Rheumatoid arthritis (RA) is a chronic, debilitating, autoimmune disease with articular and systemic manifestations. Approximately 1.3 million adults in the United States have RA.1 The disease course of RA is variable—some patients have mild, self-limited disease, whereas other patients have joint destruction; severe physical disability; and multiple comorbidities, including anemia, fatigue, osteoporosis, and cardiovascular disease.2
In addition to the medical burden, RA has substantial psychosocial effects, including impaired physical functioning, diminished work productivity, and compromised quality of life and emotional well-being.2
Furthermore, patients with RA have a 2-fold higher mortality rate than individuals in the general population.3 A 2010 study by Birnbaum and colleagues concluded that when direct and indirect costs of RA were accounted, the total estimated annual cost of RA in the United States reached $19.3 billion; this number increased to $39.2 billion when intangible costs of quality-of-life deterioration and premature mortality were included in the cost analysis.4
With a primary focus on the amelioration of symptoms and modification of the disease process, the current treatment landscape for RA includes conventional synthetic disease-modifying antirheumatic drugs (DMARDs), targeted synthetic DMARDs, and biologic DMARDs.2
A 2011 study by Shahouri and colleagues showed that despite advancements in RA care that have led to paradigm shifts in its management, only 5% to 10% of patients with RA achieve remission in clinical practice, and the probability of a remission lasting 2 years is <3%.5
Unmet clinical needs in RA include the management of patients with moderate-to-severe disease activity, certain high-risk patients (eg, congestive heart failure, history of lymphoproliferative malignancies), pregnant and breastfeeding patients, those who have renal or lung disease, and patients with infections, thus underscoring the need for new and effective therapies.
Sarilumab (Kevzara) is a novel interleukin (IL)-6 receptor inhibitor that was approved by the US Food and Drug Administration (FDA) on May 22, 2017, for the treatment of adults with moderately or severely active RA who have had an inadequate response or intolerance to 1 or more DMARDs.6,7
This Rx Profiler highlights the mechanism of action, preclinical evidence, pivotal clinical trial data, and important safety information for sarilumab in the treatment of patients with moderate-to-severe RA.
Pathogenesis of Rheumatoid Arthritis
Although the exact etiology of RA is unknown, genetic susceptibility, epigenetic contributions, and environmental triggers have been implicated in the pathogenesis of RA.2 The pathogenesis of RA involves immune activation and inflammatory cell infiltration, autoantibody production, synovial hyperplasia, and increased vascularity.8
Immune cells that infiltrate the synovial space release several proinflammatory cytokines, including tumor necrosis factor (TNF)-α, IL-1, and IL-6, which are strongly associated with the clinical manifestations and the disease progression of RA, making them rational targets for therapeutic intervention.2,9
Tumor Necrosis Factor-α
TNF-α is a pleiotropic, proinflammatory cytokine that is found in the synovial fluid of patients with RA. It plays a central role in the inflammation and joint destruction that are the hallmarks of RA.10
TNF-α plays several roles in the pathogenesis of RA, including inducing the production of other proinflammatory cytokines, such as IL-1 and IL-6; the release of chemokines that act as chemoattractants for leukocytes via the upregulation of key integrins and adhesion molecules; and the destruction of articular cartilage and bone by the induction of proteolytic and metalloproteinase enzymes. TNF-α is also involved in acute-phase protein production and hypothalamus–pituitary–adrenal (HPA) axis dysregulation.9
IL-6 is a potent, multifunctional cytokine that is strongly implicated in the pathogenesis of RA.11 The constitutive production of IL-6 and its signaling pathway play a dominant role in a wide spectrum of biological activities, including the regulation of the immune response, inflammation, and hematopoiesis, all of which are involved in the development of the many clinical characteristics of RA.11
IL-6 signaling is mediated by a cell-surface signal transducer glycoprotein 130 and an IL-6–specific receptor.11 Overall, 2 known forms of IL-6 receptor occur in vivo, including a membrane-bound form and a soluble form that lacks the transmembrane and cytoplasmic portions. IL-6 signaling transduction occurs via the classic and trans-signaling pathways that mediate different biological effects; the trans-signaling pathway has a proinflammatory effect, whereas the classic signaling pathway plays an anti-inflammatory role.11
IL-6 contributes to inflammation and joint destruction seen in RA by recruiting neutrophils, leading to the increased secretion of proteolytic enzymes and reactive oxygen intermediates, while also influencing the shift to chronic inflammation by monocyte recruitment and macrophage differentiation.12,13
