IL-6R inhibition: A new CHARISMAtic approach to RA therapy

1. IL-6R inhibition: A new CHARISMAtic approach to RA therapy Professor Gerd-Rüdiger Burmester Charité University Hospital, Berlin, Germany

2. The first antibody therapy Diphtheria Vaccine Emil von Behring, 1854~1917 Shibasaburo Kitasato, 1852~1931

3. The CHARISMA study • Chugai • Humanised • Anti-human • Recombinant • Interleukin • Six • Monoclonal • Antibody study

4. Study population • Double-blind, randomised, controlled trial • Seven treatment groups (~50 patients/group) • TCZ monotherapy (2, 4 or 8 mg/kg) • TCZ (2, 4 or 8 mg/kg) plus MTX • MTX alone • Patients with active RA who have an inadequate response (IR) to MTX • Stabilised on current dose of MTX for 4 weeks prior to randomisation • The study included patients from 57 rheumatology centres in Europe

5. Objectives • Primary endpoint • Proportion of patients achieving ACR20 response at Week 16 • Secondary endpoints • ACR50 and ACR70 • DAS28 • Changes in duration of morning stiffness • Individual disease activity measures

6. Study design (1) • TCZ (2, 4 or 8 mg/kg) ± MTX or MTX alone q4wk iv(4 infusions) • A total of 359 patients randomised • Efficacy endpoints were evaluated at Week 16 • Safety follow-up evaluations were performed at Week 20

7. FU Safety follow-up Study design (2) Screen Randomisation Treatment period Follow-up TCZ 2 mg/kg Infusions Primary endpoint TCZ 4 mg/kg FU TCZ 8 mg/kg TCZ 2 mg/kg + MTX TCZ 4 mg/kg + MTX Primary endpoint: ACR20 at Week 16 TCZ 8 mg/kg + MTX 0 2 4 6 8 10 12 14 16 18 20 Week Placebo + MTX Maini RN, et al. Arthritis Rheum 2006; 54:2817–2829.

8. Key inclusion criteria • Disease duration 6 months • Active disease (6 TJC and 6 SJC of 28) • Elevated acute phase reactant, either: • CRP 1.0 mg/dL • ESR 28 mm/hr • An inadequate response to MTX or a disease flare while receiving MTX (6 months of therapy)

9. Number of patients randomised = 359 TCZ 2 mg/kg (53) TCZ 4 mg/kg (54) TCZ 8 mg/kg (52) TCZ 2 mg/kg + MTX (52) TCZ 4 mg/kg + MTX (49) TCZ 8 mg/kg + MTX (50) MTX (49) 7 withdrew 9withdrew 12 withdrew 11withdrew 8 withdrew 6 withdrew 7 withdrew AE/PDRT –4 LOE –6 Other –5 AE/PDRT –6 LOE –5 Other –1 AE/PDRT –5 LOE –2 Other –2 AE/PDRT –3 LOE –1 Other –2 AE/PDRT –6 LOE –1 Other –2 AE/PDRT –6 LOE –1 Other –2 AE/PDRT –4 LOE –6 Other –2 40completed 43 completed 42 completed 46completed 44completed 43 completed 41 completed Enrolment, randomisation and study completion AE/PDRT = adverse event and/or possible drug-related toxicity; LOE = lack of efficacy Other: withdrew consent, used prohibited medication or experienced intercurrent illness

10. Baseline characteristics: ITT population (1) * low = 10 mg or 12.5 mg; medium = 15 mg or 17.5 mg; high = 20 mg, 22.5 mg or 25 mg Maini RN, et al. Arthritis Rheum 2006; 54:2817–2829.

11. Baseline characteristics: ITT population (2) Maini RN, et al. Arthritis Rheum 2006; 54:2817–2829.

12. Baseline characteristics: ITT population (3) Values are expressed as mean Maini RN, et al.Arthritis Rheum 2006; 54:2817–2829.

13. 0 TCZmonotherapy Significant improvement in ACR20 scores with tocilizumab ± MTX TCZ 2 mg/kg *** 80 74% TCZ 4 mg/kg * TCZ 8 mg/kg * * 64% 70 * 63% 63% 61% 60 50 41% Patients (%) 40 31% 30 20 10 MTX alone TCZ + MTX *p<0.05, ***p=0.001 vs MTX Maini RN, et al. Arthritis Rheum 2006; 54:2817–2829.

