Josef S Smolen1,2, Mark C Genovese3,4, Tsutomu Takeuchi3,4, David L Hyslop3,4, William L Macias3,4, Terence Rooney3,4, Lei Chen3,4, Christina L Dickson3,4, Jennifer Riddle Camp3,4, Tracy E Cardillo3,4, Taeko Ishii3,4, Kevin L Winthrop3,4. 1. From the Division of Rheumatology, Department of Medicine, Medical University of Vienna, Vienna, Austria; Division of Immunology and Rheumatology, Stanford University Medical Center, Palo Alto, California, USA; Division of Rheumatology, Department of Internal Medicine, Keio University, Tokyo, Japan; Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA; Lilly Research Laboratories, Eli Lilly and Co., Kobe, Japan; Oregon Health Sciences University, Portland, Oregon, USA. josef.smolen@meduniwien.ac.at. 2. J.S. Smolen, MD, Division of Rheumatology, Department of Medicine, Medical University of Vienna; M.C. Genovese, MD, Division of Immunology and Rheumatology, Stanford University Medical Center; T. Takeuchi, MD, PhD, Division of Rheumatology, Department of Internal Medicine, Keio University; D.L. Hyslop, MD, Lilly Research Laboratories, Eli Lilly and Co., USA; W. Macias, MD, PhD, Lilly Research Laboratories, Eli Lilly and Co., USA; T. Rooney, MD, Lilly Research Laboratories, Eli Lilly and Co., USA; L. Chen, MD, PhD, Lilly Research Laboratories, Eli Lilly and Co., USA; C.L. Dickson, BS Pharm, Lilly Research Laboratories, Eli Lilly and Co., USA; J. Riddle Camp, BA, Lilly Research Laboratories, Eli Lilly and Co., USA; T.E. Cardillo, MSN, Lilly Research Laboratories, Eli Lilly and Co., USA; T. Ishii, MD, PhD, Lilly Research Laboratories, Eli Lilly and Co., Japan; K.L. Winthrop, MD, MPH, Oregon Health Sciences University. josef.smolen@meduniwien.ac.at. 3. From the Division of Rheumatology, Department of Medicine, Medical University of Vienna, Vienna, Austria; Division of Immunology and Rheumatology, Stanford University Medical Center, Palo Alto, California, USA; Division of Rheumatology, Department of Internal Medicine, Keio University, Tokyo, Japan; Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA; Lilly Research Laboratories, Eli Lilly and Co., Kobe, Japan; Oregon Health Sciences University, Portland, Oregon, USA. 4. J.S. Smolen, MD, Division of Rheumatology, Department of Medicine, Medical University of Vienna; M.C. Genovese, MD, Division of Immunology and Rheumatology, Stanford University Medical Center; T. Takeuchi, MD, PhD, Division of Rheumatology, Department of Internal Medicine, Keio University; D.L. Hyslop, MD, Lilly Research Laboratories, Eli Lilly and Co., USA; W. Macias, MD, PhD, Lilly Research Laboratories, Eli Lilly and Co., USA; T. Rooney, MD, Lilly Research Laboratories, Eli Lilly and Co., USA; L. Chen, MD, PhD, Lilly Research Laboratories, Eli Lilly and Co., USA; C.L. Dickson, BS Pharm, Lilly Research Laboratories, Eli Lilly and Co., USA; J. Riddle Camp, BA, Lilly Research Laboratories, Eli Lilly and Co., USA; T.E. Cardillo, MSN, Lilly Research Laboratories, Eli Lilly and Co., USA; T. Ishii, MD, PhD, Lilly Research Laboratories, Eli Lilly and Co., Japan; K.L. Winthrop, MD, MPH, Oregon Health Sciences University.
