Tocilizumab: The first interleukin-6-receptor inhibitor

Rheumatoid arthritis (RA) is an autoimmune disease character- ized 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 associ- ated 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 thera- pies 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) signal- ing.16 This new biological agent is in clinical development for the treat- ment 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.

Purpose. The pharmacology, pharmacoki- netics, clinical efficacy, safety, and role of tocilizumab in rheumatoid arthritis (RA) are reviewed.

Summary. Tocilizumab is a novel monoclo- nal antibody that competitively inhibits the binding of interleukin-6 (IL-6) to its recep- tor (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 im- provement of the signs and symptoms of RA appears to have been substanti- ated 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 immunosuppresing capabilities, with regulatory, chemotactic, and stimulatory effects on surrounding cells.17,18 Of the many cytokines present in rheumatoid syn- ovium, proinflammatory cytokines— among them the interleukins— appear to be most directly linked to the disease process and play a critical role in joint destruction. An example of this is tumor necrosissive therapies. In general, tocilizumab as monotherapy and in combination with methotrexate appears to be well tolerat- ed. Adverse events were not dose depen- dent and were of similar frequency in all groups. Tocilizumab appears to provide an additional option for those patients who do not respond sufficiently to methotrex- ate. Since IL-6R inhibition has a distinct mechanism of action, some patients who do not respond to antitumor necrosis fac- tor agents or who have a partial response may respond to tocilizumab.

Conclusion. Tocilizumab, a novel IL-6R inhibitor, may be beneficial for the treat- ment 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.

IL-6 is produced by a variety of cell types in response to infection, trauma, and immunologic chal- lenge.19 IL-6 plays a prominent role in disease processes and has both proinflammatory and antiinflam- matory characteristics (Figure 1).20,21 It promotes inflammatory events through the expansion and activa- tion 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 intratra- cheal administration of endotoxin.22 IL-6 produces many other effects throughout the human body, both locally and systemically (Table 2).19

Many laboratory test value ab- normalities associated with RA have been linked to IL-6. For instance, severe RA is commonly associated with thrombocytosis, hypergamma- globulinemia, and elevated erythro- cyte 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 labora- tory 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 de- velop an inhibitory pharmacothera- peutic 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 re- spond 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 pro- teins. The signal is then transduced through several members of the Janus-activated kinase—signal trans- ducer and activator of transcription (JAK-STAT) pathway. The signal ul- timately leads to the transcription of genes with IL-6 response elements.28,30 The most commonly known mem- bers of the JAK-STAT pathway are the acute-phase proteins, which are a col- lection of macromolecules that flood the circulation during certain inflam- matory 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 re- ceptor. Inhibiting the entire receptor complex prevents IL-6 signal trans- duction to inflammatory mediators that summon B and T cells.21,29 To- cilizumab binds both to soluble and membrane-bound IL-6R.27
The tocilizumab molecule is a fu- sion of murine and human compo- nents. 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 im- munoglobulin G1 framework, which is associated with complement fixa- tion.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, suggest- ing that IL-6 is associated with the production of these inflammatory markers in vivo.

Pharmacokinetics

Tocilizumab has a nonlinear pharmacokinetic profile.20 The maxi- mum concentration increases in ap- proximate 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 resi- dence times are prolonged. Metho- trexate therapy, alcohol consumption, age, and race have not been found to affect tocilizumab’s pharmacokinet- ics. 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. Measur- able 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 prima- ry 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 re- sponse).34 Similarly, a 50% or 70% im- provement 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 as- sessment four weeks after the third infusion.20 Treatment with tocili- zumab 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 evi- dence of reduced joint damage pro- gression. 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.

A Phase II, double-blind trial was conducted with 359 European patients who had active RA despite methotrexate therapy (the European Clopidogrel for High Atherothrom- botic Risk and Ischemic Stabiliza- tion, Management, and Avoidance [CHARISMA] study).33 Participants received a stable dosage of metho- trexate 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 mono- therapy 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 mono- therapy 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 im- proved (74%, 53%, and 37%, respec- tively), approximately twice the re- sponses 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 inflam- matory 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 Rheuma- toid Arthritis, An IL-6 Inhibitor (SAMURAI), a Phase III study, com- pared 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 nar- rowed 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 signif- icantly improved in the tocilizumab group compared with the DMARD group. Hence, it appears that toci- lizumab 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 pathogen- esis 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 clini- cal improvements in disease activ- ity (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 lu- pus 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 ef- fective 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 dif- ferent 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 sys- tem 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 gastroin- testinal 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 as- sociated with an adverse lipid profile. However, this profile improves con- siderably 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 lipopro- tein) in the European CHARISMA and SAMURAI trials was essentially unchanged31,33,35 and no cardiovas- cular events were reported.31,35 With time, elevated lipid levels returned to normal.44

Because tocilizumab is a humanized antibody, infusion-related ad- verse events might be expected. In the European CHARISMA study, five severe hypersensitivity reactions were observed, but these were seen exclu- sively in the low-dose (2 mg/kg) tocili- zumab monotherapy study groups.45 The generation of antinuclear an- tibodies is occasionally reported in association with anti-TNF use. Anti- tocilizumab antibodies were detected in four patients in the SAMURAI trial35 (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 hypoth- esis 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 clini- cal trials, which have demonstrated a marked reduction in disease activ- ity 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 mech- anism 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 on- going to confirm reported clinical efficacy and to evaluate the safety profile.

Conclusion

Tocilizumab, a novel IL-6R in- hibitor, 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 ef- ficacy and safety.