14. Significant improvement in ACR scores with tocilizumab in combination with MTX MTX 100 TCZ 2 mg/kg + MTX TCZ 4 mg/kg + MTX *** TCZ 8 mg/kg + MTX 74% 80 * * 64% 63% * 60 53% Patients (%) 41% * 37% 37% 40 32% 29% 16% 20 14% 12% 0 ACR70 ACR20 ACR50 *p<0.05, ***p=0.001 vs MTX Maini RN, et al. Arthritis Rheum 2006; 54:2817–2829.

15. Significant improvement in DAS28 score with tocilizumab ± MTX Weeks Baseline 4 8 12 16 0.0 MTX –0.5 –1.0 –1.5 Mean change from baseline –2.0 –2.5 –3.0 –3.5 –4.0 Infusion *p<0.05, ***p=0.001 vs MTX Maini RN, et al. Arthritis Rheum 2006; 54:2817–2829.

16. Significant improvement in DAS28 score with tocilizumab ± MTX Weeks Baseline 4 8 12 16 0.0 MTX –0.5 TCZ 4 mg/kg * –1.0 * –1.5 * * Mean change from baseline –2.0 –2.5 –3.0 –3.5 –4.0 Infusion *p<0.05, ***p=0.001 vs MTX Maini RN, et al. Arthritis Rheum 2006; 54:2817–2829.

17. Significant improvement in DAS28 score with tocilizumab ± MTX Weeks Baseline 4 8 12 16 0.0 MTX –0.5 TCZ 4 mg/kg * TCZ 4 mg/kg + MTX –1.0 *** * –1.5 * * * Mean change from baseline –2.0 * * –2.5 –3.0 –3.5 –4.0 Infusion *p<0.05, ***p=0.001 vs MTX Maini RN, et al. Arthritis Rheum 2006; 54:2817–2829.

18. Significant improvement in DAS28 score with tocilizumab ± MTX Weeks Baseline 4 8 12 16 0.0 MTX –0.5 TCZ 4 mg/kg * TCZ 4 mg/kg + MTX –1.0 *** TCZ 8 mg/kg * –1.5 *** * * * Mean change from baseline –2.0 * *** * –2.5 *** –3.0 *** –3.5 –4.0 Infusion *p<0.05, ***p=0.001 vs MTX Maini RN, et al. Arthritis Rheum 2006; 54:2817–2829.

19. Significant improvement in DAS28 score with tocilizumab ± MTX Weeks Baseline 4 8 12 16 0.0 MTX –0.5 TCZ 4 mg/kg * TCZ 4 mg/kg + MTX –1.0 *** TCZ 8 mg/kg * –1.5 *** TCZ 8 mg/kg + MTX * * *** * Mean change from baseline –2.0 * *** * –2.5 *** –3.0 *** *** *** –3.5 *** –4.0 Infusion *p<0.05, ***p=0.001 vs MTX Maini RN, et al. Arthritis Rheum 2006; 54:2817–2829.

20. Adverse events (AEs) SAE = serious adverse event Maini RN, et al. Arthritis Rheum 2006; 54:2817–2829.

21. Most common SAEs SAE = serious adverse event Data on file.

22. TCZ 4 mg/kg TCZ 8 mg/kg TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX MTX Tocilizumab reduces CRP levels Treatment period 3.5 3.0 2.5 2.0 CRP (mg/dL) 1.5 1.0 0.5 ULN=0.3* 0.0 0 2 4 6 8 10 12 14 16 FU Week ULN = upper limit of normal FU = follow-up Maini RN, et al.Arthritis Rheum 2006; 54:2817–2829.*Myers GL et al.Circulation 2004;110:e545–e549.

23. TCZ 4 mg/kg TCZ 8 mg/kg TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX MTX Tocilizumab reduces ESR Treatment period 50 45 40 35 30 ULN=38*1 25 ESR (mm/hr) 20 15 10 5 0 0 2 4 6 8 10 12 14 16 FU Week *ULN = upper limit of normal for women < 60 FU = follow-up Data on file.1Wolfe F et al.J Rheumatol 1994; 21:1227–1237.

