Interleukin-6 Inhibitors

Introduction

Interleukin-6 (IL-6) is a pleiotropic cytokine that may play a role in the regulation of various aspects of the immune response, inflammation, hematopoiesis, and bone metabolism. IL-6 acts by binding to a specific receptor (IL-6R), which binds to a protein (gp130) expressed on the surface of many cell types that mediate signal transduction (Figure 17-1; see also Biologic Therapies). Elevated IL-6 levels, both in the serum and the synovial fluid in patients with rheumatoid arthritis (RA), have been shown to correlate with the disease activity and radiographic joint damage. Thus inhibition of IL-6 has been considered a potential therapeutic target in the treatment of RA. In an early study, administration of a mouse monoclonal IL-6 antibody to five patients with RA resulted in amelioration of disease activity.

Currently, two IL-6 inhibitors, tocilizumab and sarilumab, have been approved by the Food and Drug Administration (FDA) for RA.

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Tocilizumab

Tocilizumab (Actemra), a humanized monoclonal antibody to the human IL-6 receptor, is approved by the FDA for the treatment of adult patients with moderately to severely active RA who have had an inadequate response to one or more disease-modifying antirheumatic drug (DMARDs). Tocilizumab binds both soluble and membrane-expressed IL-6R, thereby inhibiting IL-6–mediated proinflammatory activity. Tocilizumab may be used as monotherapy or in combination with methotrexate (MTX) or other DMARDs.

Clinical Efficacy

The efficacy of tocilizumab was studied in several multinational phase 3 studies involving >4000 patients. Overall, these studies showed that tocilizumab, alone or in combination with MTX or other DMARDs, significantly reduced RA signs and symptoms, regardless of previous therapy, compared with DMARDs alone.

In the Rheumatoid Arthritis Study in Anti- tumor necrosis factor (TNF) Failures (RADIATE) trial, 499 patients who were intolerant of or had an inadequate response to one or more TNF antagonists were randomized to 8-mg/kg or 4-mg/kg tocilizumab or placebo intravenously every 4 weeks with stable MTX. At week 24, 50.0% and 30.4% of patients who received tocilizumab 8 mg/kg or 4 mg/kg plus MTX, respectively, achieved an ACR20 response, compared with 10.1% of patients who received placebo plus MTX (less than P <0.001, both tocilizumab groups vs control) (Figure 17-2). In addition, DAS28 remission rates (DAS28 <2.6) at week 24 were dose related, and were achieved by 30.1%, 7.6% and 1.6% of 8-mg/kg, 4-mg/kg and control groups, respectively (less than P = 0.001 for 8-mg/kg and P = 0.053 for 4-mg/kg vs control group) (Figure 17-3). Interestingly, patients responded, regardless of the number of TNF inhibitors they had previously failed.

Tocilizumab 8 mg/kg or 4 mg/kg plus stable prestudy doses of MTX were compared with placebo plus MTX in 623 patients with moderate to severe active RA in the Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders (OPTION). All other DMARDs and biologic agents were discontinued and washed out prior to randomization. At 24 weeks, significantly more patients achieved an ACR20 response with tocilizumab 8 mg/kg (59%) or 4 mg/kg (48%) compared with placebo (26%) (P <0.0001; both vs placebo).

A substudy in 416 of the 623 patients in the OPTION study measured serum biochemical markers of bone formation, bone resorption and cartilage metabolism at baseline and at weeks 4, 16 and 24. Tocilizumab induced marked dose-dependent reductions in markers of cartilage metabolism (PIIANP, HELIX-II, MMP-3) at week 4 that were maintained until week 24. Tocilizumab also induced significant decreases in bone degradation markers (CTX-I and ICTP), providing initial evidence of a beneficial effect on bone turnover. Tocilizumab-treated patients who achieved an ACR50 response or DAS28 remission had greater reductions in ICTP, HELIX-II, and MMP-3 levels compared with ACR50 nonresponders.

The Tocilizumab in Combination With Traditional DMARD Therapy (TOWARD) trial compared tocilizumab 8 mg/kg every 4 weeks or placebo, both in combination with ongoing conventional DMARD therapies, in 1220 patients with active RA. The proportion of patients achieving ACR20 response at week 24 was significantly greater in the tocilizumab plus DMARD group than in the placebo plus DMARD group (61% vs 25%; P <0.0001), with no obvious differences in response in patients receiving two or more DMARDs. The remission rates (DAS28 <2.6) were also higher in the tocilizumab group vs the control group, with 30% of patients and 3% of patients, respectively, achieving clinical remission at week 24 (P <0.0001).

