MONARCH TRIAL: Sarilumab
Sarilumab is a biologic disease-modifying antirheumatic drug (bDMARD) that targets cytokines for the treatment of patients with rheumatoid arthritis. This monoclonal antibody targets cytokines IL-6R and inhibits IL-6 mediated signaling. The presence of IL-6R in the synovial fluid of patients with rheumatoid arthritis has been linked with systemic inflammation, fatigue, and joint destruction. Rheumatoid arthritis is commonly treated with synthetic DMARDS such as methotrexate as first-line therapy, but many patients have built up an intolerance or have not mounted an adequate response to the therapy. Adalimumab, another biologic disease-modifying antirheumatic drug, like sarilumab, is globally approved for the treatment of rheumatoid arthritis and has proven successful in patients who do not respond well to methotrexate. Adalimumab targets TNF-a, a different target than sarilumab for the treatment of rheumatoid arthritis. The MONARCH trial was conducted to compare the efficacy and safety of sarilumab and adalimumab monotherapy in patients who did not reach clinical remission on synthetic DMARD therapy.
The MONARCH trial was a multicenter, randomized, active-controlled, double-blind, double-dummy, phase 3 superiority trial conducted in multiple countries that ran for 24 weeks. Inclusion criteria for patients included patients greater than 18 years of age, who fulfilled American College of Rheumatology (ACR)/European League Against Rheumatism Classification Criteria for RA and ACR class I–III functional status; had active RA, and either intolerant or considered inappropriate for continued treatment with methotrexate. The primary efficacy endpoint was a change from baseline in disease-joint activity using erythrocyte sedimentation rate (ESR). Other secondary efficacy endpoints included DAS28-ESR remission, Health Assessment Questionnaire-Disability Index (HAQ-DI); ACR 20% (ACR20), 50% (ACR50) and 70% (ACR70) responses; Medical Outcomes Short Form 36 Health Survey (V.2) (SF-36) physical component summary (PCS) score and mental component summary (MCS) score and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Clinical Disease Activity Index (CDAI). Safety was measured by assessing treatment-emergent adverse events, serious adverse events reported by investigators, as well as lab tests.
Within this study, the primary endpoint was reached. Sarilumab at a dose of 200 mg every 2 weeks was superior to adalimumab 40 mg every 2 weeks with a mean change from baseline to week 24 in DAS28-ESR of -1.08 with a 95% confidence interval. In comparison to adalimumab, the odds of reaching remission were three times more likely with sarilumab at week 12 and five times more likely at week 24. In terms of safety, the adverse events reported in both groups were similar, as well as the rate of discontinuation between the groups.
Biologics for the treatment of rheumatoid arthritis offers new options for patients who are not getting the help they need from older therapies such as methotrexate. This trial showed that sarilumab was superior to adalimumab in the reduction of disease activity with no large difference in safety. One of the most important things in patients suffering from rheumatoid arthritis is their ability to perform functional tasks without pain and fatigue. Compared to adalimumab, patients who received sarilumab reported a greater improvement in daily activities with less pain. Biologic therapy targeting different cytokines that play a role in the pathogenesis of rheumatoid arthritis is changing the way of life for patients who are plagued by this disease.
References:
1. 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(5):840-847. doi:10.1136/annrheumdis-2016-210310
2. Emery P, Rondon J, Parrino J, et al. Safety and tolerability of subcutaneous sarilumab and intravenous tocilizumab in patients with rheumatoid arthritis. Rheumatology (Oxford). 2019;58(5):849-858. doi:10.1093/rheumatology/key361
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Rheumatoid Arthritis is a chronic inflammatory disorder that can have a major impact on quality of life. In some people, this condition can damage many different body systems such as skin, eyes, lungs, heart, and blood vessels. The cause of this condition is when a person’s immune system mistakenly attacks the body’s own tissues. Rheumatoid arthritis is progressive and affects the lining of the synovial joints which causes painful swelling that can lead to bone erosion and joint deformity. If untreated, this can lead to significant pain, deformity, loss of manual function and deterioration in overall quality of life. The inflammation caused by rheumatoid arthritis can cause physical disabilities even with new types of medications having improved treatment options. Many of the treatment options for rheumatoid arthritis are NSAIDs, corticosteroids, methotrexate, tumor necrosis factor inhibitors, interleukin 1 inhibitors, rituximab, abatacept, and more. There has recently been data supporting the use of Janus Kinase Inhibitors in the treatment of rheumatoid arthritis. Some janus kinase inhibitors are upadacitinib, baricitinib, and tofacitinib. This is probably the most recent new drug class being tested for the use of this condition.
There are many trials on the use of janus kinase inhibitors. The ORAL scan trial was 24 month trial undertaken to evaluate the efficacy and safety of tofacitinib in patients with active rheumatoid arthritis that have an inadequate response to methotrexate. In this trial, there were seven hundred seventy-nine patients randomized 4:4:1:1 to receive tofacitinib 5 mg or 10 mg twice daily, or placebo switching to tofacitinib 5 mg twice daily with stable background methotrexate or placebo switching to 10 mg twice daily with stable background methotrexate. Patients receiving placebo switched to tofacitinib at month 3 or month 6 based on if they were not responding to treatment. In this trial, they evaluated clinical efficacy, structural progression, and treatment-emergent adverse events. Out of the 797 patients that were treated, 539 completed 24 months of treatment which was about 67.6 percent. The proportion of patients in whom remission or low disease activity was achieved according to the 4-variable disease activity score in 28 joins using erythrocyte sedimentation rate, clinical disease activity index, or simplified disease activity index, Boolean remission, and health assessment questionnaire disability index scores were maintained from month 12 to month 24 and were similar between the tofacitinib dosages. The safety events were also similar in type and frequency and were consistent with previous reported data. In this study, they found that the treatment of rheumatoid arthritis using janus kinase inhibitors like tofacitinib in combination with methotrexate would best sustain the effects of clinical and radiographic treatment. There was limited structural damage observed at months 12 and 24. The safety profile in this study was consistent with previous tofacitinib studies. This was a study that was conducted soon after tofacitinib has been approved for the use in the treatment of patients with moderate to severe rheumatoid arthritis. I believe studies like the ORAL scan study can help contribute to progressing treatment options for rheumatoid arthritis in the future.
References:
1. van der Heijde D, Strand V, Tanaka Y, Keystone E, Kremer J, Zerbini CAF, Cardiel MH, Cohen S, Nash P, Song YW, Tegzová D, Gruben D, Wallenstein G, Connell CA, Fleischmann R; ORAL Scan Investigators. Tofacitinib in Combination With Methotrexate in Patients With Rheumatoid Arthritis: Clinical Efficacy, Radiographic, and Safety Outcomes From a Twenty-Four-Month, Phase III Study. Arthritis Rheumatol. 2019 Jun;71(6):878-891. doi: 10.1002/art.40803. Epub 2019 Apr 24. PMID: 30666826; PMCID: PMC6593705.
2. “Rheumatoid Arthritis.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 18 May 2021, https://www.mayoclinic.org/diseases-conditions/rheumatoid-arthritis/symptoms-causes/syc-20353648.