**3.1 Clinical studies**

In a 12-week, multicenter, randomized, double-blind, placebo-controlled phase I/II study, 164 Japanese patients with refractory RA were randomly administered either placebo, or 4 mg/kg or 8 mg/kg TCZ (Nishimoto et al., 2004). A dose-dependent reduction in the American College of Rheumatology (ACR) 20 response was observed. At 3 months, 78% of patients in the 8 mg/kg group, 57% in the 4 mg/kg group, and 11% in the placebo group achieved an ACR20 response. This study was extended to evaluate the long-term efficacy and safety of TCZ 8 mg/kg monotherapy for five years and designated STREAM (long-term Safety and efficacy of Tocilizumab, an anti-interleukin-6 REceptor monoclonal Antibody, in Monotherapy, in patients with rheumatoid arthritis) (Nishimoto et al., 2009a). A total 143 patients were enrolled, and 94 patients completed 5 years. At 5 years, 84.0%, 69.1%, and

by IL-6 at concentrations of > 0.32 ng/mL, and no inhibition of cell growth by TCZ was observed in the presence of 1 µg/mL IL-6 (Australian Government, 2011). *In vivo*, serum levels of IL-6 and sIL-6R markedly increased after TCZ treatment in patients with RA. While free TCZ concentration remains 1 µg/mL or more, serum C-reactive protein (CRP) is normalized, indicating that sIL-6R is saturated with TCZ and IL-6 signaling is completely

PK data were based on a population PK analysis of 1793 patients with RA who received a 1 hour infusion of TCZ 8mg/kg every 4 weeks for 24 weeks (Frey et al., 2010). The t 1/2 of TCZ was concentration-dependent. The effective t 1/2 decreased with decreasing concentrations of TCZ within a dosing interval from 14 days to 8 days. After administration of TCZ, the predicted steady-state the mean area under the concentration-time curve (AUC), maximum concentration (Cmax), the steady-state volume of distribution, and the trough concentration (Cmin) values were 35.0 mg·h/mL, 183 µg/mL, 6.4 L, and 9.7 µg/mL, respectively. The Cmin value is 91 fold higher that the Kd of TCZ for the binding at the sIL-6R (Kd is 0.71 nM = 0.10 µg/ml). Therefore, IL-6R was completely occupied even at the end of each 8 mg/kg dosing interval in most of the patients. Age, gender and ethnicity did not affect the PK of TCZ. TCZ is not excreted via the renal or biliary route. Instead, TCZ is predominantly eliminated via catabolism including degradation in plasma and distribution to tissues. TCZ undergoes biphasic elimination from the circulation. Total clearance is concentration dependent and includes linear at higher TCZ concentrations and non-linear clearance at low TCZ concentration. No formal studies on the effect of renal or hepatic impairment on the PK of TCZ have been conducted. Mild renal impairment (creatinine clearance based on Cockcroft-

Nor is the clearance of TCZ affected by concomitant use of methotrexate (MTX), nonsteroidal anti-inflammatory drugs (NSAIDs), or corticosteroids. TCZ may normalize the expression of hepatic cytochrome P450 (CYP) isozymes which are suppressed by IL-6 (Oldfield et al., 2009). Therefore, administration or discontinuation of TCZ may affect the serum concentrations of drugs metabolized via CYP3A4, CYP1A2, CYP2C9 or CYP2C19 (e.g., omeprazole, dextromethorphan, atorvastatin, simvastatin, calcium channel blockers,

In a 12-week, multicenter, randomized, double-blind, placebo-controlled phase I/II study, 164 Japanese patients with refractory RA were randomly administered either placebo, or 4 mg/kg or 8 mg/kg TCZ (Nishimoto et al., 2004). A dose-dependent reduction in the American College of Rheumatology (ACR) 20 response was observed. At 3 months, 78% of patients in the 8 mg/kg group, 57% in the 4 mg/kg group, and 11% in the placebo group achieved an ACR20 response. This study was extended to evaluate the long-term efficacy and safety of TCZ 8 mg/kg monotherapy for five years and designated STREAM (long-term Safety and efficacy of Tocilizumab, an anti-interleukin-6 REceptor monoclonal Antibody, in Monotherapy, in patients with rheumatoid arthritis) (Nishimoto et al., 2009a). A total 143 patients were enrolled, and 94 patients completed 5 years. At 5 years, 84.0%, 69.1%, and

Gault < 80 ml/min and ≥ 50 ml/min) did not affect the PK of TCZ.

inhibited (Nishimoto et al., 2008).

