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From American Journal of Health-System Pharmacy

Tocilizumab: The First Interleukin-6-Receptor Inhibitor
Anthony Sebba, M.D.
Published: 10/10/2008
Abstract and Introduction

Abstract

Purpose: The pharmacology, pharmacokinetics, clinical efficacy, safety, and role of tocilizumab in rheumatoid
arthritis (RA) are reviewed.
Summary: Tocilizumab is a novel monoclonal antibody that competitively inhibits the binding of interleukin-6
(IL-6) to its receptor (IL-6R). Inhibiting the entire receptor complex prevents IL-6 signal transduction to
inflammatory mediators that summon B and T cells. Tocilizumab has a nonlinear pharmacokinetic profile. The
hypothesis that targeting and inhibiting IL-6R with tocilizumab can result in significant improvement of the signs
and symptoms of RA appears to have been substantiated in one Phase III and two Phase II clinical trials, which
have demonstrated a marked reduction in disease activity and the acute-phase response. The results of these
studies indicate that tocilizumab treatment, both as a combination with methotrexate and as monotherapy, has
a safety profile consistent with that of other biological and immunosuppressive therapies. In general,
tocilizumab as monotherapy and in combination with methotrexate appears to be well tolerated. Adverse
events were not dose dependent and were of similar frequency in all groups. Tocilizumab appears to provide
an additional option for those patients who do not respond sufficiently to methotrexate. Since IL-6R inhibition
has a distinct mechanism of action, some patients who do not respond to antitumor necrosis factor agents or
who have a partial response may respond to tocilizumab.
Conclusion: Tocilizumab, a novel IL-6R inhibitor, may be beneficial for the treatment of RA in patients who do
not respond to methotrexate or disease-modifying antirheumatic drugs. A large clinical trial is needed to confirm
tocilizumab's clinical efficacy and safety.

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease characterized clinically by bilateral symmetrical

inflammation of the small joints of the hands, feet, and other peripheral joints, with potential for joint
destruction.[1,2] RA is also associated with systemic symptoms such as fatigue, [3] heart disease,[4,5] anemia,[6] and
elevation of acute-phase reactants, such as C-reactive protein (CRP).[7] In the past decade, there have been
several therapeutic advances in the treatment of RA, as biological therapies targeting specific elements of the
immune response have become increasingly available ( Table 1 ).[14,15] Tocilizumab is a humanized anti-
interleukin-6-receptor (IL-6R) monoclonal antibody (mAb) that inhibits interleukin-6 (IL-6) signaling.[16] This new
biological agent is in clinical development for the treatment of inflammatory autoimmune diseases such as RA
and systemic onset juvenile idiopathic arthritis, in which IL-6 inhibition appears to provide both local and
systemic benefits.

Table 1.
Examples of Biological Response Modifiers in Rheumatoid Arthritis

This article reviews the concept of IL-6R inhibition with tocilizumab to acquaint pharmacists with the properties
of this new agent.

IL-6 in RA Pathogenesis

Cytokines have intricate signaling capabilities, with regulatory, chemotactic, and stimulatory effects on
surrounding cells.[17,18] Of the many cytokines present in rheumatoid synovium, proinflammatory cytokines
among them the interleukinsappear to be most directly linked to the disease process and play a critical role in
joint destruction. An example of this is tumor necrosis factor (TNF), which acts as a major cytokine in the
cytokine cascade and regulates the production of several other proinflammatory molecules, including
interleukin-1, IL-6, interleukin-9, interleukin-15, and granulocyte-macrophage colony-stimulating factor.
Modulation of TNF with anti-TNF agents has been shown to have a significant clinical effect in patients with RA.
Interestingly, as with hormones, some effects of cytokines occur at local sites and some at distant sites. IL-6 is
a cytokine associated with arthritis that appears also to have systemic effects, such as the hepatic production
of CRP.

IL-6 is produced by a variety of cell types in response to infection, trauma, and immunologic challenge. [19] IL-6
plays a prominent role in disease processes and has both proinflammatory and antiinflammatory characteristics
(Figure 1).[20,21] It promotes inflammatory events through the expansion and activation of T cells and the
differentiation of B cells. IL-6 has also demonstrated a protective role in disease processes. For example, in a
septic shock model, IL-6 protected mice against death by suppressing acute neutrophil accumulation caused
by intratracheal administration of endotoxin.[22] IL-6 produces many other effects throughout the human body,
both locally and systemically ( Table 2 ).[19]

Table 2.

