The availability of biologic disease-modifying antirheumatic drugs (DMARDs) represents a major advance in the treatment of rheumatoid arthritis (RA); however, not all patients have an adequate response to these medications. The oral selective Janus kinase (JAK) inhibitor baricitinib may offer an alternative for those who have an inadequate response to treatment with tumor necrosis factor (TNF) inhibitor, despite treatment with conventional DMARDs.1

The promising news about baricitinib was reported in findings from the RA-BEACON study, published in The New England Journal of Medicine.1 The study was conducted after previous reports confirmed the agent’s ability to reduce disease activity in DMARD-naive patients.2,3



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The phase 3 study, conducted by Mark C. Genovese, MD, of Stanford University Medical Center in Palo Alto, California, and an international team of colleagues, included 527 patients with adult-onset RA as defined by American College of Rheumatology(ACR)/ European League Against Rheumatism (EULAR) 2010 criteria.

 Participants were from 178 centers in 24 countries. All patients were receiving conventional DMARD therapy at the time of enrollment in the study and had discontinued biologic DMARD therapy because of either inadequate response or adverse events.

Patients were randomly assigned in a 1:1:1 ratio to receive baricitinib at a daily dosage of 2 mg or 4 mg or placebo for 24 weeks, in addition to standard care. The primary end point of the study was the proportion of patients who had ACR 20% (ACR20) response at week 12. ACR20 includes ≥ 20% reduction in the number of tender and swollen joints and ≥ 20% improvement in ≥ 3 of the following measures: patient assessment of pain, physician and/or patient global assessment, physical function per the Health Assessment Questionnaire-Disability Index (HAQ-DI), and/or acute-phase reactant measures. 

Secondary end points included HAQ-DI physical function score, 28-joint C-reactive protein level Disease Activity Score (DAS28-CRP), and Simplified Disease Activity Index (SDAI) score. ACR50 and ACR70 responses were included in the secondary outcomes but were not reported.

The researchers found that significantly more patients receiving baricitinib at the higher dosage of 4 mg/day achieved ACR20 response at week 12 compared with those taking placebo (55% vs 27%, P < .001). Differences in HAQ-DI physical function score and DAS28-CRP score were also significant for higher-dosage baricitinib vs placebo (P < .001), but there was no difference between groups for the SDAI score.

Because of these findings and on the basis of hierarchic testing, the research team ultimately chose not to evaluate efficacy outcomes for the 2-mg/day dosage of baricitinib but did include the data in safety outcomes. They found that adverse event rates through week 24 were higher for patients receiving baricitinib 4 mg/day than for those receiving 2 mg (77% vs71%), and these rates were higher than the rate seen among patients receiving placebo (64%). 

The rates of infection in the baricitinib 4-mg, baricitinib 2-mg, and placebo groups were 44% , 40%, and 31%, respectively, but rates of serious infection were low and comparable across groups (3%, 2%, and 3%, respectively).

Rates of overall serious adverse events in the baricitinib 4-mg, baricitinib 2-mg, and placebo groups were 4%, 10%, and 7%, respectively, including 2 cases of nonmelanoma skin cancer and 2 cardiovascular events in the higher-dose baricitinib group. The cardiovascular events included fatal stroke in a 76-year-old woman who had preexisting diabetes and myocardial infarction in a 92-year-old woman who had preexisting diabetes and hypertension. The researchers also reported that baricitinib was associated with a small reduction in neutrophil level and increases in serum creatinine and low-density lipoprotein cholesterol levels.

In all, the findings showed that baricitinib at a dosage of 4 mg/day was associated with clinical improvement in those with RA who had an inadequate response to or who could not tolerate treatment with biologic and/or conventional DMARDS. Thus, baricitinib may offer a therapeutic alternative for patients who fail DMARD therapy.

Summary and Clinical Applicability

The selective JAK inhibitor baricitinib, given at a dosage of 4 mg/day for 12 weeks, was associated with short-term clinical improvements of RA disease activity in patients who had an inadequate response to or who could not tolerate therapy with conventional DMARDs and/or biologic DMARDs. Of clinical relevance is the possibility of a narrow-spectrum JAK inhibitor as a therapeutic option for those with RA who cannot tolerate or who do not respond adequately to DMARDs.

It is important for clinicians to note that study participants receiving baricitinib had increases in serum creatinine kinase levels.

Limitations and Disclosures

A major limitation of the study was its cutoff at 24 weeks, which is considered too short a time to evaluate whether baricitinib has the capacity to slow the rate of radiographically detected structural joint damage. Further phase 3 studies, however, are planned to evaluate the agent’s effect on progressive radiographic joint damage.

This study was supported by Eli Lilly and Incyte. Based on results from this trial, Eli Lilly has filed with the U.S. Food and Drug Administration for approval of baricitinib.  

References

1. Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016;374(13):1243-1252.

2. Keystone EC, Taylor PC, Drescher E, et al. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann Rheum Dis. 2015;74(2):333-340.

3. Tanaka Y, Emoto K, Cai Z, et al. Efficacy and safety of baricitinib in Japanese patients with active rheumatoid arthritis receiving background methotrexate therapy: a 12-week, double-blind, randomized placebo-controlled study. J Rheumatol. 2016;43(3):504-511.