**2.2 Pharmacokinetic properties** 

cyclosporine, and warfarin).

**3. Therapeutic efficacy** 

**3.1 Clinical studies** 

43.6% of the patients achieved ACR20, ACR50, and ACR70 responses, respectively. Remission (the 28-joint disease activity score using erythrocyte sedimentation rate (DAS28ESR) <2.6) was achieved in 55.3% of the patients.

The CHARISMA (the Chugai Humanized Anti-human Recombinant Interleukin-Six Monoclonal Antibody) study was a 16-week, multicenter, randomized, double-blind, placebo-controlled phase II trial in 359 European patients in whom the response to MTX was inadequate (Maini et al., 2006). ACR20 response was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of TCZ as monotherapy, respectively.

There are seven phase III studies (Table 1). SAMURAI (Study of Active controlled Monotherapy Used for Rheumatoid Arthritis, an Interleukin-6 inhibitor) was a randomized, 52-week, multicenter, x-ray reader-blinded, controlled phase III trial to evaluate the ability of TCZ monotherapy to inhibit progression of structural joint damage in patients with RA of <5 years' duration (Nishimoto et al., 2007). A total 306 Japanese patients were randomly assigned to two groups: (i) TCZ 8 mg/kg (n = 158) and (ii) conventional disease-modifying anti-rheumatic drug (DMARD) therapy (n = 148). At week 52, the TCZ group showed statistically less radiographic change in modified Total Sharp Score (mTSS) (mean 2.3) than the DMARD group (mean 6.1). The TCZ group also showed significantly better results than the DMARD group in ACR20, 50, and 70 responses, DAS28ESR, and Modified Health Assessment Questionnaire (MHAQ) scores.


Table 1. Phase III trials of TCZ in patients with RA

SATORI (Study of Active controlled Tocilizumab mOnotherapy for Rheumatoid arthritis patients with an Inadequate response to metotrexate) was a 24-week, multicenter, randomized, double-blind, placebo-controlled phase III trial in patients with RA in whom the response to MTX was inadequate (Nishimoto et al., 2009b). A total 125 Japanese patients were randomly assigned to one of two groups: (i) TCZ 8 mg/kg plus MTX placebo (n = 61)

The Role of Tocilizumab in the Treatment of Rheumatoid Arthritis 55

compared with MTX (weighted difference between treatments: 0.12 for ACR50 (95% confidence interval (CI) 0.04 to 0.20; p = 0.002); and 0.14 for ACR70 (95% CI 0.07 to 0.22; p<0.001). The superiority of TCZ to MTX was also shown in improvement of HAQ-DI at week 24. No significant difference was seen in the incidence of serious adverse events between TCZ

LITHE (tociLIzumab safety and THE prevention of structural joint damage) is a 2 (or 3) year, multicenter, randomized, double-blind, placebo-controlled phase III trial evaluating the ability of TCZ add-on therapy to inhibit progression of structural joint damage and improve physical function in patients with moderate to severe RA who respond inadequately to MTX. A total of 1196 patients from 14 countries were randomly assigned to three groups: (i) placebo plus MTX (n = 393), (ii) TCZ 4 mg/kg plus MTX (n = 399), and (iii) TCZ 8 mg/kg plus MTX (n = 398). Results from year 1 were reported (Kremer et al., 2011). Mean change in the total Genant-modified Sharp score was 0.29 and 0.34 with TCZ 8 mg/kg plus MTX and 4 mg/kg plus MTX, respectively, versus 1.13 with placebo plus MTX (P <0.0001). Additionally, the HAQ-DI significantly decreased in the groups of TCZ (8 mg/kg

and 4 mg/kg) add-on treatment compared with the group with placebo plus MTX.

