Living Medical eTextbook

Tocilizumab: interleukin-6 receptor inhibitor

Interleukin-6 (IL-6) is a pleiotropic cytokine produced by several different cell types, including lymphocytes, monocytes, and fibroblasts.¹¹ The multifactorial involvement of IL-6 in the pathogenesis of RA includes promotion of autoantibody formation due to B-cell differentiation,¹² T-cell activation, overactive hematopoietic cell growth, and osteoclast differentiation, which leads to joint deterioration.¹¹ Because elevated levels of IL-6 are associated with increased RA disease activity,¹³ blocking IL-6 activity is an important treatment strategy.

Tocilizumab is a monoclonal antibody that blocks both soluble and transmembrane IL-6 receptors, thereby inhibiting the proinflammatory activity of IL-6.¹¹ Tocilizimab also disrupts IL-6 receptor complexes that have already formed, effectively preventing IL-6 signal transduction through the receptors.¹²

10/23/12DAS28-ESR cutoff of 1.54 may predict achievement of remission based on new Boolean criteria in patients taking tocilizumab.

10/26/12 CRP level is a marker for suppression of IL-6 signalling and response to tocilizumab.

5/1/13Baseline serum IL-6, but not TNF-alpha, is a potential biomarker of disease activity and may predict response to tocilizumab and potentially be used to estimate disease activity after tocilizumab treatment.

3/1/13A cumulative analysis shows that, for the 4.6 years it has been studied, tocilizumab has demonstrated long-term safety and durable efficacy.

The randomized, placebo-controlled, phase III RADIATE trial demonstrated the efficacy of tocilizumab in improving signs and symptoms of RA in patients who had discontinued TNF-inhibitor therapy due to inefficacy.¹⁴ Patients received 8 or 4 mg/kg tocilizumab or placebo with a background of methotrexate (MTX). At 24 weeks, the primary endpoint of 20% improvement in arthritis signs and symptoms according to the American College of Rheumatology (ACR) criteria was achieved in 50% and 30% of patients in the tocilizumab 8-mg/kg and 4-mg/kg groups, respectively, compared with 10% of patients in the control group (P <.001). ACR20 response rate was not influenced by the type or number of TNF inhibitors previously failed. Disease Activity Score in 28 joints (DAS28) remission rates were dose related, achieved by 30.1%, 7.6%, and 1.6% in the 8-mg/kg, 4-mg/kg, and control groups, respectively.¹⁴

10/1/12Tocilizumab improved patient-reported outcomes in phase III RADIATE trial of patients with inadequate response to TNF inhibitors.

10/1/12Tocilizumab reduced levels of biochemical markers of bone metabolism in phase III RADIATE trial.

Supporting these findings are data from four other randomized, double-blind, controlled, phase III trials of tocilizumab in different patient populations, including patients refractory to MTX or other disease-modifying antirheumatic drugs (DMARDs) (OPTION,¹⁵ TOWARD,¹¹ LITHE¹⁶) and MTX-naive patients (AMBITION¹⁷). In all of these trials, the primary endpoint of ACR20 response at 24 weeks was achieved in significantly more patients taking tocilizumab compared with controls.^11,15-17 Durable response rates lasting more than 3 years have been reported from ongoing, open-label, extension studies.¹⁸

11/11/12Post hoc analysis of AMBITION extension study up to 240 weeks showed durable efficacy with tocilizumab monotherapy.

11/12/12Tocilizumab safety profile remained stable over a mean treatment duration of 3.7 years in analysis of five placebo-controlled trials.Long-term follow-up data from the LITHE trial, which evaluated efficacy of tocilizumab plus MTX in patients refractory to MTX,¹⁶ has shown continued efficacy, including inhibition of radiographic progression, at 3 years and a safety pattern that is unchanged compared with 2-year follow-up.¹⁹

1/15/13 LITHE study 2-year results are published.A subset of patients from LITHE showed inhibited joint damage progression with tocilizumab irrespective of its anti-inflammatory effects,²⁰ similar to observations from studies of TNF inhibitors.^21,22

