By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved the second injectable interleukin-6 receptor antagonist (IL-6RA) for the treatment of rheumatoid arthritis (RA), joining tocilizumab. Sarilumab is a human recombinant monoclonal antibody marketed as Kevzara.
INDICATIONS
Sarilumab is indicated for the treatment of adults with moderately to severely active RA who have demonstrated an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs).1 It may be used alone or in combination with methotrexate or other conventional (non-biological) DMARDs.
DOSAGE
The recommended dose is 200 mg administered subcutaneously once every two weeks.1 The dose should be modified because of low neutrophil count, low platelet count, or elevated liver enzyme levels. Sarilumab initiation is not recommended in patients with low absolute neutrophil count < 2,000/mm3, platelet count < 50,000/mm3, or liver enzymes > 1.5 times the upper limit of normal (ULN).1 Sarilumab should not be used with biological DMARDs.
POTENTIAL ADVANTAGES
Sarilumab offers another non-tumor necrosis factor (TNF) biologic and the second IL-6RA for the treatment of RA.
POTENTIAL DISADVANTAGES
Adverse reactions (compared to placebo) include injection site reactions (7% vs. 1%), a decrease in neutrophil count to < 1,000/mm3 (6% vs. 0%), a decrease in platelet count to < 100,000/mm3 (1% vs. 0%), and an elevation of liver enzymes (AST/ALT; between > ULN to three times ULN; 30-43% vs. 15-25%). The frequency of neutropenia was 10% vs. 0.2% for placebo. Increases in low-density lipoprotein cholesterol and triglyceride levels have been reported with mean increase of 16 mg/dL and 27 mg/dL, respectively. Neutralizing antibodies were detected in 1-1.6% of subjects exposed to sarilumab compared to 0.2% for placebo exposure. Gastrointestinal perforation has been reported (0.11 events per 100 patient-years), primarily as a complication of diverticulosis or concomitant use of nonsteroidal anti-inflammatory drugs or corticosteroids. Sarilumab shares a boxed warning regarding serious infections similar to that of other biological DMARDs.
COMMENTS
IL-6 is a proinflammatory cytokine produced by various cells, including synovial and endothelial cells.1 Elevated levels have been reported in serum and synovial fluids of RA patients. Sarilumab binds to both soluble and membrane-bound IL-6 receptors, thereby inhibiting IL-6 signaling. The efficacy and safety of sarilumab were assessed in two randomized, double-blind, placebo-controlled studies in adult subjects with moderately to severely active RA.1-4 The first study included subjects with inadequate response to methotrexate (n = 1,197), and the second study included those who demonstrated an inadequate response to or were intolerant of one or more TNF-alpha antagonists. Patients were randomized to sarilumab 150 mg or 200 mg every two weeks or placebo. The primary endpoint was a 20% improvement in the American College of Rheumatology Criteria (ACR20) at week 24. Other endpoints were physical function (Health Assessment Questionnaire Disability Index at week 16 in the first study and week 12 in the second study). Change from baseline in van der Heijde-modified Total Sharp Score (mTSS) was assessed at week 52 in the first study. Major clinical response also was assessed in the first study, which was defined as a 70% improvement (ACR70) for at least 24 consecutive weeks during the 52-week period. ACR20 at week 24 for the first study was 58% for the 150 mg group, 66.4% for the 200 mg group, and 33.4% for the placebo group. For the second study, the results were 55.8%, 60.9%, and 33.7%, respectively. Both doses in each study were statistically significant at P < 0.0001 compared to placebo. There were significant improvements in patient-reported outcomes.1,4,5 The treatment benefit was maintained through week 52 in the first study.1,2 There also was significantly less radiographic progression of structural damage compared to placebo. Major clinical response was 12.8% and 14.8% for the two doses of sarilumab, compared to 3% for placebo. Currently, there are no published comparative trials with the first approved IL-6RA, tocilizumab. In an indirect comparison of the drugs in a similar study with moderately to severely active RA, in patients who demonstrated inadequate response to methotrexate, the addition of sarilumab 200 mg or tocilizumab 8 mg/kg every four weeks to methotrexate produced similar ACR20 responses at week 24.1,6 The adverse reaction profiles for tocilizumab and sarilumab also appear similar as they are regarded as class effects. Both drugs have been reported to be more effective than adalimumab as monotherapy in active RA patients who should not continue with methotrexate because of intolerance or inadequate response.7,8 However, the IL-6RAs were more likely to cause reduced neutrophil and platelet counts and increase liver enzymes.
CLINICAL IMPLICATIONS
Currently, there are two classes of biologics to treat RA: TNF inhibitors (TNFi) and non-TNF biologics. The majority target TNF-alpha (etanercept, adalimumab, infliximab, certolizumab, and golimumab). Non-TNF drugs are anakinra, which targets IL-1RA; tocilizumab, which targets IL-6; and rituximab, which targets B lymphocytes. Sarilumab is the second IL-6RA approved for moderately to severely active RA. The American College of Rheumatology recommends the addition of a TNFi or non-TNF biologic with methotrexate as options in patients with established RA who have failed DMARD monotherapy.9 The cost of sarilumab is $3,000 for a four-week supply, compared to $1,796-$3,592 depending on body weight and clinical response for tocilizumab.
REFERENCES
- Kevzara Prescribing Information. Regeneron and Sanofi Genzyme. May 2017.
- Genovese MC, et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: Results of a phase III study. Arthritis Rheumatol 2015:1427-1437.
- Fleischmann R, 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 Rheum 2017;69:277-290.
- Strand V, 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 Sep 6;18:198. doi: 10.1186/s13075-016-1096-9.
- Strand V, et al. Sarilumab improves patient-reported outcomes in rheumatoid arthritis patients with inadequate response/intolerance to tumour necrosis factor inhibitors. RMD Open 2017 Mar 7;3(1):e000416. doi: 10.1136/rmdopen-2016-000416. eCollection 2017.
- Actemra Prescribing Information. Genentech, Inc. May 2017.
- Burmester GR, 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.
- Gabay C, et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): A randomised, double-blind, controlled phase 4 trial. Lancet 2013;381:1541-1550.
- Singh JA, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2016;68:1-25.
Sarilumab is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis who have demonstrated an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs.
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