MTX has the highest efficacy among conventional DMARDs and has been used as an anchor drug in the treatment of RA. The AMBITION study and the SATORI study demonstrated that TCZ monotherapy is superior to MTX monotherapy. Several studies have demonstrated that MTX monotherapy is equivalent or superior to TNF inhibitor monotherapy (Donahue et al., 2008). Comparison of TCZ with abatacept demonstrated that the rate of withdrawal due to no effect in TCZ treatment was lower than that in abatacept treatment (Leffers et al., 2011). A meta-analysis revealed that the effectiveness of TCZ appeared to be greater for ACR70 (Bergman et al., 2010). Thus, TCZ is superior to MTX, TNF inhibitors, and abatacept in the case of monotherapy. The superiority between TCZ monotherapy and TCZ plus MTX treatment has not yet been established. Yamanaka et al. (2011) reported that the improvement of DAS28ESR and HAQ-DI in TCZ plus MTX treatment was better than that in TCZ monotherapy. Nakashima et al. (2010) reported that there was no significant difference in the improvement of DAS28ESR between TCZ monotherapy and TCZ plus MTX treatment. Data from the ACT-RAY study demonstrated that TCZ provided clinical benefit, regardless of whether it was given in combination with MTX or as a monotherapy

Infections are the most frequent adverse events during therapy with TCZ and other biologics or DMARDs. In the AMBITION study, TCZ monotherapy was compared with MTX monotherapy (Jones et al., 2010). Infection rates per patient year were similar (TCZ 1.06 vs MTX 1.09). In both groups, nasopharyngitis and upper respiratory tract infection were common. The common serious infections were pneumonia. Neither opportunistic infections nor tuberculosis were reported in the patients receiving TCZ. Similar results were observed in a meta-analysis of TCZ monotherapy in Japanese patients (Nishimoto et al., 2010). Long-term exposure did not increase the incidence of serious infections. TCZ may not

treatment (3.8%) and MTX treatment (2.8%) (p = 0.50).

**3.2 Additional remarks** 

(Dougados et al., 2011).

**4. Safety and tolerability** 

and (ii) TCZ placebo plus MTX (n = 66). At week 24, 25.0% in the MTX group and 80.3% in the TCZ group achieved ACR20 response. Additionally, serum vascular endothelial growth factor (VEGF) levels were signicantly decreased by TCZ treatment, but not by MTX treatment.

RADIATE (Research on Actemra Determining effIcacy after Anti-TNF failurEs) was a 24 week, multicenter, randomized, double-blind, placebo-controlled, parallel-group phase III trial to evaluate the efficacy and safety of TCZ in patients with active RA refractory to TNF antagonist therapy (Emery et al., 2008). A total 498 US and Western Europe patients were randomly assigned to three groups: (i) TCZ 8 mg/kg plus MTX (n = 175), (ii) TCZ 4 mg/kg (n = 163) plus MTX, and (iii) TCZ placebo plus MTX (n = 160). ACR20 was achieved at 24 weeks by 50.0%, 30.4% and 10.1% of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively. Patients responded regardless of most recently failed anti-TNF or the number of failed treatments.

OPTION (tOcilizumab Pivotal Trial in methotrexate Inadequate respONders) was a 24 week, multicenter, randomized, double-blind, placebo-controlled phase III trial in patients with active RA in whom the response to MTX was inadequate (Smolen et al., 2008). A total 623 patients from 17 countries were randomly assigned to three groups: (i) TCZ 8 mg/kg plus MTX (n = 205), (ii) TCZ 4 mg/kg (n = 214) plus MTX, and (iii) placebo plus MTX (n = 204). ACR20 achieved at 24 weeks by 59%, 48%, and 26% of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively. Signicantly greater numbers of patients receiving TCZ showed ACR50/ACR70 responses or clinical remission (DAS28ESR <2.6) at week 24 than did those receiving placebo. In patients receiving TCZ, there were greater improvements in HAQ-DI score, the Short-Form 36 Health Survey (SF-36), and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue assessment indicating that TCZ treatment significantly improves physical and mental function.

TOWARD (Tocilizumab in cOmbination With traditional DMARD therapy) was a 24-week, multicenter, randomized, double-blind, placebo-controlled phase III trial to evaluate the efficacy and safety of TCZ combined with conventional DMARDs in patients with active RA (Genovese et al., 2008). A total 1220 patients from 18 countries were randomly assigned to two groups: (i) TCZ 8 mg/kg plus DMARD (n = 805) and (ii) TCZ placebo plus DMARD therapy (n = 415). ACR20 achieved at 24 weeks 61% for TCZ 8 mg/kg versus 25% for placebo. Similar to the results of OPTION, the TCZ group showed significantly better results than the placebo group in ACR50/ACR70 response, clinical remission rate (DAS28ESR <2.6), HAQ-DI, SF-36 and FACIT-Fatigue assessment.