1/13ACT-RAY study suggests switching to tocilizumab monotherapy may be just as effective as adding tocilizumab to methotrexate, with less risk of transaminase increases, in RA patients with an inadequate response to initial methotrexate therapy.In addition, data from the recent ROSE study have shown that tocilizumab is a rapidly acting drug with clinical activity commencing as early as 1 week.²³

1/10/13Randomized, placebo-controlled trial shows tocilizumab improves patient-reported measures as early as 1 week after first infusion. Tocilizumab also demonstrates a dose-response relationship, as shown in a recent evaluation of data from phase III trials.²⁴

10/11/12 FDA updates tocilizumab label, expanding the indication to include patients with moderately to severely active RA who have had an inadequate response to one or more DMARDS, and also revising warning on hypersensitivity reactions.

11/21/12 European consensus statement provides guidance on use of tocilizumab in RA.

Tocilizumab monotherapy

Several recent studies have expanded our knowledge on the use of tocilizumab as monotherapy.

In ACT-SURE, a 24-week phase IIIb open-label trial in more than 1600 patients, efficacy and safety of tocilizumab 8 mg/kg monotherapy was similar to that of combination tocilizumab-DMARD therapy in patients with inadequate response to DMARDs,²⁵ including those refractory to TNF inhibitors.²⁶

In the 24-week, open-label ACT-STAR trial, tocilizumab monotherapy demonstrated comparable efficacy and safety with two tocilizumab-DMARD combination therapy regimens (4 or 8 mg/kg tocilizumab plus DMARD) in patients with inadequate response to biologic or nonbiologic DMARDs.²⁷ A substudy of ACT-STAR evaluated the risk-benefit profile of tocilizumab monotherapy in patients who were previously treated with anti-TNF agents.²⁸ In this study, rates of serious adverse events and serious infections were comparable between the tocilizumab-DMARD combination groups, but higher than those in the tocilizumab monotherapy group (Table 2).²⁸ DAS28 remission rates were significantly improved in all treatment groups (Table 2).²⁸

Table 2. ACT-STAR Substudy: Safety and Efficacy in Patients Previously Treated with Anti-TNF Agents²⁸

	Tocilizumab 8 mg/kg (n = 129)	Tocilizumab 4-8 mg/kg + DMARD (n = 202)	Tocilizumab 8 mg/kg + DMARD (n = 221)
Safety
a?￥1 SAE, n (%)	5 (4.6)	15 (7.4)	19 (7.9)
a?￥1 SI, n (%)	2 (1.8)	9 (4.4)	9 (3.8)
Efficacy
DAS28 change from baseline, mean (SD)	-1.95 (1.445)^*	-1.76 (1.283)*	-1.85 (1.373)*

^*P <.0001.

Abbreviations: DAS28, Disease Activity Score in 28 joints; DMARD, disease-modifying antirheumatic drug; SAE, serious adverse event; SD, standard deviation; SI, serious infection.

11/12/12ACT-STAR laboratory substudy shows tocilizumab selectively lowers IL-21 production by CD4 T-cells and serum IgG4-specific autoantibody levels, which suggests involvement of IL-21 in B-cell activation, and blocking IL-6 may downregulate this pathway.

In the randomized, double-blind ACT-RAY trial in 512 patients refractory to MTX, clinical outcomes at 24 weeks were comparable between patients switched to tocilizumab monotherapy and patients who had tocilizumab added to ongoing MTX therapy.²⁹ The incidence of increased alanine aminotransferase levels was higher with combination treatment.²⁹ Both treatment strategies produced meaningful reductions in disease activity, including progression of joint damage as measured by change in Genant-modified Sharp Score (Table 3).²⁹

Table 3. ACT-RAY: Comparable and Meaningful Reductions in Disease Activity Between Tocilizumab Monotherapy and Tocilizumab plus MTX²⁹

	Tocilizumab + Placebo (n = 252)	Tocilizumab + MTX (n = 260)	P value
DAS28 <2.6, %	34.8	40.4	.19 (ns)
GSS a?¤SDC, %	87.3	90.6	.18 (ns)
ACR20, %	70.3	71.5	.87 (ns)
ACR50, %	40.2	45.5	.30 (ns)
ACR70, %	25.4	24.5	.68 (ns)
ACR90, %	5.1	5.8	.84 (ns)

Abbreviations: ACR, American College of Rheumatology; DAS28, Disease Activity Score in 28 joints; GSS ≤SDC, Genant-modified Sharp Score progression ≤ smallest detectable change; MTX, methotrexate; ns, not significant.