The IL-6–hepcidin axis plays a critical role in anemia, with increased liver hepcidin expression resulting in decreased serum iron levels.9,13 In addition, IL-6–mediated regulation of the HPA axis and the increased production of adrenocorticotropic hormone and cortisol cause fatigue.8,13
IL-6 signaling results in bone destruction and osteoporosis by inducing osteoclast activity, reducing bone formation, and causing defective ossification.11,13
Treatment Options for Patients with Rheumatoid Arthritis
The RA treatment landscape comprises 4 classes of biologic DMARDs, including the TNF-α inhibitors adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi), and infliximab (Remicade); agents that block T-cell costimulation via the inhibition of CD80 and CD86, such as abatacept (Orencia); rituximab (Rituxan), an anti-CD20 agent that causes B-cell depletion; and the anti–IL-6 receptor blocker tocilizumab (Actemra).2
These agents are indicated for the treatment of patients who have had an inadequate response to therapy with conventional DMARDs.2 The conventional DMARD methotrexate continues to be the cornerstone of RA therapy, and TNF-α inhibitors are regarded as the standard of care in patients with an inadequate response to methotrexate.14
2015 American College of Rheumatology Guideline on the Use of Biologic DMARDs
The American College of Rheumatology (ACR) guideline serves as a tool for clinicians to make pharmacologic treatment decisions in different clinical settings.14 The primary recommendation in the early (<6 months disease duration) and established RA disease settings is to adopt a treat-to-target strategy rather than an empiric, nontargeted treatment approach.14
Early disease. For patients with early RA and low disease activity who are DMARD-naïve, monotherapy with conventional DMARDs, preferably methotrexate, is recommended as initial therapy over combination DMARD therapy.14
For patients with moderate or high disease activity despite conventional DMARD monotherapy (with or without glucocorticoids), the guideline recommends using combination DMARDs or adding a TNF inhibitor or a non-TNF inhibitor biologic drug or tofacitinib (Xeljanz); all treatment choices are recommended with or without methotrexate, and in no particular order of preference, over continuing conventional DMARD monotherapy alone. Because of its superior efficacy, the combination of biologic therapy plus methotrexate is recommended over biologic monotherapy, whenever possible.14
Established disease. For patients with established RA who have low disease activity and are DMARD-naïve, conventional DMARD monotherapy, preferably methotrexate, is recommended over a TNF inhibitor.14
For patients with moderate or high disease activity after an inadequate response to conventional DMARDs, the use of combination DMARDs or adding a TNF inhibitor, a non-TNF biologic drug, or tofacitinib is recommended rather than continuing DMARD monotherapy. If patients do not respond to TNF inhibitor therapy, the guideline recommends switching to a non-TNF inhibitor biologic therapy with a novel mechanism of action (with or without methotrexate) over another TNF inhibitor or tofacitinib.14
Special patient populations. The updated guideline includes recommendations for patients with select high-risk comorbidities, including congestive heart failure, malignancy, and infections.14 Given that TNF inhibitors are contraindicated in patients with congestive heart failure, the guideline recommends using a combination of conventional DMARDs, a non-TNF inhibitor biologic, or tofacitinib, over TNF inhibitors.14
To reduce the risk for recurrence of malignancies with the use of biologic DMARDs, conventional DMARDs are conditionally recommended over biologic therapy or tofacitinib in patients with a history of melanoma or nonmelanoma skin cancers.14 Rituximab is recommended over a TNF inhibitor, and combination DMARDs, abatacept, or tocilizumab are conditionally recommended over TNF inhibitors in patients with a history of lymphoproliferative disorders.14
Unmet Clinical Needs in Rheumatoid Arthritis
Although methotrexate continues to be the cornerstone of DMARD therapy for patients with RA, it is ineffective or intolerable in up to 50% of patients.15 For patients with inadequate response to methotrexate, TNF inhibitors are regarded as the standard of care for patients with RA; however, up to 40% of patients have persistent disease activity after receiving TNF inhibitors, and their use is contraindicated in certain patient populations.16
Furthermore, the use of combination therapy with methotrexate may not be appropriate in many clinical conditions, including pregnancy; breastfeeding; heavy alcohol consumption; renal or lung disease; or an infection, such as herpes zoster.
A continued need for effective agents with novel mechanisms of action exists in these clinical settings, and the use of non-TNF inhibitor biologic DMARDs, such as IL-6 receptor antagonists, may fill these treatment gaps.