AMBITION (Actemra versus Methotrexate double-Blind Investigative Trial In mONotherapy) was a 24-week, multicenter, randomized, double-blind, double-dummy, placebo-controlled phase III trial evaluating the efficacy and safety of TCZ monotherapy versus MTX in patients with active RA (Jones et al., 2010). A total of 673 patients from the US, Canada, and Israel were randomly assigned to three groups: (i) MTX (escalating dose regimen: initial dose 7.5 mg/week, increasing to 15 mg/week at week 4 and 20 mg/week at week 8) for 24 weeks (n = 284), (ii) TCZ 8 mg/kg for 24 weeks (n = 288), and (iii) TCZ placebo for 8 weeks then TCZ 8 mg/kg for 16 weeks (n = 101). The intention-to-treat analysis demonstrated that TCZ was better than MTX treatment with a higher ACR20 response (69.9 vs 52.5%; p<0.001) and rate of DAS28ESR <2.6 (33.6 vs 12.1%) at week 24. The superiority of TCZ to MTX was observed in the intention-to-treat population from week 2 and throughout this study. The proportion of ACR50 (44%) and ACR70 (28%) responders at week 24 was also statistically superior for TCZ compared with MTX (weighted difference between treatments: 0.12 for ACR50 (95% confidence interval (CI) 0.04 to 0.20; p = 0.002); and 0.14 for ACR70 (95% CI 0.07 to 0.22; p<0.001). The superiority of TCZ to MTX was also shown in improvement of HAQ-DI at week 24. No significant difference was seen in the incidence of serious adverse events between TCZ treatment (3.8%) and MTX treatment (2.8%) (p = 0.50).

LITHE (tociLIzumab safety and THE prevention of structural joint damage) is a 2 (or 3) year, multicenter, randomized, double-blind, placebo-controlled phase III trial evaluating the ability of TCZ add-on therapy to inhibit progression of structural joint damage and improve physical function in patients with moderate to severe RA who respond inadequately to MTX. A total of 1196 patients from 14 countries were randomly assigned to three groups: (i) placebo plus MTX (n = 393), (ii) TCZ 4 mg/kg plus MTX (n = 399), and (iii) TCZ 8 mg/kg plus MTX (n = 398). Results from year 1 were reported (Kremer et al., 2011). Mean change in the total Genant-modified Sharp score was 0.29 and 0.34 with TCZ 8 mg/kg plus MTX and 4 mg/kg plus MTX, respectively, versus 1.13 with placebo plus MTX (P <0.0001). Additionally, the HAQ-DI significantly decreased in the groups of TCZ (8 mg/kg and 4 mg/kg) add-on treatment compared with the group with placebo plus MTX.

#### **3.2 Additional remarks**

54 Rheumatoid Arthritis – Treatment

and (ii) TCZ placebo plus MTX (n = 66). At week 24, 25.0% in the MTX group and 80.3% in the TCZ group achieved ACR20 response. Additionally, serum vascular endothelial growth factor (VEGF) levels were signicantly decreased by TCZ treatment, but not by MTX

RADIATE (Research on Actemra Determining effIcacy after Anti-TNF failurEs) was a 24 week, multicenter, randomized, double-blind, placebo-controlled, parallel-group phase III trial to evaluate the efficacy and safety of TCZ in patients with active RA refractory to TNF antagonist therapy (Emery et al., 2008). A total 498 US and Western Europe patients were randomly assigned to three groups: (i) TCZ 8 mg/kg plus MTX (n = 175), (ii) TCZ 4 mg/kg (n = 163) plus MTX, and (iii) TCZ placebo plus MTX (n = 160). ACR20 was achieved at 24 weeks by 50.0%, 30.4% and 10.1% of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively. Patients responded regardless of most recently failed anti-TNF or the number

