Safety profile of baricitinib for the treatment of rheumatoid arthritis over a median of 3 years of treatment: an updated integrated safety analysis.

Abstract

Baricitinib is an oral selective inhibitor of Janus kinase (JAK) 1 and JAK2, approved for the treatment of patients with active rheumatoid arthritis. Because baricitinib, like other disease-modifying antirheumatic drugs, is used chronically, continuous assessment of its long-term safety profile is important. Here we provide updated data supporting the existing safety profile of baricitinib in this patient population. In this safety analysis, integrated data were included from nine phase 3, phase 2, and phase 1b clinical trials, and one long-term extension study with data up to 360 weeks, ending Feb 13, 2018. We analysed three integrated datasets, the largest of which was the all-bari-RA dataset, which includes patients who received any dose of baricitinib. We compared the safety of baricitinib with placebo on the basis of data from seven studies with baricitinib 4 mg and placebo and four studies with baricitinib 2 mg, including placebo to week 24 (placebo-controlled dataset). We did a dose-response assessment based on four studies with baricitinib 2 mg and 4 mg, including long-term extension data (2-4 mg extended dataset). We did an exploratory analysis of deaths and venous thromboembolic events in a subset of data from the all-bari-RA dataset that included patients who had ever taken baricitinib 2-mg or baricitinib 4-mg. We did an analysis for malignancies (excluding non-melanoma skin cancer) in the as-randomised population (patients not censored at rescue or dose change). We collected data for 3770 patients who were given baricitinib for 10 127 patient-years of exposure in the all-bari-RA dataset (median 1115 days [IQR 426-1441], maximum 2520 days). The placebo-controlled dataset comprised 2836 patients, with 1215 in the placebo group, with 451 patient-years of exposure data; 479 in the baricitinib 2 mg group, with 186 patient-years of exposure data; and 1142 in the baricitinib 4 mg group, with 472 patient-years of exposure data. The 2-4 mg extended dataset comprised 958 patients, with 479 in both the 2 mg and 4 mg groups. No significant differences were seen for baricitinib 4 mg or 2 mg versus placebo, or for 4 mg versus 2 mg in the incidence of death, malignancy, serious infection, or major adverse cardiovascular events. Incidence of herpes zoster per 100 patient-years was higher for baricitinib (4 mg: 4·4 [95% CI 2·7-6·7]; 2 mg: 3·1 [1·1-6·8]) versus total placebo group (1·1 [0·4-2·5]), as were treatment-emergent infections (4 mg: 89·7 [81·3-98·6]; 2 mg: 84·0 [71·3-98·2] vs placebo 75·4 [67·6-83·9]). Consistent with previous reports, incidences in the all-bari-RA dataset for venous thromboembolic events was 0·5 (95% CI 0·4-0·6) per 100 patient-years, deep-vein thrombosis was 0·3 (0·2-0·5) per 100 patient-years, and pulmonary embolism was 0·2 (0·2-0·4) per 100 patient-years. Incidences of malignancy (excluding non-melanoma skin cancer) in the 2-4 mg extended dataset were 0·8 (0·4-1·5) per 100 patient-years for baricitinib 2 mg and 1·0 (0·5-1·7) per 100 patient-years for baricitinib 4 mg, without censoring patients who had dose changes or received rescue treatment. We found no indication of higher incidence of venous thromboembolic events in the baricitinib 4 mg group compared with the 2 mg group in the 2-4 mg extended dataset. In this updated integrated analysis of patients with active rheumatoid arthritis exposed to baricitinib for a maximum of almost 7 years, baricitinib 2 mg and 4 mg maintained a similar safety profile to earlier analyses. No new safety signals were identified. Patients in the long-term extension study continue to be followed up to date. Eli Lilly and Company, under license from Incyte Corporation.