Phase 3 Primary Endpoint Met For New JAK Inhibitor For RA

The efficacy of baricitinib, an experimental small molecule JAK kinase inhibitor, was assessed in a phase 3 trial of patients with rheumatoid arthritis who had either failed treatment with conventional and synthetic DMARDs, or who were not tolerant of DMARD treatment.

HealthDay News – Results from a phase 3 trial evaluating treatment of severe rheumatoid arthritis (RA) with baricitinib, a orally administered reversible JAK1/JAK2 tyrosine kinase inhibitor, resulted in improvements in ACR20 responses at the 12-week mark when compared to placebo.  These findings were recently published in the the New England Journal of Medicine.

Mark C. Genovese, MD, from Stanford University in Palo Alto, California, and colleagues conducted a phase 3 study in which 527 patients with severe RA were randomized (1:1:1) to baricitinib at a dose of 2 or 4 mg daily or placebo for 24 weeks. 

Patients previously had inadequate response to or unacceptable side effects associated with one or more tumor necrosis factor inhibitors (TNFi), other biologic disease-modifying antirheumatic drugs (DMARDS), or both.

The researchers found that significantly more patients receiving baricitinib (4 mg) had an American College of Rheumatology 20 percent (ACR20) response at week 12 versus the placebo group (P<.001). The higher-dose baricitinib group also saw a significant improvement on the Health Assessment Questionnaire-Disability Index and the 28-joint Disease Activity Score based on C-reactive protein level (DAS28-CRP) compared to the placebo group. 

However, there was no significant difference in the score of 3.3 or less on the Simplified Disease Activity Index. Baricitinib patients (at either 2mg or 4mg) had higher rates of adverse events, including reduced neutrophil counts, increased creatinine levels, and increased low-density lipoprotein cholesterol levels, through 24 weeks versus patients receiving placebo.

“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 treatment with both conventional synthetic DMARDs and biologic DMARDs”, the authors conclude.

Summary and Clinical Applicability

Patients with severe RA previously treated with one or more TNFis requiring subsequent discontinuation due to non-response or severe adverse drug effects demonstrated a clinical response to baricitinib, as measured by select disease activity scores, when compared to placebo.

“Our findings have particular relevance because of the unmet need for effective treatment of rheumatoid arthritis in patients receiving a conventional synthetic DMARD with inadequate disease control despite previous treatment with multiple biologic agents,” the authors stated. 

Limitations and Disclosures

These results were limited by lack of long-term follow-up and absence of radiographic measures of disease activity. Further head-to-head comparisons between baricitinib and specific combinations of TNFis will need to be established.

Eli Lilly and Incyte, the manufacturers of baricitinib, funded the study.  


Genovese MC, Kremer J, Zamani O, et al. Baricitinib in Patients with Refractory Rheumatoid Arthritis. N Engl J Med. 2016;374(13):1243-1252.