Role of IL-6 Receptor Antagonists in Rheumatoid Arthritis
Overall, 2 IL-6–targeted biologic drugs, tocilizumab and sarilumab, are FDA approved for the treatment of patients with RA. Tocilizumab is a recombinant, humanized, anti–IL-6 receptor monoclonal antibody that was the first IL-6–targeting biologic DMARD that was approved for the treatment of patients with moderately to severely active RA with an inadequate response to 1 or more DMARDs.17
On May 22, 2017, sarilumab was approved by the FDA for the treatment of adults with moderately to severely active RA who had an inadequate response to 1 or more DMARDs.6,7
Mechanism of Action
Sarilumab is a human, recombinant, monoclonal antibody that specifically binds to the transmembrane and soluble forms of the IL-6 receptor, which inhibits IL-6–mediated cis and trans-signaling in a dose-dependent manner.7
Pharmacodynamics and Pharmacokinetics
The pharmacodynamic characterization of sarilumab (200 mg and 150 mg) using a single-dose subcutaneous administration in patients with RA led to a rapid reduction of C-reactive protein (CRP) levels, which were restored to normal within 2 weeks after starting sarilumab therapy.7 In addition, the absolute neutrophil counts decreased to nadir between 3 and 4 days and thereafter recovered toward baseline. Furthermore, fibrinogen and serum amyloid A levels decreased, whereas hemoglobin and serum albumin levels increased.7
The pharmacokinetics of sarilumab were characterized in 1770 patients with RA who received a subcutaneous injection of sarilumab 150 mg (N = 631) or 200 mg (N = 682) every 2 weeks for up to 52 weeks.7
The median time that sarilumab was present at the maximum concentration (Cmax) was 2 to 4 days. A 2-fold increase in the exposure of sarilumab, as measured by the area under the curve (AUC), was observed at the steady-state concentration, with an increase in sarilumab dose from 150 mg to 200 mg every 2 weeks. The steady-state concentration was reached in 14 to 16 weeks, with a 2- to 3-fold accumulation compared with single-dose exposure.7
For the 150-mg sarilumab dose regimen (every 2 weeks), the estimated mean (± standard deviation) steady-state AUC, minimum concentration, and Cmax were 202 ± 120 mg.day/L, 6.35 ± 7.54 mg/L, and 20.0 ± 9.20 mg/L, respectively. For the 200-mg sarilumab dose regimen (every 2 weeks), the estimated mean (± standard deviation) steady-state AUC, minimum concentration, and Cmax were 395 ± 207 mg.day/L, 16.5 ± 14.1 mg/L, and 35.6 ± 15.2 mg/L, respectively.7
At higher concentrations, sarilumab is eliminated predominantly through the linear, nonsaturable proteolytic pathways, whereas at lower concentrations, sarilumab is eliminated through the nonlinear, saturable target-mediated pathways.7 The concentration-dependent half-life of sarilumab 200 mg and 150 mg every 2 weeks are 10 days and 8 days, respectively, in patients with RA at steady state.
After the last steady-state dose of sarilumab 150 mg and 200 mg, the median times to nondetectable concentrations are 28 days and 43 days, respectively. There is a trend toward higher apparent clearance of sarilumab in the presence of antisarilumab antibodies.7
The binding affinity of sarilumab to the human IL-6 receptor Fc-fusion was 12.8 pM; cross-reactivity to mouse IL-6 receptor was not observed.18 Sarilumab demonstrated a 15- to 22-fold greater affinity for human IL-6 receptor compared with tocilizumab.18
Clinical Development of Sarilumab
A robust clinical program demonstrated the safety, efficacy, and patient-reported outcomes of sarilumab in patients with moderate-to-severe RA.7
Phase 1 Studies
Sarilumab 50 mg, 100 mg, 150 mg, and 200 mg were evaluated in 3 randomized, double-blind, placebo-controlled phase 1 clinical trials (ie, Study 801, Study 802, Study 803) in 83 patients with RA (placebo, N = 24); patients received concomitant methotrexate.19
There was a dose-dependent reduction in the levels of acute-phase reactants, with >90% reduction in high-sensitivity CRP (median reduction, 91.7%) and serum amyloid A levels (median reduction, 92.5%) after a single dose of sarilumab 200 mg.