Pleiotropic Effects of IL-619,a

Figure 1. Cells producing interleukin-6 (IL-6) and the actions of IL-6 in the body. Ig = immunoglobulin, CRP =
C-reactive protein, SAA = serum amyloid A protein. Reprinted, with permission, from reference 21.

Many laboratory test value abnormalities associated with RA have been linked to IL-6. For instance, severe RA
is commonly associated with thrombocytosis, hypergamma-globulinemia, and elevated erythrocyte
sedimentation rate (ESR) and CRP levels. Such abnormalities tend to rise in parallel with plasma and synovial
levels of IL-6.[23] Persistently elevated levels of CRP predict a very poor outcome for RA patients.[24] Systemic
and periarticular bone loss, common in severe disease, is highly correlated with IL-6 levels in bone marrow.[25,26]
Consistent with these data, therapeutic studies in which the effects of IL-6 are blocked have noted
improvements in clinical and laboratory variables.[16,27]

IL-6R Complex
Characterization of IL-6 allowed the identification of the structure and signaling function of IL-6R, which is
central to understanding how to develop an inhibitory pharmacotherapeutic agent. IL-6 binds to a specific IL-6R
and a signal transducer, called glycoprotein 130 (gp130),[27] which is expressed on the surface of most cells. IL-
6R exists in both membrane-bound and soluble forms; IL-6 can bind equally to both, and both types of
receptors can bind gp130.[28,29] Hence, cells that do not express the membrane-bound IL-6R can still respond to
IL-6 plus the soluble IL-6R through gp130, a mechanism known as transsignaling.

In order to signal, IL-6 and its receptors form a four-part complex at the cell surface that comprises IL-6, an IL-
6R, and two gp130 proteins. The signal is then transduced through several members of the Janus-activated
kinasesignal transducer and activator of transcription (JAK-STAT) pathway. The signal ultimately leads to the
transcription of genes with IL-6 response elements.[28,30] The most commonly known members of the JAK-STAT
pathway are the acute-phase proteins, which are a collection of macromolecules that flood the circulation
during certain inflammatory disorders; the best known acute-phase protein in RA is CRP.

Pharmacology

IL-6 signaling can be inhibited by suppressors of cytokine signaling, such as antibodies directed against IL-
6R.[16,21] Tocilizumab is a novel mAb therapy that competitively inhibits the binding of IL-6 to its receptor.
Inhibiting the entire receptor complex prevents IL-6 signal transduction to inflammatory mediators that summon
B and T cells.[21,29] Tocilizumab binds both to soluble and membrane-bound IL-6R.[27]

The tocilizumab molecule is a fusion of murine and human components. In order to minimize potential
immunogenic responses in human patients, tocilizumab was engineered by grafting the antigen-binding regions
of the murine antihuman IL-6R antibody to the human immunoglobulin G1 framework, which is associated with
complement fixation.[31] This humanized antibody is equivalent to the original murine antibody in terms of
antigen binding and inhibition of IL-6 functions. The altered antibody has a longer half-life in human serum than
do murine antibodies, with the half-life reached about 240 hours after the third dose of 8 mg tocilizumab per
kilogram of body weight in humans.[20] As long as free tocilizumab was detectable in the serum, serum levels of
CRP and the ESR remained normal, suggesting that IL-6 is associated with the production of these
inflammatory markers in vivo.

Pharmacokinetics

Tocilizumab has a nonlinear pharmacokinetic profile.[20] The maximum concentration increases in approximate
proportion to increases in dosage, whereas the area under the concentration-time curve increases
disproportionately. As the dosage increases, clearance and the apparent elimination rate constant decrease
and terminal half-life and mean residence times are prolonged. Methotrexate therapy, alcohol consumption,
age, and race have not been found to affect tocilizumab's pharmacokinetics. Tocilizumab binds to soluble IL-6R
in a dose-dependent manner and saturates the receptor at approximately 0.1 g/mL. Tocilizumab also
competitively inhibits IL-6 binding to soluble IL-6R; complete inhibition is seen at approximately 4 g/mL.[32]

