4 SIE/100 pt-yrs for non-biologic DMARDs

15. Arthritis Advisory Committee July 29, 2008 15 Deaths 5 patients died of cardiac etiologies (4 MI and 1 cardiac failure) 4 patients died of infectious etiologies

16. Arthritis Advisory Committee July 29, 2008 16 Neoplasms/Malignancies

17. Arthritis Advisory Committee July 29, 2008 17 Serious infections No protocol-mandated TB screening or prophylaxis 68 (52 in TCZ-groups) patients had a history of TB and/or positive PPD at baseline (but patients with active or history of recurrent TB were excluded) No patients developed reactivation or dissemination of TB 2 cases of extrapulmonary mycobacterial infection in LTE (1 patient PPD neg, the other without history of risk factors or exposure)

18. Arthritis Advisory Committee July 29, 2008 18 Serious Adverse Events Exposure adjusted rates –Were similar for placebo/DMARD and TCZ/DMARD treatment arms (16 & 17/100 pt-yrs, respectively) –Were lower for TCZ 8 mg/kg and MTX monotherapy groups (10 & 12/100 pt-yrs, respectively) –Did not rise in LTE (13/100 pt-yrs) Most common SAEs –Infections (2% in controlled period, 5% in LTE) –GI and Injury SOCs (1% in controlled period, 2% in LTE) Exposure adjusted rates –Were similar for placebo/DMARD and TCZ/DMARD treatment arms (16 & 17/100 pt-yrs, respectively) –Were lower for TCZ 8 mg/kg and MTX monotherapy groups (10 & 12/100 pt-yrs, respectively) –Did not rise in LTE (13/100 pt-yrs) Most common SAEs –Infections (2% in controlled period, 5% in LTE) –GI and Injury SOCs (1% in controlled period, 2% in LTE) LTE=Long-term extension

19. Arthritis Advisory Committee July 29, 2008 19 Serious Adverse Events Myocardial infarction –15 events/4158 pt-yrs = 0.35/100 pt-yrs –Published rates in RA patients 0.47/100 pt-yrs, ARAMIS database 0.76/100 pt-yrs, NDBRD Cerebrovascular accidents –9 events/4158 pt-yrs = 0.22/100 pt-yrs –Published rates in RA patients 0.11/100 pt-yrs in female RA pts within Nurse’s Health Study 0.76/100 pt-yrs in UK General Practice Research database Myocardial infarction –15 events/4158 pt-yrs = 0.35/100 pt-yrs –Published rates in RA patients 0.47/100 pt-yrs, ARAMIS database 0.76/100 pt-yrs, NDBRD Cerebrovascular accidents –9 events/4158 pt-yrs = 0.22/100 pt-yrs –Published rates in RA patients 0.11/100 pt-yrs in female RA pts within Nurse’s Health Study 0.76/100 pt-yrs in UK General Practice Research database ARAMIS=Arthritis, Rheumatism and Aging Medical Information System NDBRD=National Data Bank for Rheumatic Diseases

20. Arthritis Advisory Committee July 29, 2008 20 AE Causing Discontinuation

21. Arthritis Advisory Committee July 29, 2008 21 Other AE of Interest: GI Perforations 11 events in the 5 RA pivotal studies/LTE 5 events in the Chugai RA studies Patients were receiving TCZ 8 mg/kg at time of event (except one who remains on blinded treatment) Most patients were receiving prednisone and/or NSAIDs concomitantly

22. Arthritis Advisory Committee July 29, 2008 22 Other AE of Interest: Demyelinating AE ~4700 patients have been exposed to TCZ for ~7961 pt-yrs exposure in the global RA program These 4 cases = 0.05 per 100 pt-yrs Background rate of demyelinating disorders in RA patients is not currently known

23. Arthritis Advisory Committee July 29, 2008 23 Lab Abnormalities: Hematology 23

24. Arthritis Advisory Committee July 29, 2008 24 Lab Abnormalities: Lipids All lipid parameters, including HDL, increased; however the TC/HDL ratio was also increased

25. Arthritis Advisory Committee July 29, 2008 25 Lab Abnormalities: Liver Enzymes

26. Arthritis Advisory Committee July 29, 2008 26 Lab Abnormalities: Liver Enzymes

27. Arthritis Advisory Committee July 29, 2008 27 Predicting Serious Hepatotoxicity Hy’s law: based on the observation by the eponymous Dr. Hy Zimmerman that drug-induced jaundice caused by hepatocellular injury, without an obstructive component, has a high rate of bad outcomes (10-50% mortality) Hy’s law components: –Transaminase elevations >3 x ULN and –Total bilirubin >2 x ULN and –No evidence of biliary obstruction (elevated alkaline phosphatase) or Gilbert’s syndrome Based on original estimates of mortality, severe drug-induced liver injury can be estimated to occur at a rate of at least 1/10 th the rate of Hy’s law cases Hy’s law utilized by FDA to identify drugs likely to be capable of causing severe liver injury Hy’s law: based on the observation by the eponymous Dr. Hy Zimmerman that drug-induced jaundice caused by hepatocellular injury, without an obstructive component, has a high rate of bad outcomes (10-50% mortality) Hy’s law components: –Transaminase elevations >3 x ULN and –Total bilirubin >2 x ULN and –No evidence of biliary obstruction (elevated alkaline phosphatase) or Gilbert’s syndrome Based on original estimates of mortality, severe drug-induced liver injury can be estimated to occur at a rate of at least 1/10 th the rate of Hy’s law cases Hy’s law utilized by FDA to identify drugs likely to be capable of causing severe liver injury