In addition to reductions in high-sensitivity CRP and serum amyloid levels, dose-related reductions were also reported in the erythrocyte sedimentation rate (ESR; median reduction, 33.8%), and serum hepcidin levels (median reduction, 66.2%), with concomitant increases in IL-6 levels.19
The most frequently reported adverse events were upper respiratory infection, increases in alanine aminotransferase (ALT) levels, and RA flares.19
Phase 2 MOBILITY Part A Clinical Trial
The MOBILITY (Monoclonal Antibody to IL-6Rα in RA Patients: A Pivotal Trial with X-ray) clinical trial was a seamless, 2-part, phase 2/3, randomized, double-blind, placebo-controlled, multicenter study that evaluated the safety and efficacy of sarilumab in patients with moderate-to-severe RA.20,21
Study design. In the dose-ranging, phase 2, MOBILITY Part A clinical trial, 306 patients were randomized to receive placebo or 5 different regimens of subcutaneous sarilumab plus methotrexate: 100 mg weekly, 150 mg weekly, 100 mg every 2 weeks, 150 mg every 2 weeks, or 200 mg every 2 weeks.20 The study duration was 22 weeks, including 4 weeks of screening, 12 weeks of treatment, and 6 weeks posttreatment follow-up. Eligible patients had active RA with inadequate response to methotrexate for at least 12 weeks.20
The primary objective was to demonstrate that sarilumab once weekly or every 2 weeks plus methotrexate reduced the signs and symptoms of RA at week 12, and to select 1 or more dose regimens that would be evaluated in the phase 3 MOBILITY Part B clinical trial. The secondary objectives were to evaluate the safety of sarilumab in combination with methotrexate and to characterize its pharmacokinetic and pharmacodynamic profile.20
The primary end point was the proportion of patients who achieved improvement of ≥20% according to the ACR criteria (ACR20 response) at week 12; the secondary end points included ACR50 and ACR70 responses, change from baseline in individual disease activity measures, and Disease Activity Score in 28 joints (DAS28) using CRP.20
Efficacy. At 12 weeks, 72% of patients who received sarilumab 150 mg once weekly achieved an ACR20 response compared with 46.2% of patients who received placebo (multiplicity adjusted P = .0203).20 In addition, 67% of patients who received sarilumab 150 mg every 2 weeks achieved ACR20 (unadjusted P = .0363), and 65% of patients who received sarilumab 200 mg every 2 weeks achieved ACR20 (unadjusted P = .0426) compared with patients who received placebo. Higher ACR50, ACR70, and DAS28-CRP rates were achieved with sarilumab 150 mg every 2 weeks and higher dose cohorts compared with placebo.20
Safety. Across the 5 dose cohorts, the rates of adverse events ranged from 43% to 72% with sarilumab versus 47% with placebo.20 Adverse events that occurred in ≥5% of patients who received sarilumab or placebo included infections and infestations, neutropenia, and increased ALT levels. Infections and infestations were the most common adverse events in patients who received sarilumab doses of 150 mg every 2 weeks (23.1%) and higher (100 mg weekly, 26%; 150 mg weekly, 20%; 200 mg every 2 weeks, 23.5%) compared with placebo (13.7%), but none were serious. Treatment-emergent serious adverse events occurred in approximately 6% of patients who received sarilumab 100 mg every 2 weeks or 100 mg weekly versus 3.9% of patients who received placebo.20
Sarilumab 150 mg and 200 mg every 2 weeks were selected to be evaluated in the phase 3 MOBILITY Part B clinical trial, based on the overall efficacy, safety, and dosing convenience of these regimens.20
Phase 3 MOBILITY Part B Clinical Trial
Study design. The phase 3 MOBILITY Part B clinical trial enrolled patients into 2 cohorts: cohort 1 (N = 172) included patients from the dose-finding, MOBILITY Part A study who were randomized to receive placebo or 1 of 5 subcutaneous doses of sarilumab, and cohort 2 (N = 1197) included patients who were randomized in a 1:1:1 ratio to receive placebo, sarilumab 150 mg every 2 weeks, or sarilumab 200 mg every 2 weeks, in combination with weekly methotrexate.21
Overall, 88 patients from the MOBILITY Part A clinical trial who received placebo, sarilumab 150 mg every 2 weeks, or sarilumab 200 mg every 2 weeks continued the 52-week study, while the rest of the patients were allowed to participate in the open-label, extension period, in which they received sarilumab 200 mg every 2 weeks (Figure).21
The study duration was 62 weeks, comprising 4 weeks of screening, 52 weeks of treatment, and 6 weeks of posttreatment follow-up.21 The 3 coprimary end points were the proportion of patients who achieved ACR20 response at week 24; change from baseline in physical function, as assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI) at week 16; and the change from baseline in the modified Sharp/van der Heijde score (SHS) of radiographic damage at week 52. The key secondary end point was the proportion of patients who maintained an ACR70 response for ≥6 consecutive months; additional secondary end points included DAS28-CRP and the Clinical Disease Activity Index (CDAI).21
Efficacy. Patients who received sarilumab 150 mg or 200 mg every 2 weeks achieved significant improvements in all 3 coprimary end points.21 The ACR20 response at week 24 was 58.0% with sarilumab 150 mg plus methotrexate and 66.4% with sarilumab 200 mg plus methotrexate versus 33.4% with placebo plus methotrexate (P <.0001).
The mean change from baseline in HAQ-DI scores at week 16 was –0.53 with sarilumab 150 mg plus methotrexate and –0.55 with sarilumab 200 mg plus methotrexate versus –0.29 with placebo plus methotrexate (P <.0001).
