Baricitinib, an oral Janus kinase (JAK) inhibitor taken once daily, improved signs and symptoms of rheumatoid arthritis (RA) in patients who were refractory to other treatments, including tumor necrosis factor (TNF) inhibitors, or other biologic disease-modifying antirheumatic drugs (DMARDs), according to investigators in a placebo-controlled, phase 3 trial reported on recently in the New England Journal of Medicine.
“These results provide evidence that selective inhibition of JAK1 and JAK2 with once-daily baricitinib has clinical efficacy in patients with active [RA] that is refractory to aggressive standard-of-care treatments with both conventional synthetic DMARDs and biologic DMARDs,” observed Marc C. Genovese, MD, Stanford University Medical Center, Palo Alto, CA, and colleagues. “The treatment benefits were larger with the 4-mg dose than with the 2-mg dose.”
Adverse events included infections and abnormal laboratory test results (eg, increases in low-density lipoprotein cholesterol and creatinine levels). “These changes were predominantly minor and did not lead to withdrawal from the study,” according to the investigators.
Previously, phase 2 studies showed that baricitinib reduced disease activity in patients with RA who were naïve to biologic DMARDs. This phase 3 trial included 527 patients who had an inadequate response to—or experienced unacceptable side effects associated with—previous treatment with biologic DMARDs. Patients were randomized in a 1:1:1 ratio to baricitinib 2 mg or 4 mg per day, or placebo, and treated for 24 weeks.
A significantly higher number of patients treated with a 4-mg dose of baricitinib had ≥20% improvement in signs and symptoms of RA—according to American College of Rheumatology criteria—at week 12 versus those who received placebo (55% vs 27%, respectively; P <.001). The 4-mg dose group also had significantly higher scores compared with the placebo group on the Health Assessment Questionnaire-Disability Index, and the 28-joint Disease Activity Score based on C-reactive protein level (P <.001 for both measures).
Baricitinib 4 mg daily was numerically—but not statistically—superior to placebo on the Simplified Disease Activity Index score of ≤3.3 (indicating remission) at 12 weeks, but the difference between these 2 treatment arms became significant at 24 weeks (P <.01).
A beneficial effect of baricitinib was observed in all analyzed subgroups, regardless of how heavily pretreated with biologic DMARDs they were.
The authors pointed out that the patients enrolled in this trial had particularly refractory disease, having received multiple previous biologic therapies. They wrote that the beneficial treatment effect observed in this study appeared to be favorable compared with historical trials of currently approved therapies for patients with inadequate responses to TNF inhibitors. This population is growing, and treatment for them represents an unmet need, they wrote.
Limitations of the study include limiting the treatment effect to 24 weeks, and lack of radiographic data showing the effect of treatment on structural joint damage. Other phase 3 trials, however, will address these limitations.
Based on results of this and other studies, Eli Lilly and Incyte filed for US Food and Drug Administration approval for baricitinib in January 2016, and approval is expected to be granted later this year.
- Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016;374:1243-1252.