11/13/121-year ACT-STAR data show sustained clinical improvements with both tocilizumab switch and add-on strategies, but with radiographic progression in significantly more switch patients.

5/3/13DREAM study demonstrates drug-free remission and low disease activity after tocilizumab monotherapy is stopped.

5/17/13RESTORE study shows that retreatment with tocilizumab is effective in patients who had responded to prior tocilizumab monotherapy and then experienced loss of efficacy after cessation of tocilizumab in the DREAM study.

6/15/13The randomized, active-controlled, parallel-group phase III SUMMACTA trial found comparable efficacy and safety between SC and IV tocilizumab at 24 weeks.

9/12/13This trial is now published in Annals of the Rheumatic Diseases.

Comparing tocilizumab with TNF-inhibitor therapy

Gabay and colleagues reported superior disease control with tocilizumab monotherapy compared with the anti-TNF agent adalimumab in the 24-week phase IV ADACTA trial, the first head-to-head study comparing these two biologic agents.³⁰ As shown in Figure 1,³⁰ all endpoints measured were significantly improved with tocilizumab, including the primary endpoint of mean change from baseline in DAS28 (a??3.3 versus a??1.8, P <.0001). A criticism of the ADACTA trial is that both agents were administered as monotherapy and it is well established that TNF inhibitors have superior efficacy when combined with MTX. However, patients in ADACTA were intolerant to or unable to take MTX,³⁰ and for this subset of patients, the results of ADACTA are significant.

3/15/13The ADACTA trial is now published in The Lancet.

Figure 1. ADACTA: Superior Disease Control with Tocilizumab Monotherapy Versus Adalimumab Monotherapy³⁰

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Abbreviations: ACR, American College of Rheumatology; DAS28, Disease Activity Score in 28 joints; LDA, low disease activity.

5/24/13DAS28 score, adherence, and patient and physician satisfaction were superior with tocilizumab compared with TNF inhibitors in 24-week retrospective cohort study.

8/27/13Subcutaneous tocilizumab monotherapy had comparable efficacy and safety to intravenous tocilizumab monotherapy in a 24-week phase III study of Japanese RA patients refractory to DMARD therapy.

Safety

The most common adverse effects associated with tocilizumab include minor infections, but serious infections are seen as well (eg, pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis, and bacterial arthritis); opportunistic infections (eg, tuberculosis [TB], cryptococcal infection, aspergillosis, candidiasis, and pneumocystosis) have also been reported. Tocilizumab should not be administered during an active infection, and treatment should be stopped if a serious infection develops, and then reinitiated once the infection is controlled. Patients should be tested for latent TB before starting treatment and monitored during treatment for signs and symptoms of TB. Live vaccinations should not be concurrently administered with tocilizumab. In a recent investigation, tocilizumab did not interfere with antibody response to vaccination with inactive trivalent influenza vaccine (A/H1N1, A/H3N2, and B/B1 strains).³¹

Other risks include gastrointestinal perforation; infusion reactions; and abnormal laboratory parameters, particularly hepatic transaminase elevations, neutropenia, and altered lipid profile.^7,32 Alanine aminotransferase and aspartate aminotransferase levels should be monitored every 4 to 8 weeks, as well as lipid parameters at 4 to 8 weeks after initiation and then every 24 weeks.⁷ Stable rates of adverse effects with long-term tocilizumab suggest that the safety profile of this agent is similar to that established in phase III studies.³³

10/16/12 A recent case study suggests tocilizumab may have inhibited production of factor FXIII, leading to hematoma.

Tocilizumab may reduce the bioavailability of cytochrome P450 (CYP)-metabolized drugs, so caution should be used when tocilizumab is co-prescribed with CYP-metabolized drugs.³⁴