The mean change from baseline in SHS at week 52 was 0.90 with sarilumab 150 mg plus methotrexate and 0.25 with sarilumab 200 mg plus methotrexate versus 2.78 with placebo plus methotrexate (P <.0001; Table 1). Both sarilumab dosage groups also demonstrated improvements in ACR70, DAS28-CRP, and CDAI scores compared with placebo.21
Safety. Adverse events were more common in patients who received sarilumab 150 mg (74.5%) or 200 mg (78.1%) compared with patients who received placebo (61.6%). Infections were the most common adverse events in each treatment group (sarilumab 150 mg, 40.1%; sarilumab 200 mg, 39.6%; placebo, 31.1%), with serious infections occurring in 2.6%, 4.0%, and 2.3% of patients who received sarilumab 150 mg, sarilumab 200 mg, or placebo every 2 weeks, respectively (Table 2). Opportunistic infections were reported in 3 (0.7%) patients who received sarilumab 150 mg plus methotrexate, in 4 (0.9%) patients who received sarilumab 200 mg plus methotrexate, and in 2 (0.5%) patients who received placebo plus methotrexate.21
Hypersensitivity reactions were reported in 6.7% of patients in the sarilumab 150-mg group, in 7.8% of patients in the sarilumab 200-mg group, and in 4.7% of patients in the placebo group, the majority of which were injection-site reactions. There were no cases of anaphylaxis.21
Patients who received sarilumab had increases in ALT levels (sarilumab 150 mg, 8.6%; sarilumab 200 mg, 7.5%; placebo, 3.3%), leading to treatment discontinuation in 24 patients who had increases in ALT levels of >3-fold the upper limit of normal.21
Elevations in fasting total cholesterol levels were reported in 36.8%, 43.0%, and 18.3% of patients who received sarilumab 150 mg, sarilumab 200 mg, or placebo, respectively, which led to treatment with lipid-modifying agents in 29 patients.21
Furthermore, reductions in the absolute neutrophil count of 0.5 to <1.0 × 109/L were reported in 5.1% of patients who received sarilumab 150 mg and in 7.8% of patients who received sarilumab 200 mg.21
Overall, 8 neoplasms were reported during the study, including 4 in the sarilumab 150-mg group, 3 in the sarilumab 200-mg group, and 1 in the placebo group.21
Health-related quality of life. Health-related quality of life is a desirable treatment outcome in patients with RA, because diminished physical functioning as a result of RA symptoms compromises patients’ ability to perform daily activities at home and at work.22 Patient-reported outcomes data, including patient global assessment of disease activity (PtGA), pain visual analog scale, Short Form-36 Health Survey (SF-36), HAQ-DI, and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), were reported in the phase 3 MOBILITY clinical trial.23
The patient-reported outcomes instruments were administered at baseline, weeks 2 and 4 of therapy, and every 4 weeks thereafter. Compared with patients in the placebo group, patients in the sarilumab 150-mg and 200-mg dose cohorts showed clinically meaningful improvements from baseline by week 24 in patient-reported outcomes of PtGA, pain, FACIT-F, and HAQ-DI, which were maintained until week 52.23
Phase 3 TARGET Clinical Trial
Although TNF inhibitors are indicated for patients with an inadequate response to conventional DMARDs, up to 40% of patients do not respond or are intolerant to TNF inhibitors.16 Given that the ACR guideline recommends switching these patients from a TNF inhibitor to a biologic DMARD with a different mechanism of action, the use of an IL-6 blocker may be an appropriate treatment approach, which was assessed in the TARGET and the MONARCH clinical trials.