The relatively slow clearance of tocilizumab and the decrease in clearance with dosage elevation are
consistent with the possibility of a capacity-limited process for the elimination of this drug. Measurable levels
increase with sequential infusions. In clinical trials, the agent has been administered intravenously once every
four weeks.[33]

Clinical Efficacy
Two Phase II studies and one Phase III study have been conducted with tocilizumab to date. The primary
endpoint for many trials of drugs to treat RA is a 20% improvement in the majority of a set of disease criteria
defined by the American College of Rheumatology (i.e., the ACR20 response).[34] Similarly, a 50% or 70%
improvement in these criteria is defined as the ACR50 or ACR70 response.

In a placebo-controlled study, Japanese patients with RA of less than five years of duration (n = 162) were
given tocilizumab 4- or 8-mg/ kg i.v. infusions every four weeks for three months, with the final assessment four
weeks after the third infusion.[20] Treatment with tocilizumab was generally well tolerated, and the results of the
study showed significantly higher ACR20, ACR50, and ACR70 response rates with to-cilizumab compared with
placebo ( Table 3 ). A clear dose response was evident at four weeks, as was evidence of reduced joint
damage progression. As would be suggested from the known association between IL-6 and CRP, CRP was
normalized by 76% and 26% in the 8- and 4-mg/kg groups, respectively.

Table 3.

Treatment Response with Tocilizumab Versus Placebo in Patients with Rheumatoid Arthritis According to the
American College of Rheumatology (ACR) Criteria[20]

A Phase II, double-blind trial was conducted with 359 European patients who had active RA despite
methotrexate therapy (the European Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization,
Management, and Avoidance [CHARISMA] study).[33] Participants received a stable dosage of methotrexate for
at least four weeks and were then randomized to one of seven treatment groups: tocilizumab at doses of 2, 4,
or 8 mg/kg as monotherapy and in combination with methotrexate and methotrexate plus placebo. The baseline
disease activity score in 28 joints (DAS28) indicated a high level of disease activity in these patients. The
efficacy of 2 mg/ kg tocilizumab as monotherapy was similar to that of methotrexate plus placebo. The best
results for monotherapy were seen with tocilizumab 8 mg/kg, with a 63% ACR20 response, a 41% ACR50
response, and a 16% ACR70 response; however, when tocilizumab was combined with methotrexate, the ACR
responses improved (74%, 53%, and 37%, respectively), approximately twice the responses seen with
methotrexate plus placebo. In the tocilizumab 8-mg/kg monotherapy and the tocilizumab plus methotrexate
groups, there may have been a sustained effect, as the DAS28 did not plateau by the end of the study.
Alterations in the inflammatory response were reflected in the decrease in CRP levels, which was also seen in
the study previously described.[20]

The Study of Active Controlled Monotherapy Used for Rheumatoid Arthritis, An IL-6 Inhibitor (SAMURAI), a
Phase III study, compared the effects of tocilizumab 8 mg/kg with conventional disease-modifying
antirheumatic drugs (DMARDs) on the progression of structural and joint damage over 52 weeks of
treatment.[35] Progression was measured using radiographs scored with the van der Heijde modified Total Sharp
Score (TSS) method. Participants in the trial (n = 306) had active RA for a mean duration of 2.3 years, a TSS of
29.4, and a DAS28 of 6.5 at baseline. After treatment, markers of disease activity were reduced: joint spaces
had narrowed less, the mean change in TSS was lower (2.3 versus 6.1), the mean DAS28 was reduced to
about 2.3 (a DAS28 of <2.6 is often considered an indicator of remission), and ACR20, ACR50 and ACR70
responses significantly improved in the tocilizumab group compared with the DMARD group. Hence, it appears
that tocilizumab also has a benefit for patients in terms of radiographic progression of disease.