Monotherapy with tocilizumab 8 mg/kg every 4 weeks was compared with MTX monotherapy in 673 patients with relatively early but active RA who were naïve to biological agents and not currently taking DMARDs in the Actemra vs Methotrexate Double-Blind Investigative Trial in Monotherapy (AMBITION). Tocilizumab monotherapy was superior to MTX monotherapy (with the mean weekly MTX dose over 24 weeks of 15.5 mg) as indicated by higher rates of ACR20 response (69.9% vs 52.5%; P <0.001), ACR50 response (44.1% vs 33.5%; P = 0.0023) and ACR70 response (28.0% vs 15.1%; P = 0.0002).

The 2-year, double-blind ACT-RAY study compared the efficacy of monotherapy with tocilizumab 8 mg/kg every 4 weeks or tocilizumab in combination with stable doses of MTX in 556 patients with active RA despite previous MTX. The primary end point was DAS28 remission at week 24. Progression of structural damage and quality of life were also assessed. There was no significant difference in the DAS28 remission rates in the tocilizumab-MTX and tocilizumab monotherapy groups (40.4% and 34.8%, respectively; P = 0.190). There also were no significant differences between the ACR20/50/70/90 responder rates in the tocilizumab-MTX and tocilizumab monotherapy groups (72%/45%/25%/6% and 71%/41%/26%/5%, respectively; all P = NS). Progression of structural damage at week 24 was low in both groups as indicated by no significant between-group difference in the proportion of patients with no progression in Genant-modified Sharp Score (65.3% and 58.7%, in the tocilizumab-MTX and tocilizumab monotherapy groups, respectively). HAQ-DI and RAQoL improved significantly from baseline, with no differences between groups. Although this study did not demonstrate clinical superiority of tocilizumab combination therapy over tocilizumab monotherapy, the investigators concluded that since clinically meaningful responses can be obtained with tocilizumab monotherapy, MTX may not be a required concomitant treatment with tocilizumab.

A postmarketing surveillance study examined the efficacy of tocilizumab 8 mg/kg every 4 weeks for 28 weeks in all patients (n = 7901) with RA who were treated in a clinical practice setting in Japan. In these patients, TNF inhibitor use was 62.8% and concomitant MTX use was 55.8%, with concomitant glucocorticoid use at 74.0%. Mean baseline DAS28-ESR was 5.5, which declined to 2.9 at week 28. DAS28-ESR ≤2.6 was achieved in 47.6% of patients. DAS28 remission in patients with disease duration ≤2 years was significantly greater than those in patients with ≥10 years’ disease duration (P ≤0.001). TNF inhibitor–naïve patients showed significantly better response than the patients with prior anti-TNF use (P <0.001).

The 24-week multicenter, randomized, double-blind, phase 4 ADACTA trial compared monotherapy with tocilizumab or adalimumab in patients with RA of ≥6 months duration and DAS >5.1 who were MTX intolerant or for whom continued MTX treatment was considered ineffective or inappropriate. The baseline characteristics of the intent-to-treat population were similar: mean age 54.4 and 53.3 years; mean RA duration 7.3 and 6.3 years; and mean DAS28 6.72 and 6.76. Patients were randomized (1:1) to tocilizumab 8 mg/kg IV every 4 weeks (plus adalimumab placebo) or adalimumab 40 mg SC every 2 weeks (plus tocilizumab placebo). Escape to weekly adalimumab/placebo was permitted at week 16; 10 adalimumab- and 7 tocilizumab-treated patients escaped. The primary end point was mean change from baseline in DAS28 at 24 weeks.

At 24 weeks, mean change from baseline in DAS28 was significantly greater with tocilizumab than with adalimumab monotherapy (Table 17-1). Statistical significance was also achieved in favor of tocilizumab in DAS28 remission and low disease activity (LDA) and ACR20/50/70 responses. A numerical difference between treatment arms in favor of tocilizumab in swollen and tender joint counts also observed from week 8 onward. The incidence of adverse events was similar in each group (tocilizumab 82.1%; adalimumab 82.7%). Serious adverse events and serious infections also were similar (tocilizumab: 11.7%, 3.1%; adalimumab 9.9%, 3.1%). Changes in laboratory values, including transaminases and LDL increases and neutrophil reductions, occurred with both treatments, although the proportions of patients with abnormal values were higher with tocilizumab.