24. TCZ 4 mg/kg TCZ 8 mg/kg TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX MTX 10 0 2 4 6 8 10 12 14 16 FU Week Effect of tocilizumab on ALT 40 ULN = 40 U/L 30 ALT (U/L) 20 Treatment period ULN = upper limit of normal FU = follow-up Maini RN, et al. Arthritis Rheum 2006; 54:2817–2829.

25. TCZ 4 mg/kg TCZ 8 mg/kg TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX MTX Effect of tocilizumab on HDL 2.0 1.5 Mean HDL (mmol/L) 1.0 LLN = 1.04 mmol/L ~ 40 mg/dL Treatment period 0.5 0 2 4 6 8 10 12 14 16 FU Week LLN = lower limit of normal FU = follow-up Maini RN, et al. Arthritis Rheum 2006; 54:2817–2829.

26. TCZ 4 mg/kg TCZ 8 mg/kg TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX MTX Effect of tocilizumab on total cholesterol 8.0 300 6.0 200 4.0 Cholesterol (mmol/L) Cholesterol (mg/dL) ULN = 5.17 mmol/L (~ 200 mg/dL) 100 2.0 Treatment period 0.0 0 0 2 4 6 8 10 12 14 16 FU ULN = upper limit of normal FU = follow-up Maini RN, et al. Arthritis Rheum 2006; 54:2817–2829.

27. Consistent lipid changes with cytokine targeted therapy in RA TCZ 8 mg/kg + MTX1 Infliximab 3–5 mg/kg + DMARD2 Pooled anti-TNF3 250 200 ULN = 5.17 mmol/L (~ 200 mg/dL) 150 Cholesterol (mg/dL) 100 50 0 0 30 10 20 Week ULN = upper limit of normal 1.Maini RN, et al. Arthritis Rheum 2006; 54:2817–2829.2. Allonore Y et al. Clin Chim Acta 2006; 365:143–148.3. Seriolo B et al. Ann N Y Acad Sci 2006; 1069:414–419.

28. 45 40 35 30 25 20 15 10 5 0 Consistent lipid changes with cytokine targeted therapy in RA Change from baselinein total cholesterol Change in cholesterol (mg/dL) TCZ 8 mg/kg + MTX1 Infliximab2 Pooled anti-TNF3 1.Maini RN, et al. Arthritis Rheum 2006; 54:2817–2829.2. Allonore Y et al. Clin Chim Acta 2006; 365:143–148.3. Seriolo B et al. Ann N Y Acad Sci 2006; 1069:414–419.

29. Mean atherogenic index is unchanged with tocilizumab • Moderate but reversible increases in mean levels of: • Cholesterol • HDL • Triglycerides • Mean atherogenic index remained unchanged • Atherogenic index was below initial level by Week 20 in patients receiving 8 mg/kg TCZ ± MTX • Similar changes are seen with other biologics (anti-TNF-)

30. Effect of tocilizumab on neutrophil count TCZ 4 mg/kg TCZ 8 mg/kg TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX MTX 8.0 7.0 6.0 5.0 Neutrophil count (x109/L) 4.0 3.0 Treatment period 2.0 LLN = 1.8 x 109/L 1.0 0.0 2 4 6 8 10 12 14 16 FU 0 LLN = lower limit of normal FU = follow-up Week Maini RN, et al. Arthritis Rheum 2006; 54:2817–2829.

31. Safety summary • Overall incidence of AEs ~50% for all study groups • No dose-related pattern of occurrence • Low incidence of serious infections (no TB) • Transient elevations in liver enzymes • Serum lipids increased but atherogenic index was unchanged • Transient lowering of neutrophils – not associated with infections • Hypersensitivity reactions observed only with low-dose monotherapy

32. Conclusions • CHARISMA confirms the efficacy and safety of tocilizumab previously observed1,2 • Tocilizumab demonstrated significant benefit3 • As monotherapy (8 mg/kg) • In combination with MTX (4 and 8 mg/kg) • Tocilizumab is well tolerated in the majority of cases as monotherapy or in combination with MTX • Multicentre Phase III trials will provide further evidence for this approach 1. Nishimoto N, et al. Ann Rheum Dis 2007; 66:1162–1167. 2. Nishimoto N, et al. Ann Rheum Dis 2006; 65(Suppl II):59. 3. Maini RN, et al. Arthritis Rheum 2006; 54:2817–2829.

34. Acknowledgements