Use in Other Autoimmune Diseases

Elevated serum levels of IL-6 are also implicated in the pathogenesis of other autoimmune diseases.[36]
Consistent with findings in adult RA, participants with systemic onset juvenile idiopathic arthritis treated with
tocilizumab in an open-label Phase II trial (n = 18) achieved clinical improvements in disease activity (ACR30,
ACR50, and ACR70 responses), reduced CRP levels, and improved quality of life.[37] Likewise, participants in a
trial examining the effect of tocilizumab on systemic lupus erythematosus for 12 weeks (n = 15) showed
decreases in swollen joint counts, CRP levels, and antinuclear antibody levels.[38]

Early clinical studies in RA have demonstrated that tocilizumab is effective as a monotherapy and that the
efficacy is further amplified with the concurrent use of methotrexate. The results of Phase III studies examining
tocilizumab as both monotherapy and concomitant therapy in different populations of patients with inadequate
responses to their current treatment are forthcoming.[39,40]

Safety

In general, tocilizumab as mono-therapy and in combination with methotrexate appears to be well tolerated.
Adverse events were not dose dependent and were of similar frequency in all groups.[33,39,40] Liver function
changes and neutropenia were observed but were mild and transient. The hepatic effects of tocilizumab are
consistent with the systemic effects of IL-6.

Modulation of the immune system can lead to an increased risk of infections, as has been observed with TNF-
blocking therapies.[41] The most frequent adverse events seen in tocilizumab studies are upper- respiratory-tract
infections, headache, nasopharyngitis, and gastrointestinal events.[39] However, infections did not correlate with
neutrophil count in the European CHARISMA trial.[33]

RA is an independent risk factor for increased coronary artery disease (CAD), potentially due to high levels of
markers of systemic inflammation (e.g., IL-6, CRP), as well as being associated with an adverse lipid profile.
However, this profile improves considerably after effective RA treatment, an improvement that may reduce the
risk of CAD in patients with RA.[42] IL-6 has also been reported to affect lipid metabolism. Mice lacking the IL-6
gene developed an adult-onset obesity that was partially reversible with the reintroduction of IL-6.[43] It is
therefore important to examine the levels of atherogenic lipids in patients with RA, changes in which may lead
to a cardiovascular event. An increase of approximately 30% in cholesterol and triglycerides was observed in
one Phase II study;[31] though a moderate increase in these markers was also seen, the atherogenic index (total
cholesterol/high-density lipoprotein) in the European CHARISMA and SAMURAI trials was essentially
unchanged[31,33,35] and no cardiovascular events were reported.[31,35] With time, elevated lipid levels returned to
normal.[44]

Because tocilizumab is a humanized antibody, infusion-related adverse events might be expected. In the
European CHARISMA study, five severe hypersensitivity reactions were observed, but these were seen
exclusively in the low-dose (2 mg/kg) tocilizumab monotherapy study groups.[45] The generation of antinuclear
antibodies is occasionally reported in association with anti-TNF use. Antitocilizumab antibodies were detected
in four patients in the SAMURAI trial[35] (one patient developed a skin reaction, the other three remained
asymptomatic), but these antibodies were not detected in patients in the European CHARISMA study.[33]

Future Role in RA Therapy

IL-6 is an important proinflammatory cytokine that is integral to the pathogenesis of RA and other autoimmune
diseases. The hypothesis that targeting and inhibiting IL-6R with tocilizumab can result in significant
improvement of the signs and symptoms of RA appears to have been substantiated in clinical trials, which have
demonstrated a marked reduction in disease activity and acute-phase response. When combined with
methotrexate and as monotherapy, tocilizumab appears to provide an additional option for those patients who
do not respond sufficiently to methotrexate. Since IL-6R inhibition has a distinct mechanism of action, some
patients who do not respond to anti-TNF agents or who respond partially may be expected to respond to
tocilizumab. Large-scale Phase III studies are ongoing to confirm reported clinical efficacy and to evaluate the
safety profile.

Conclusion

Tocilizumab, a novel IL-6R inhibitor, may be beneficial for the treatment of RA in patients who do not respond
to methotrexate or DMARDs. A large clinical trial is needed to confirm tocilizumab's efficacy and safety.

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Authors and Disclosures

Anthony Sebba, M.D., is Assistant Clinical Professor, University of South Florida, 36338 U.S. Highway 19
North, Palm Harbor, FL 34684-1528 ( sebba@tampabay.rr.com ).

Disclosure: Dr. Sebba has received financial support in the form of research grants and lecture honoraria from
Hoffmann-La Roche Inc.

American Journal of Health-System Pharmacy. 2008;65(15):1413-1418. 2008 American Society of Health-System Pharmacists

Pleiotropic Effects of IL-619,a