Study design. The TARGET clinical trial was a 3-arm, multicenter, randomized, double-blind, placebo-controlled, phase 3 study that evaluated the safety and efficacy of sarilumab in 546 patients who did not respond to TNF inhibitor therapy.24
Eligible patients were randomized to receive subcutaneous sarilumab 150 mg, sarilumab 200 mg, or placebo every 2 weeks in combination with background conventional synthetic DMARDs for 24 weeks; patient stratification was based on the number of exposures to previous TNF inhibitors (1 or >1 exposure) and on the geographic region.24
The coprimary end points were ACR20 response rate at week 24 and the change from baseline in the HAQ-DI at week 12. The secondary end points included the change from baseline in DAS28-CRP at week 24, ACR50 and ACR70 response rates at week 24, DAS28-CRP <2.6 at week 24, and the change from baseline in the HAQ-DI at week 24.24
Efficacy. A significantly higher percentage of patients who received sarilumab 150 mg or 200 mg every 2 weeks achieved an ACR20 response at week 24 compared with patients who received placebo (sarilumab 150 mg, 55.8%; sarilumab 200 mg, 60.9%; placebo, 33.7%; P <.0001; Table 3).24 The mean change from baseline in the HAQ-DI score at week 12 was significantly higher for patients who received sarilumab compared with those who received placebo (least squares mean change for sarilumab 150 mg, –0.46, P = .0007; sarilumab 200 mg, –0.47, P = .0004; placebo, –0.26).24
Patients who received sarilumab also achieved clinically meaningful ≥0.22 units of improvement from baseline in HAQ-DI at week 24 versus placebo (sarilumab 150 mg, 47.5%, P = .0137; sarilumab 200 mg, 56.0%, P <.0001; placebo, 35.4%).24
Furthermore, more patients in the sarilumab group versus the placebo group achieved an ACR50 response (sarilumab 150 mg, 37.0%; sarilumab 200 mg, 40.8%; placebo 18.2%; P <.0001 for both comparisons), ACR70 response (sarilumab 150 mg, 19.9%, P = .0002; sarilumab 200 mg, 16.3%, P = .0056; placebo, 7.2%), DAS28-CRP <2.6 at week 24 (sarilumab 150 mg, 24.9%; sarilumab 200 mg, 28.8%; placebo, 7.2%; P <.0001 for both comparisons), and DAS28-CRP scores <3.2 at week 24 (sarilumab 150 mg, 32.6%; sarilumab 200 mg, 40.2%; placebo, 13.8%; P <.0001 for both comparisons).24
Overall, more patients in the placebo group required rescue treatment by the end of the study (34.8%) compared with patients in the sarilumab 150-mg group (13.8%) and patients in the sarilumab 200-mg group (14.1%).24
Safety. The safety profile of sarilumab 150 mg and 200 mg was consistent with that previously reported in the MOBILITY clinical trial, including infections, laboratory abnormalities, and blood or lymphatic disorders. Infections were the most frequently reported adverse events across the treatment groups; no cases of tuberculosis or systemic disseminated opportunistic infections were reported.24
Serious adverse events were reported in 6 (3.3%) patients in the sarilumab 150-mg group, in 6 (3.3%) patients in the sarilumab 200-mg group, and in 10 (5.4%) patients in the placebo group. Infections were the most common serious adverse event across the treatment groups, and decreased neutrophil counts, elevated transaminase levels, and cardiovascular disorders (1 case each of endocarditis of the mitral valve, atrioventricular block, venous thrombosis) were the most common serious adverse events in the sarilumab 200-mg group.24
Hypersensitivity reactions were reported in 10 (5.5%) patients who received sarilumab 150 mg and in 11 (6.0%) patients who received sarilumab 200 mg compared with 7 (3.9%) patients who received placebo; none of the hypersensitivity reactions were serious.24
Laboratory abnormalities included reductions in absolute neutrophil counts 3 times the upper limit of normal (sarilumab 150 mg, 2.2%; sarilumab 200 mg, 4.3%; placebo, 1.1%).24
MONARCH Clinical Trial: Frontline Sarilumab Monotherapy versus Adalimumab Monotherapy
Study design. MONARCH was a multicenter, randomized, double-blind, double-dummy, phase 3 clinical trial that evaluated the safety and efficacy of sarilumab versus the TNF inhibitor adalimumab in patients with active RA.25 Patients were randomized to receive subcutaneous sarilumab 200 mg plus placebo once every 2 weeks (N = 184) or adalimumab 40 mg plus placebo once every 2 weeks (N = 185) for 24 weeks.25
The primary efficacy end point was the change from baseline in DAS28 using ESR at week 24. The secondary efficacy end points at week 24 included DAS28-ESR remission (<2.6), HAQ-DI, ACR20, ACR50 and ACR70 responses, Medical Outcomes SF-36 Health Survey (v2), physical component summary score, mental component summary score, and FACIT-F.25
Efficacy. Sarilumab 200 mg every 2 weeks was superior to adalimumab 40 mg every 2 weeks with regard to the mean change from baseline to week 24 in DAS28-ESR (−3.28 vs −2.20, respectively; difference, −1.08; 95% confidence interval [CI], −1.36 to −0.79; P <.0001; Table 4).25
In addition, the odds of achieving DAS28-ESR remission at week 12 were approximately 3-fold greater with sarilumab than with adalimumab (odds ratio [OR], 2.61; 95% CI, 1.31-5.20; nominal P = .0051) and 5-fold greater at week 24 (OR, 4.88; 95% CI, 2.54-9.39; P <.0001).25