28. Arthritis Advisory Committee July 29, 2008 28 Single Hy’s Law Case Identified in Tocilizumab Global RA Program Female, late 50’s, completed 6-months of TCZ 8 mg/kg monotherapy with only isolated increases in total bilirubin >1 x ULN and without simultaneous increase in transaminases or alkaline phosphatase Enrolled in LTE, began MTX at 20 mg weekly without dose titration, began treatment with open-label TCZ 8 mg/kg Week 5, noted to have ↑AST 2 x ULN, ↑ALT 4 x ULN and ↑T Bili < 2 x ULN Week 9, AST peaked at >10 x, ALT at >16 x, and T bili at >2 x; TCZ and MTX withheld, elevations normalized by week 12 Week 11, MTX re-started at 10 mg/week Week 12, TCZ re-started at 4 mg/kg Week 15, transaminases and total bilirubin were above ULN Week 16, study treatment discontinued and patient withdrawn Week 20, transaminases and total bilirubin were normal No clinical adverse events were associated Female, late 50’s, completed 6-months of TCZ 8 mg/kg monotherapy with only isolated increases in total bilirubin >1 x ULN and without simultaneous increase in transaminases or alkaline phosphatase Enrolled in LTE, began MTX at 20 mg weekly without dose titration, began treatment with open-label TCZ 8 mg/kg Week 5, noted to have ↑AST 2 x ULN, ↑ALT 4 x ULN and ↑T Bili < 2 x ULN Week 9, AST peaked at >10 x, ALT at >16 x, and T bili at >2 x; TCZ and MTX withheld, elevations normalized by week 12 Week 11, MTX re-started at 10 mg/week Week 12, TCZ re-started at 4 mg/kg Week 15, transaminases and total bilirubin were above ULN Week 16, study treatment discontinued and patient withdrawn Week 20, transaminases and total bilirubin were normal No clinical adverse events were associated

29. Arthritis Advisory Committee July 29, 2008 29 Implications of Hy’s Law Case Confounded by concomitant initiation of relatively high dose MTX, which has known hepatotoxicity, but with positive re-challenge to TCZ 1 case in approximately 4700 patients in the TCZ global RA program: –Using estimate of severe drug-induced liver injury as occurring at 1/10 th the rate of Hy’s Law cases, 1 case might be expected in 47,000 treated patients Confounded by concomitant initiation of relatively high dose MTX, which has known hepatotoxicity, but with positive re-challenge to TCZ 1 case in approximately 4700 patients in the TCZ global RA program: –Using estimate of severe drug-induced liver injury as occurring at 1/10 th the rate of Hy’s Law cases, 1 case might be expected in 47,000 treated patients

30. Arthritis Advisory Committee July 29, 2008 30 Plausible Mechanisms? IL6 appears to have a hepatoprotective effect on various forms of liver injury and promotes hepatocyte regeneration –Inhibition could lead to increased hepatocyte susceptibility to hepatotoxic insults Hepatocytes express high levels of IL6 receptor –With ubiquitous anti-IL6R mAb binding in the liver, could even minimal complement-mediated cytotoxicity (CDC) or antibody dependent cellular cytotoxicity (ADCC) result in some hepatic injury? IL6 appears to have a hepatoprotective effect on various forms of liver injury and promotes hepatocyte regeneration –Inhibition could lead to increased hepatocyte susceptibility to hepatotoxic insults Hepatocytes express high levels of IL6 receptor –With ubiquitous anti-IL6R mAb binding in the liver, could even minimal complement-mediated cytotoxicity (CDC) or antibody dependent cellular cytotoxicity (ADCC) result in some hepatic injury?

31. Arthritis Advisory Committee July 29, 2008 31ImmunogenicityImmunogenicity 2% (46/2553) of patients tested were positive for anti-TCZ antibodies; 3% (13/477) of patients tested in the LTE 6% (10/159) of patients tested for events of potentially immunogenic origin were positive; 3% (2/75) of patients tested in the LTE In patients tested for loss of efficacy, 0/14 in the 6-month controlled period and 1/50 in the LTE were positive 31

32. Arthritis Advisory Committee July 29, 2008 32 Infusion Reactions 7-9% of pts in TCZ tx groups experienced an acute infusion-related AE, compared to 5% of pts on placebo infusions, slightly higher (11%) in LTE Discontinuations due to infusional AEs were uncommon Of the 6 patients experiencing anaphylaxis, 3 were anti-TCZ antibody positive, 1 was negative, 2 were not tested Anaphylaxis events tended to occur at the 2 nd to 4 th infusions 32

33. Arthritis Advisory Committee July 29, 2008 33 Risk-Benefit Overview

34. Arthritis Advisory Committee July 29, 2008 34 Summary Efficacy –Treatment with tocilizumab resulted in statistically significant increases in clinical responses Safety –Treatment with tocilizumab appears to be associated with increased risk of serious infection and significant liver enzyme elevation –Malignancies, GI perforations and demyelinating adverse events were observed in the clinical trials but the relative risk and role of TCZ treatment for the development of these AEs is not well-defined Decision to approve and optimal patient population requires careful balancing of benefits and risks Efficacy –Treatment with tocilizumab resulted in statistically significant increases in clinical responses Safety –Treatment with tocilizumab appears to be associated with increased risk of serious infection and significant liver enzyme elevation –Malignancies, GI perforations and demyelinating adverse events were observed in the clinical trials but the relative risk and role of TCZ treatment for the development of these AEs is not well-defined Decision to approve and optimal patient population requires careful balancing of benefits and risks