**2. Pharmacological properties**

#### **2.1 Pharmacodynamics**

Human IL-6 binds to human IL-6 R with a dissociation constant (Kd) of 5.5 nM, and this low affinity complex subsequently recruits a gp130 molecule to form a high-affinity complex (IL-6/IL-6R/gp130 ternary complex) with a Kd of 50 pM (Hibi et al, 1990). TCZ binds selectively and competitively to both soluble IL-6R (sIL-6R) and membrane bound IL-6R (mIL-6R) with a Kd of 0.71 nM and 2.54 nM, respectively (Japan Pharmacists Education Center, 2008; Mihara et al., 2005). TCZ suppressed the binding of IL-6 (10 ng/mL) to sIL-6R in a dose dependent manner at of a concentration between 0.002 and 4 µg/mL and completely inhibited at concentrations of > 4 µg/mL. Moreover, TCZ was able to dissociate IL-6/sIL-6R preformed complex which was made by mixing IL-6 (200 ng/mL) and sIL-6R (40 ng/mL). The percentage binding of IL-6 to sIL-6R fell in a TCZ concentration-dependent manner, and was less than 10% of the binding seen in the presence of TCZ at concentrations of > 1 µg/mL. On the other hand, the binding of TCZ to sIL-6R rose in a concentrationdependent manner and reached a plateau at 0.1 µg/mL (Mihara et al., 2005). *In vitro*, 100 µg/mL of TCZ completely inhibited cell growth of IL-6 dependent KT-3 cells in the presence of up to 0.32 ng/mL IL-6. Cell growth inhibition by TCZ was dose-dependently decreased

The Role of Tocilizumab in the Treatment of Rheumatoid Arthritis 53

43.6% of the patients achieved ACR20, ACR50, and ACR70 responses, respectively. Remission (the 28-joint disease activity score using erythrocyte sedimentation rate

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

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

TCZ DMARDs

MTX+

MTX+

MTX+

MTX+ placebo

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)

DMARDs+

arm Primary endpoint Dura-

at week 52

placebo ACR at week 24 24 w

placebo ACR at week 24 24 w

placebo ACR at week 24 24 w

placebo ACR at week 24 24 w

ACR at week 24; mTSS and HAQ at week 52 2 y

TCZ MTX ACR at week 24 24 w

ACR, DAS28ESR, mHAQ, and mTSS tion

52 w

(DAS28ESR) <2.6) was achieved in 55.3% of the patients.

Assessment Questionnaire (MHAQ) scores.

Population

refractory to DMARDs n=306

refractory to MTX n=125

refractory to anti-TNFs n=498

refractory to MTX n=623

refractory to DMARDs n=1220

MTX-naïve or MTX-free for ≥6

refractory to MTX n=1196

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

months n=673

**SAMURAI**  (Nishimoto et al., 2007)

**SATORI**  (Nishimoto et al., 2009b)

**RADIATE**  (Emery et al., 2008)

**OPTION**  (Smolen et al., 2008)

**TOWARD**  (Genovese et al., 2008)

**AMBITION**  (Jones et al., 2010)

**LITHE**  (Kremer et al., 2011)

receiving 4 mg/kg and 8 mg/kg of TCZ as monotherapy, respectively.

Size (n=) Subject Control

TCZ+ placebo

MTX+ TCZ

MTX+ TCZ

MTX+ TCZ

DMARDs+ TCZ

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 inhibited (Nishimoto et al., 2008).