A higher percentage of patients who received sarilumab achieved ACR20 response compared with patients who received adalimumab (71.7% vs 58.4%, respectively; P ≤.0074), ACR50 response (45.7% vs 29.7%, respectively; P ≤.0074), ACR70 response (23.4% vs 11.9%, respectively; P ≤.0074), improvement in HAQ-DI scores (–0.61 vs 0.43, respectively; P = .0037), and CDAI remission at week 24 (7.1% vs 2.7%, respectively; nominal P = .0468).25
Furthermore, at week 24, patients who received sarilumab had a significantly greater improvement in the SF-36 physical component summary score compared with patients who received adalimumab, and improvements in SF-36 mental component summary score and FACIT-F were similar between the 2 groups, with a trend toward greater improvement in FACIT-F with sarilumab versus adalimumab.25
Safety. The incidence rates of adverse events (sarilumab, 64%; adalimumab, 64%), serious adverse events (sarilumab, 4.9%; adalimumab, 6.5%), and discontinuation rates (sarilumab, 6.0%; adalimumab, 7.1%) were similar between the treatment groups.25
The incidence rates of neutropenia (sarilumab, 13.6%; adalimumab, 0.5%) and injection-site erythema (sarilumab, 7.6%; adalimumab, 3.3%) were higher in the sarilumab group than in the adalimumab group, whereas the incidence rates of headache (sarilumab, 3.8%; adalimumab, 6.5%) and dyslipidemia (sarilumab, 1.6%; adalimumab, 4.3%) were more common in the adalimumab group than in the sarilumab group. However, infection rates (sarilumab, 28.8%; adalimumab, 27.7%) and elevations in ALT levels (sarilumab, 3.8%; adalimumab, 3.8%) were similar between the 2 groups.25
Important Safety Information
The most common adverse reactions with sarilumab are neutropenia, increased ALT levels, injection-site erythema, upper respiratory infections, and urinary tract infections.7
Sarilumab is contraindicated in patients with known hypersensitivity to sarilumab or any of the inactive ingredients.7
Warnings and Precautions
The prescribing information for sarilumab contains a box warning stating that sarilumab is associated with an increased risk for serious infections that may lead to hospitalization or death.7 Opportunistic infections because of bacterial, mycobacterial, invasive fungal, or viral pathogens have been reported in patients receiving immunosuppressive drugs for RA, such as methotrexate or corticosteroids.7
The most common serious infections with sarilumab included pneumonia and cellulitis, and common opportunistic infections included tuberculosis, candidiasis, and pneumocystis. Therefore, the use of sarilumab should be avoided in patients with an active infection, and the risks and benefits of sarilumab treatment should be considered before starting therapy in patients with chronic or recurrent infection.7
Patients should be tested for tuberculosis before and during sarilumab therapy, and latent tuberculosis infection should be treated with antimycobacterial therapy before sarilumab therapy. Patients must be closely monitored for the signs and symptoms of infection during treatment with sarilumab; if a serious infection develops, sarilumab therapy must be withheld until the infection is controlled. Furthermore, the concurrent use of live vaccines during treatment with sarilumab should be avoided.7
Laboratory abnormalities associated with sarilumab treatment include a decrease in absolute neutrophil counts (including neutropenia), a decrease in platelet counts, elevations in transaminase levels, and increase in lipid parameters.7 Neutrophil count, platelet count, and transaminase levels should be assessed before starting sarilumab therapy, monitored 4 to 8 weeks after starting therapy, and every 3 months or 6 months (lipid levels) thereafter. Because of the risk for elevations in transaminase levels, sarilumab therapy is not recommended in patients with active hepatic disease or hepatic impairment.7
In addition, sarilumab may increase the risk for gastrointestinal perforation with the concurrent use of nonsteroidal anti-inflammatory drugs or corticosteroids. There is also an increased risk for malignancies when sarilumab is used in combination with immunosuppressant drugs.7
Sarilumab should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. Given the excretion of small amounts of sarilumab in human milk, the benefits of breastfeeding and the potential adverse effects of sarilumab on the breastfed child should be considered, in addition to the mother’s clinical need for sarilumab.7
Sarilumab represents a novel and effective biologic therapy in the treatment armamentarium for RA. Despite the treatment advances achieved with biologic DMARDs in patients with RA, inadequate response or intolerance to biologic DMARDs, or contraindications to the use of specific biologic DMARDs in certain patient populations are clinical realities that need to be addressed.
Given the central role of IL-6 in the pathogenesis of RA, FDA-approved IL-6 inhibitors, such as sarilumab, are indicated for the treatment of patients with moderate-to-severe RA who have had an inadequate response or intolerance to other DMARDs, including methotrexate and TNF inhibitors.
Although the efficacy and safety data for sarilumab are similar to that of tocilizumab in patients with RA who had an inadequate response to methotrexate, sarilumab has a greater affinity to IL-6 than does tocilizumab, and in the absence of head-to-head comparisons, this may potentially reflect higher potency and better efficacy with sarilumab versus tocilizumab.
