Daniel J Wallace1, Richard A Furie2, Yoshiya Tanaka3, Kenneth C Kalunian4, Marta Mosca5, Michelle A Petri6, Thomas Dörner7, Mario H Cardiel8, Ian N Bruce9, Elisa Gomez10, Tara Carmack10, Amy M DeLozier10, Jonathan M Janes10, Matthew D Linnik11, Stephanie de Bono10, Maria E Silk10, Robert W Hoffman10. 1. Division of Rheumatology, Cedars-Sinai Medical Center, University of California at Los Angeles, Los Angeles, CA, USA. Electronic address: danielwallac@gmail.com. 2. Division of Rheumatology, Zucker School of Medicine at Hofstra, Northwell, New York, NY, USA. 3. The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. 4. Division of Rheumatology, University of California at San Diego School of Medicine, La Jolla, CA, USA. 5. Division of Rheumatology, University of Pisa, Pisa, Italy. 6. Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 7. Division of Rheumatology, Charite Universitätsmedizin Berlin, Berlin, Germany. 8. Centro de Investigación Clínica de Morelia SC, Morelia, México. 9. Arthritis Research UK Centre for Epidemiology, Faculty of Biology, Medicine and Health, The University of Manchester and NIHR Manchester Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. 10. Eli Lilly and Company, Indianapolis, IN, USA. 11. Lilly Biotechnology Center, San Diego, CA, USA.
Abstract
BACKGROUND:Patients with systemic lupus erythematosus have substantial unmet medical need. Baricitinib is an oral selective Janus kinase (JAK)1 and JAK2 inhibitor that we hypothesised might have therapeutic benefit in patients with systemic lupus erythematosus. METHODS: In this double-blind, multicentre, randomised, placebo-controlled, 24-week phase 2 study, patients were recruited from 78 centres in 11 countries. Eligible patients were aged 18 years or older, had a diagnosis of systemic lupus erythematosus, and had active disease involving skin or joints. We randomly assigned patients (1:1:1) to receive once-daily baricitinib 2 mg, baricitinib 4 mg, or placebo for 24 weeks. The primary endpoint was the proportion of patients achieving resolution of arthritis or rash at week 24, as defined by Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K). Efficacy and safety analyses included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02708095. FINDINGS:Between March 24, 2016, and April 27, 2017, 314 patients were randomly assigned to receive placebo (n=105), baricitinib 2 mg (n=105), or baricitinib 4 mg (n=104). At week 24, resolution of SLEDAI-2K arthritis or rash was achieved by 70 (67%) of 104 patients receiving baricitinib 4 mg (odds ratio [OR] vs placebo 1·8, 95% CI 1·0-3·3; p=0·0414) and 61 (58%) of 105 patients receiving baricitinib 2 mg (OR 1·3, 0·7-2·3; p=0·39). Adverse events were reported in 68 (65%) patients in the placebo group, 75 (71%) patients in the baricitinib 2 mg group, and 76 (73%) patients in the baricitinib 4 mg group. Serious adverse events were reported in ten (10%) patients receiving baricitinib 4 mg, 11 (10%) receiving baricitinib 2 mg, and five (5%) receiving placebo; no deaths were reported. Serious infections were reported in six (6%) patients with baricitinib 4 mg, two (2%) with baricitinib 2 mg, and one (1%) with placebo. INTERPRETATION: The baricitinib 4 mg dose, but not the 2 mg dose, significantly improved the signs and symptoms of active systemic lupus erythematosus in patients who were not adequately controlled despite standard of care therapy, with a safety profile consistent with previous studies of baricitinib. This study provides the foundation for future phase 3 trials of JAK1/2 inhibition with baricitinib as a new potential oral therapy for systemic lupus erythematosus. FUNDING: Eli Lilly and Company.
RCT Entities:
BACKGROUND:Patients with systemic lupus erythematosus have substantial unmet medical need. Baricitinib is an oral selective Janus kinase (JAK)1 and JAK2 inhibitor that we hypothesised might have therapeutic benefit in patients with systemic lupus erythematosus. METHODS: In this double-blind, multicentre, randomised, placebo-controlled, 24-week phase 2 study, patients were recruited from 78 centres in 11 countries. Eligible patients were aged 18 years or older, had a diagnosis of systemic lupus erythematosus, and had active disease involving skin or joints. We randomly assigned patients (1:1:1) to receive once-daily baricitinib 2 mg, baricitinib 4 mg, or placebo for 24 weeks. The primary endpoint was the proportion of patients achieving resolution of arthritis or rash at week 24, as defined by Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K). Efficacy and safety analyses included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02708095. FINDINGS: Between March 24, 2016, and April 27, 2017, 314 patients were randomly assigned to receive placebo (n=105), baricitinib 2 mg (n=105), or baricitinib 4 mg (n=104). At week 24, resolution of SLEDAI-2K arthritis or rash was achieved by 70 (67%) of 104 patients receiving baricitinib 4 mg (odds ratio [OR] vs placebo 1·8, 95% CI 1·0-3·3; p=0·0414) and 61 (58%) of 105 patients receiving baricitinib 2 mg (OR 1·3, 0·7-2·3; p=0·39). Adverse events were reported in 68 (65%) patients in the placebo group, 75 (71%) patients in the baricitinib 2 mg group, and 76 (73%) patients in the baricitinib 4 mg group. Serious adverse events were reported in ten (10%) patients receiving baricitinib 4 mg, 11 (10%) receiving baricitinib 2 mg, and five (5%) receiving placebo; no deaths were reported. Serious infections were reported in six (6%) patients with baricitinib 4 mg, two (2%) with baricitinib 2 mg, and one (1%) with placebo. INTERPRETATION: The baricitinib 4 mg dose, but not the 2 mg dose, significantly improved the signs and symptoms of active systemic lupus erythematosus in patients who were not adequately controlled despite standard of care therapy, with a safety profile consistent with previous studies of baricitinib. This study provides the foundation for future phase 3 trials of JAK1/2 inhibition with baricitinib as a new potential oral therapy for systemic lupus erythematosus. FUNDING: Eli Lilly and Company.
Authors: Rishi R Goel; Xinghao Wang; Liam J O'Neil; Shuichiro Nakabo; Kowser Hasneen; Sarthak Gupta; Gustaf Wigerblad; Luz P Blanco; Jeffrey B Kopp; Maria I Morasso; Sergei V Kotenko; Zu-Xi Yu; Carmelo Carmona-Rivera; Mariana J Kaplan Journal: Proc Natl Acad Sci U S A Date: 2020-02-24 Impact factor: 11.205