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Safety in RA

As with virtually all effective immune-modulating drugs evaluated in clinical trials in RA patients, a variety of infections have been observed and they tend to be somewhat more common among patients receiving tocilizumab in studies. In the phase 3, 6-month, controlled clinical trials, the rate of all infections in the tocilizumab monotherapy group was 119 events per 100 patient-years and was similar in the MTX monotherapy group.

In the 4-mg/kg and 8-mg/kg tocilizumab plus DMARD groups, the infection rates were 133 and 127 events per 100 patient-years respectively, compared with 112 events per patient-years in the placebo plus DMARD group. The most common infections (5% to 8% of patients) were upper respiratory tract infections and nasopharyngitis. Serious infections, some requiring hospitalization, including active tuberculosis, invasive fungal infections and bacterial, viral and other infections due to opportunistic organisms, but also others such as pneumonia, urinary tract infection, herpes zoster, gastroenteritis and sepsis, have been reported in patients receiving tocilizumab. Most patients who developed such infections were taking concomitant immunosuppressants, such as MTX or corticosteroids. The rate of all serious infections among patients receiving tocilizumab monotherapy in the 6-month controlled trials was 3.6 events per 100 patient-years compared with a rate of 1.5 events per 100 patient-years among those treated with MTX monotherapy. During treatment, patients should be closely monitored for signs and symptoms of infection. If a serious infection develops, treatment with tocilizumab should be interrupted until the infection is controlled. Prior to initiating therapy, test patients for latent TB; if positive, consider starting treatment for latent TB prior to initiating therapy

In patients receiving 4-mg/kg or 8-mg/kg tocilizumab plus one or more DMARDs, the rates were 4.4 and 5.3 events per 100 patient-years compared with 3.9 events per 100 patient-years in those treated with placebo plus a DMARD. Whether these abnormalities will result in clinically important sequelae remains to be fully delineated.

Gastrointestinal perforations, generally as a complication of diverticulitis, have been reported among patients treated with tocilizumab and mostly in those taking concurrent NSAIDS, corticosteroids, or MTX. Among all 4009 patients who received at least one dose of tocilizumab in a clinical trial, the overall rate of GI perforation was 0.28 events per 100 patient-years. Tocilizumab treatment also has been associated with dose-related changes in several laboratory tests, including elevated serum lipids and liver enzymes, neutropenia, and thrombocytopenia. Hypersensitivity reactions may rarely occur.

Dosage and Administration

Tocilizumab may be used as monotherapy or concomitantly with MTX or other DMARDs. When administered by intravenous infusion, in combination with DMARDs or as monotherapy, the recommended starting dose in the United Sstates according to the package insert is 4 mg/kg every 4 weeks followed by an increase to 8 mg/kg every 4 weeks based on clinical response. Doses exceeding 800 mg per infusion are not recommended. The recommended subcutaneous dosage regimen depends on patient weight. In patients weighing <100 kg, the recommended dose is 162 mg tocilizumab administered every other week, followed by an increase to every week based on clinical response. In patients at or above 100 kg, 162 mg tocilizumab should be administered every week.

Tocilizumab has not been studied in combination biological DMARDs (eg, TNF antagonists, IL-6R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators) and its use with these agents should be avoided. Tocilizumab should not be initiated in patients with an absolute neutrophil count <2000/mm3, platelet count <100,000/mm³, or those in whom the ALT or AST is >1.5 times the upper limits of normal. Tocilizumab should be used with caution in patients with an increased risk of intestinal perforation, such as those with a history of diverticulitis; patients on tocilizumab who present with new onset abdominal symptoms should be evaluated for GI perforation. As with other immunomodulatory agents, the concurrent use of live vaccines should be avoided with tocilizumab since clinical safety has not been established. Neutrophil and platelet counts should be monitored 4 to 8 weeks after the start of therapy and every 3 months thereafter; ALT and AST levels every 4 to 8 weeks after start of therapy for the first 6 months and then every 3 months thereafter; and lipid levels 4 to 8 weeks after start of therapy and managed according to lipid management guidelines thereafter. Dosage reductions should be considered in the event of clinically significant laboratory abnormalities.

Sarilumab

Sarilumab (Kevzara), a human recombinant mono-clonal antibody that binds to the IL-6 receptor, is approved by the FDA for the treatment of adult patients with moderately to severely active RA who have had an inadequate response or intolerance to one or more DMARDs. Sarilumab may be used along or in combination with MTX or other csDMARDs. Like tocilizumab, sarilumab binds both soluble and membrane-bound IL-6R, thereby inhibiting IL-6–mediated signaling.