Furthermore, by demonstrating superiority over adalimumab, sarilumab may represent a better treatment option for patients who have an inadequate response or are intolerant to methotrexate and for whom biologic DMARD monotherapy is indicated. Results from future studies will help define the role of sarilumab in the current treatment algorithm for the management of RA.
- Helmick CG, Felson DT, Lawrence RC, et al; for the National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: part I. Arthritis Rheumatol. 2008;58:15-25.
- Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388:2023-2038. Erratum in: Lancet. 2016;388:1984.
- Gonzalez A, Maradit Kremers H, Crowson CS, et al. The widening mortality gap between rheumatoid arthritis patients and the general population. Arthritis Rheum. 2007;56:3583-3587.
- Birnbaum H, Pike C, Kaufman R, et al. Societal cost of rheumatoid arthritis patients in the US. Curr Med Res Opin. 2010;26:77-90.
- Shahouri SH, Michaud K, Mikuls TR, et al. Remission of rheumatoid arthritis in clinical practice: application of the American College of Rheumatology/European League Against Rheumatism 2011 remission criteria. Arthritis Rheum. 2011;63:3204-3215.
- Regeneron. Regeneron and Sanofi announce FDA approval of Kevzara (sarilumab) for the treatment of moderately to severely active rheumatoid arthritis in adult patients. Press release. May 22, 2017. http://investor.regeneron.com/releaseDetail.cfm?releaseid=1027419. Accessed July 6, 2017.
- Kevzara (sarilumab) injection [prescribing information]. Tarrytown, NY: Regeneron Pharmaceuticals; Bridgewater, NJ: sanofi-aventis U.S.; May 2017.
- Hashizume M, Mihara M. The roles of interleukin-6 in the pathogenesis of rheumatoid arthritis. Arthritis. 2011;2011:765624.
- Choy E. Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford). 2012;51(suppl 5):v3-v11.
- Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest. 2008;118:3537-3545.
- Yoshida Y, Tanaka T. Interleukin 6 and rheumatoid arthritis. Biomed Res Int. 2014;2014:698313.
- Gabay C. Interleukin-6 and chronic inflammation. Arthritis Res Ther. 2006;8 (suppl 2):53.
- Dayer JM, Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology (Oxford). 2010;49:15-24.
- Singh JA, Saag KG, Bridges SL Jr, et al; for the American College of Rheumatology. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2016;68:1-25.
- Curtis JR, Zhang J, Xie F, et al. Use of oral and subcutaneous methotrexate in rheumatoid arthritis patients in the United States. Arthritis Care Res (Hoboken). 2014;66:1604-1611.
- Vander Cruyssen B, Van Looy S, Wyns B, et al. Four-year follow-up of infliximab therapy in rheumatoid arthritis patients with long-standing refractory disease: attrition and long-term evolution of disease activity. Arthritis Res Ther. 2006;8:R112.
- Actemra (tocilizumab) injection [prescribing information]. South San Francisco, CA: Genentech; May 2017.
- Rafique A, Martin J, Blome M, et al. AB0037 Evaluation of the binding kinetics and functional bioassay activity of sarilumab and tocilizumab to the human il-6 receptor (il-6r) alpha. Ann Rheum Dis. 2013;72(suppl 3):A797.
- Radin AR, Mellis SJ, Jasson M, et al. REGN88/SAR153191, a fully-human interleukin-6 receptor monoclonal antibody, reduces acute phase reactants in patients with rheumatoid arthritis: preliminary observations from phase 1 studies. Arthritis Rheum. 2010;62(10 suppl):Abstract 1121.
- Huizinga TW, Fleischmann RM, Jasson M, et al. Sarilumab, a fully human monoclonal antibody against IL-6Rα in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY Part A trial. Ann Rheum Dis. 2014;73: 1626-1634.
- Genovese MC, Fleischmann R, Kivitz AJ, et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a phase III study. Arthritis Rheumatol. 2015;67:1424-1437.
- Strand V, Wright GC, Bergman MJ, et al. Patient expectations and perceptions of goal-setting strategies for disease management in rheumatoid arthritis. J Rheumatol. 2015;42:2046-2054.
- Strand V, Kosinski M, Chen CI, et al. Sarilumab plus methotrexate improves patient-reported outcomes in patients with active rheumatoid arthritis and inadequate responses to methotrexate: results of a phase III trial. Arthritis Res Ther. 2016;18:198.
- Fleischmann R, van Adelsberg J, Lin Y, et al. Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors. Arthritis Rheumatol. 2017;69:277-290.
- Burmester GR, Lin Y, Patel R, et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis. 2017;76:840-847.