OPTION (tOcilizumab Pivotal Trial in methotrexate Inadequate respONders) was a 24 week, multicenter, randomized, double-blind, placebo-controlled phase III trial in patients with active RA in whom the response to MTX was inadequate (Smolen et al., 2008). A total 623 patients from 17 countries were randomly assigned to three groups: (i) TCZ 8 mg/kg plus MTX (n = 205), (ii) TCZ 4 mg/kg (n = 214) plus MTX, and (iii) placebo plus MTX (n = 204). ACR20 achieved at 24 weeks by 59%, 48%, and 26% of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively. Signicantly greater numbers of patients receiving TCZ showed ACR50/ACR70 responses or clinical remission (DAS28ESR <2.6) at week 24 than did those receiving placebo. In patients receiving TCZ, there were greater improvements in HAQ-DI score, the Short-Form 36 Health Survey (SF-36), and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue assessment indicating that TCZ

TOWARD (Tocilizumab in cOmbination With traditional DMARD therapy) was a 24-week, multicenter, randomized, double-blind, placebo-controlled phase III trial to evaluate the efficacy and safety of TCZ combined with conventional DMARDs in patients with active RA (Genovese et al., 2008). A total 1220 patients from 18 countries were randomly assigned to two groups: (i) TCZ 8 mg/kg plus DMARD (n = 805) and (ii) TCZ placebo plus DMARD therapy (n = 415). ACR20 achieved at 24 weeks 61% for TCZ 8 mg/kg versus 25% for placebo. Similar to the results of OPTION, the TCZ group showed significantly better results than the placebo group in ACR50/ACR70 response, clinical remission rate (DAS28ESR

AMBITION (Actemra versus Methotrexate double-Blind Investigative Trial In mONotherapy) was a 24-week, multicenter, randomized, double-blind, double-dummy, placebo-controlled phase III trial evaluating the efficacy and safety of TCZ monotherapy versus MTX in patients with active RA (Jones et al., 2010). A total of 673 patients from the US, Canada, and Israel were randomly assigned to three groups: (i) MTX (escalating dose regimen: initial dose 7.5 mg/week, increasing to 15 mg/week at week 4 and 20 mg/week at week 8) for 24 weeks (n = 284), (ii) TCZ 8 mg/kg for 24 weeks (n = 288), and (iii) TCZ placebo for 8 weeks then TCZ 8 mg/kg for 16 weeks (n = 101). The intention-to-treat analysis demonstrated that TCZ was better than MTX treatment with a higher ACR20 response (69.9 vs 52.5%; p<0.001) and rate of DAS28ESR <2.6 (33.6 vs 12.1%) at week 24. The superiority of TCZ to MTX was observed in the intention-to-treat population from week 2 and throughout this study. The proportion of ACR50 (44%) and ACR70 (28%) responders at week 24 was also statistically superior for TCZ

treatment significantly improves physical and mental function.

<2.6), HAQ-DI, SF-36 and FACIT-Fatigue assessment.

treatment.

of failed treatments.

MTX has the highest efficacy among conventional DMARDs and has been used as an anchor drug in the treatment of RA. The AMBITION study and the SATORI study demonstrated that TCZ monotherapy is superior to MTX monotherapy. Several studies have demonstrated that MTX monotherapy is equivalent or superior to TNF inhibitor monotherapy (Donahue et al., 2008). Comparison of TCZ with abatacept demonstrated that the rate of withdrawal due to no effect in TCZ treatment was lower than that in abatacept treatment (Leffers et al., 2011). A meta-analysis revealed that the effectiveness of TCZ appeared to be greater for ACR70 (Bergman et al., 2010). Thus, TCZ is superior to MTX, TNF inhibitors, and abatacept in the case of monotherapy. The superiority between TCZ monotherapy and TCZ plus MTX treatment has not yet been established. Yamanaka et al. (2011) reported that the improvement of DAS28ESR and HAQ-DI in TCZ plus MTX treatment was better than that in TCZ monotherapy. Nakashima et al. (2010) reported that there was no significant difference in the improvement of DAS28ESR between TCZ monotherapy and TCZ plus MTX treatment. Data from the ACT-RAY study demonstrated that TCZ provided clinical benefit, regardless of whether it was given in combination with MTX or as a monotherapy (Dougados et al., 2011).