Clinical Efficacy

The efficacy of sarilumab was assessed in three randomized, double-blind, placebo-controlled, phase 3 trials: MOBILITY, TARGET and MONARCH. In MOBILITY and TARGET, patients were >18 years of age with moderately to severely active RA and at least eight tender and six swollen joints at baseline. In addition, the 1,197 patients evaluated in MOBILITY had inadequate clinical response to MTX; the 546 patients in TARGET had an inadequate clinical response or were intolerant to one or more TNF-α antagonists. In both studies, patients received subcutaneous sarilumab 200 mg, sarilumab 150 mg, or placebo every 2 weeks. In MOBILITY, patients received concomitant MTX; in TARGET, patients received concomitant conventional DMARD(s), including MTX, sulfasalazine, leflunomide, and/or hydroxychloroquine. Patients with an inadequate response could be rescued with sarilumab 200 mg in both studies, after week 16 in MOBILITY and week 12 in TARGET.

The primary endpoint of MOBILITY and TARGET was the proportion of patients who achieved an ACR20 response at week 24. Other key endpoints included change from baseline in van der Heijde­ mTSS at week 52 in MOBILITY and change from baseline in HAQ-DI. In both studies, patients treated with either dose of sarilumab had higher ACR20/50/70 response rates compared to placebo-treated patients at week 24 (Figure 17-4). A greater proportion of patients treated with sarilumab 200 mg or 150 mg also achieved a low level of disease activity, as measured by DAS28-CRP <2.6, compared with placebo. Patients in the 200-mg sarilumab and 150-mg sarilumab groups demonstrated greater improvement from baseline in physical function, as assessed by HAQ-DI, compared to placebo at week 16 in MOBILITY and week 12 in TARGET.

Structural joint damage was assessed radiographically in MOBILITY at baseline, week 24 and week 52. Both doses of sarilumab were superior to placebo in the change from baseline in mTSS over 52 weeks: 0.25 for sarilumab 200 mg, 0.90 for sarilumab 150 mg and 2.78 for placebo (Figure 17-5). Progression was also reduced for both erosion and joint space narrowing scores with sarilumab compared to placebo. Significantly less radiographic progression of structural damage was observed in the sarilumab groups compared with placebo at week 52: 55.6% of patients receiving sarilumab 200 mg and 47.8% of patients receiving sarilumab 150 mg had no progression of structural damage (as defined by a change in the Total Sharp Score of 0 or less) compared with 38.7% of patients receiving placebo.

MONARCH was a superiority trial that compared the safety and efficacy of sarilumab monotherapy to adalimumab monotherapy in patients intolerant to, or with inadequate response to, MTX. Eligible patients were ≥18 years of age with active RA, a disease duration of ≥3 months and no prior treatment with bDMARDs. Patients were randomized to receive either sarilumab 200 mg every 2 weeks or adalimumab 40 mg every 2 weeks, plus matching placebos. The primary efficacy endpoint was change from baseline in DAS28-ESR at Week 24, with other endpoints including CDAI, HAQ-DI, ACR20/50/70 response rates and others.

At Week 24 of MONARCH, sarilumab was significantly superior to adalimumab in terms of mean change from baseline in DAS28-ESR (-3.28 vs -2.20; P <0.0001; Figure 17-6), with improvement seen by Week 12. In a pre-specified subgroup analysis, sarilumab demonstrated greater improvement in DAS28-ESR at Week 24 irrespective of previous MTX response. Changes in DAS28-CRP were consistent with DAS28-ESR (-2.86 vs -1.97; P <0.0001; Figure 17-6). Additionally, sarilumab demonstrated greater efficacy compared to adalimumab in terms of CDAI, CDAI remission rate, HAQ-DI and SF-36 physical component summary score at Week 24. The proportion of patients achieving ACR20/50/70 responses was 71.7%/45.7%/23.4% in the sarilumab group compared to 58.4%/29.7%/11.9% in the adalimumab group (all P ≤0.0074; Figure 17-7). Altogether, MONARCH demonstrated that sarilumab can improve the signs, symptoms and functional disability of RA and is a suitable monotherapy for patients intolerant to or unresponsive to MTX, with demonstrated superiority to adalimumab monotherapy in terms of DAS28-ESR at Week 24.

