In patients with rheumatoid arthritis who had had an inadequate response to methotrexate, baricitinib was associated with significant clinical improvements as compared with placebo and adalimumab. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01710358 .).

In patients with rheumatoid arthritis and an inadequate response to biologic DMARDs, baricitinib at a daily dose of 4 mg was associated with clinical improvement at 12 weeks. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01721044.).

BackgroundBaricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor.MethodsIn this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with rheumatoid arthritis and inadequate response or intolerance to ≥1 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4 mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score ≤3.3.ResultsMore patients achieved ACR20 response at week 12 with baricitinib 4 mg than with placebo (62% vs 39%, p≤0.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4 mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4 mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4 mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein.ConclusionsIn patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage.Trial registration numberNCT01721057; Results.

ObjectiveWe undertook this phase III study to evaluate baricitinib, an orally administered JAK‐1/JAK‐2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX monotherapy in patients with active rheumatoid arthritis (RA) who had received no or minimal conventional synthetic disease‐modifying antirheumatic drugs (DMARDs) and who were naive to biologic DMARDs.MethodsA total of 588 patients were randomized 4:3:4 to receive MTX monotherapy (once weekly), baricitinib monotherapy (4 mg once daily), or the combination of baricitinib and MTX for 52 weeks. The primary end point assessment was a noninferiority comparison of baricitinib monotherapy to MTX monotherapy based on the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 24.ResultsThe study met its primary objective. Moreover, baricitinib monotherapy was found to be superior to MTX monotherapy at week 24, with a higher ACR20 response rate (77% versus 62%; P ≤ 0.01). Similar results were observed for combination therapy. Compared to MTX monotherapy, significant improvements in disease activity and physical function were observed for both baricitinib groups as early as week 1. Radiographic progression was reduced in both baricitinib groups compared to MTX monotherapy; the difference was statistically significant for baricitinib plus MTX. The rates of serious adverse events (AEs) were similar across treatment groups, while rates of some treatment‐emergent AEs, including infections, were increased with baricitinib plus MTX. Three deaths were reported, all occurring in the MTX monotherapy group. Malignancies, including nonmelanoma skin cancer, were reported in 1 patient receiving MTX monotherapy, 1 receiving baricitinib monotherapy, and 4 receiving baricitinib plus MTX.ConclusionBaricitinib alone or in combination with MTX demonstrated superior efficacy with acceptable safety compared to MTX monotherapy as initial therapy for patients with active RA.

ObjectivesTo investigate baricitinib (LY3009104, formerly INCB028050), a novel, oral inhibitor of JAK1/JAK2 in patients with moderate to severe rheumatoid arthritis (RA) despite treatment with methotrexate.MethodsIn this phase IIb study, 301 patients were randomised 2:1:1:1:1 to receive once daily doses of placebo or 1, 2, 4 or 8 mg baricitinib for 12 weeks. Patients assigned to 2, 4 and 8 mg baricitinib continued blinded treatment for an additional 12 weeks. Patients assigned to placebo or 1 mg baricitinib were reassigned to 2 mg twice daily or 4 mg once daily baricitinib between weeks 12–24. The primary endpoint was the proportion of patients in the combined 4 and 8 mg groups achieving an American College of Rheumatology 20% (ACR20) response versus placebo at week 12.ResultsSignificantly more patients in the combined baricitinib 4 and 8 mg groups compared with placebo achieved an ACR20 response at week 12 (76% vs 41%, p<0.001). At week 12, significant differences versus placebo were also observed in patients achieving ACR50, ACR70 and remission as measured by Disease Activity Score for 28-joint counts, Clinical Disease Activity Index and Simplified Disease Activity Index. Patients receiving 2, 4, or 8 mg baricitinib maintained or improved in all measures through 24 weeks. Similar proportions of patients experienced at least one adverse event in the placebo and baricitinib groups. Serious infections developed in three patients receiving baricitinib. No cases of tuberculosis, herpes zoster, opportunistic infections or deaths were reported. Dose-dependent decreases in haemoglobin were observed with baricitinib.ConclusionsBaricitinib improved the signs and symptoms of RA in methotrexate inadequate responders with active disease. Baricitinib was well tolerated with no unexpected safety findings through week 24.Trial registration numberNCT01185353.