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Safety in RA

The safety of sarilumab in combination with conventional DMARDs was evaluated based on data from seven studies, with the safety population consisting of 2887 patients. The most frequent adverse reactions in the clinical studies, occurring in at least 3% of patients treated with sarilumab in combination with DMARDs, were neutropenia, increased ALT, injection site erythema, upper respiratory infections and urinary tract infections. The most common serious adverse reactions were infections. Premature discontinuation due to adverse reactions in the pre-rescue population of MOBILITY and TARGET occurred in 8%, 6% and 3% of patients treated with sarilumab 200 mg, sarilumab 150 mg, and placebo, respectively. The most common adverse reaction, occurring in >1% of patients, that resulted in discontinuation of therapy with sarilumab was neutropenia.

In the pre-rescue population of MOBILITY and TARGET, the rate of infections was 110 events per 100 patient-years in the sarilumab 200 mg group, 105 events per 100 patient-years in the sarilumab 150 mg group, and 81 events per 100 patient-years in the placebo group. The most commonly reported infections, occurring in 2% to 4% of patients, were upper respiratory tract infections, urinary tract infections, and nasopharyngitis. In the same pre-rescue population, the rate of serious infections in the sarilumab 200 mg and 150 mg groups was 3.8 and 4.4 events per 100 patient-years, respectively, compared to 2.5 events per 100 patient-years in the placebo group. Pneumonia and cellulitis were the most frequently observed serious infections.

Sarilumab treatment also has been associated with dose-related changes in several laboratory tests. In the pre-rescue population of MOBILITY and TARGET, decreases in neutrophil counts <1000/mm³ occurred in 6%, 4%, and 0% of patients in the sarilumab 200 mg, sarilumab 150 mg, and placebo groups, respectively. In the same population, decreases in platelet counts <100,000/mm³ occurred in 1%, 0.7%, and 0% of patients, and liver enzyme elevations of >ULN to ≤3 × ULN occurred in 30%, 27%, and 15% of patients in the sarilumab 200 mg, sarilumab 150 mg, and placebo groups, respectively. Elevations in liver enzymes were not associated with clinical evidence of hepatitis or hepatic impairment.

In MONARCH, the safety profiles of sarilumab and adalimumab were generally comparable, with the safety profile of sarilumab being consistent with those from other studies. The incidence of serious adverse events was 4.9% in the sarilumab group compared to 6.5% in the adalimumab group, with 6.0% and 7.1% of patients discontinuing treatment, respectively. Infection rates were also similar between treatment groups (sarilumab 28.8% vs 27.7% adalimumab), with two patients in each group experiencing a serious infection. Neutrophil counts <1.0 G/L were more frequent in the sarilumab group, consistent with other studies of sarilumab, but no association between low neutrophil count and risk of infection or serious infection was found. Other drug class effects on laboratory values were observed, including changes to liver transaminases and total cholesterol.

Sarilumab treatment has been associated with gastrointestinal perforation, hypersensitivity reactions, injection site reactions, lipid abnormalities and other adverse reactions.

Dosage and Administration

Sarilumab may be used as monotherapy or in combination with MTX or other conventional DMARDs. The recommended dosage is 200 mg once every 2 weeks, administered as a subcutaneous injection. Dosage should be reduced to 150 mg once every 2 weeks for the management of neutropenia, thrombocytopenia, and elevated liver enzymes. Treatment initiation is not recommended in patients with an absolute neutrophil count of <2000/mm³, platelet count <150,000/mm³, or who have ALT or AST >1.5 times the upper limit of normal. Laboratory parameters, including neutrophil and platelet counts, ALT/AST levels, and lipid parameters should be assessed before initiation of therapy, 4-8 weeks after initiation, and then monitored every 3 months thereafter (every 6 months for lipids).

Sarilumab contains a black box warning since patients treated with sarilumab are at increased risk for developing serious infections that may lead to hospitalization or death. Opportunistic infections have also been reported in patients receiving sarilumab. Most patients who developed infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. As such, use of sarilumab should be avoided in patients with an active infection. During treatment, patients should be closely monitored for signs and symptoms of infection. If a serious infection develops, treatment with sarilumab should be interrupted until the infection is controlled. Prior to initiating sarilumab, test patients for latent TB; if positive, consider starting treating for latent TB prior to initiating sarilumab.

The concurrent use of sarilumab with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti­CD20 monoclonal antibodies, and selective co-stimulation modulators has not been studied. Avoid using sarilumab with biological DMARDs due to the possibility of increased immunosuppression and increased risk of infection.