Abstract
OBJECTIVE:Baricitinib is an oral, once-daily selective Janus kinase (JAK1/JAK2) inhibitor for adults with moderately to severely active rheumatoid arthritis (RA). We evaluated baricitinib's safety profile through 288 weeks (up to September 1, 2016) with an integrated database [8 phase III/II/Ib trials, 1 longterm extension (LTE)]. METHODS: The "all-bari-RA" group included patients who received any baricitinib dose. Placebo comparison was based on the 6 studies with 4 mg and placebo up to Week 24 ("placebo-4 mg" dataset). Dose response assessment was based on 4 studies with 2 mg and 4 mg including LTE data ("2 mg-4 mg-extended"). The uncommon events description used the non-controlled all-bari-RA. RESULTS: There were 3492 patients who received baricitinib for 6637 total patient-years (PY) of exposure (median 2.1 yrs, maximum 5.5 yrs). No differences in rates of death, adverse events leading to drug discontinuation, malignancies, major adverse cardiovascular event (MACE), or serious infections were seen for 4 mg versus placebo or for 4 mg versus 2 mg. Infections including herpes zoster were significantly more frequent for 4 mg versus placebo. Deep vein thrombosis/pulmonary embolism were reported with 4 mg but not placebo [all-bari-RA incidence rate (IR) 0.5/100 PY]; the IR did not differ between doses (0.5 vs 0.6/100 PY, 2 mg vs 4 mg, respectively) or compared to published RA rates. All-bari-RA had 6 cases of lymphoma (IR 0.09/100 PY), 3 gastrointestinal perforations (0.05/100 PY), 10 cases of tuberculosis (all in endemic areas; 0.15/100 PY), and 22 all-cause deaths (0.33/100 PY). IR for malignancies (0.8/100 PY) and MACE (0.5/100 PY) were low and did not increase with prolonged exposure. CONCLUSION: In this integrated analysis of patients with moderate to severe active RA with exposure up to 5.5 years, baricitinib has an acceptable safety profile in the context of demonstrated efficacy. Trial registration numbers: NCT01185353, NCT00902486, NCT01469013, NCT01710358, NCT01721044, NCT01721057, NCT01711359, and NCT01885078 at clinicaltrials.gov.
RCT Entities:
OBJECTIVE:Baricitinib is an oral, once-daily selective Janus kinase (JAK1/JAK2) inhibitor for adults with moderately to severely active rheumatoid arthritis (RA). We evaluated baricitinib's safety profile through 288 weeks (up to September 1, 2016) with an integrated database [8 phase III/II/Ib trials, 1 longterm extension (LTE)]. METHODS: The "all-bari-RA" group included patients who received any baricitinib dose. Placebo comparison was based on the 6 studies with 4 mg and placebo up to Week 24 ("placebo-4 mg" dataset). Dose response assessment was based on 4 studies with 2 mg and 4 mg including LTE data ("2 mg-4 mg-extended"). The uncommon events description used the non-controlled all-bari-RA. RESULTS: There were 3492 patients who received baricitinib for 6637 total patient-years (PY) of exposure (median 2.1 yrs, maximum 5.5 yrs). No differences in rates of death, adverse events leading to drug discontinuation, malignancies, major adverse cardiovascular event (MACE), or serious infections were seen for 4 mg versus placebo or for 4 mg versus 2 mg. Infections including herpes zoster were significantly more frequent for 4 mg versus placebo. Deep vein thrombosis/pulmonary embolism were reported with 4 mg but not placebo [all-bari-RA incidence rate (IR) 0.5/100 PY]; the IR did not differ between doses (0.5 vs 0.6/100 PY, 2 mg vs 4 mg, respectively) or compared to published RA rates. All-bari-RA had 6 cases of lymphoma (IR 0.09/100 PY), 3 gastrointestinal perforations (0.05/100 PY), 10 cases of tuberculosis (all in endemic areas; 0.15/100 PY), and 22 all-cause deaths (0.33/100 PY). IR for malignancies (0.8/100 PY) and MACE (0.5/100 PY) were low and did not increase with prolonged exposure. CONCLUSION: In this integrated analysis of patients with moderate to severe active RA with exposure up to 5.5 years, baricitinib has an acceptable safety profile in the context of demonstrated efficacy. Trial registration numbers: NCT01185353, NCT00902486, NCT01469013, NCT01710358, NCT01721044, NCT01721057, NCT01711359, and NCT01885078 at clinicaltrials.gov.
Authors: Shuai Shao; Lam C Tsoi; Mrinal K Sarkar; Xianying Xing; Ke Xue; Ranjitha Uppala; Celine C Berthier; Chang Zeng; Matthew Patrick; Allison C Billi; Joseph Fullmer; Maria A Beamer; Bethany Perez-White; Spiro Getsios; Andrew Schuler; John J Voorhees; Sung Choi; Paul Harms; J Michelle Kahlenberg; Johann E Gudjonsson Journal: Sci Transl Med Date: 2019-09-25 Impact factor: 17.956
Authors: Fabiola Atzeni; Javier Rodríguez-Carrio; Călin D Popa; Michael T Nurmohamed; Gabriella Szűcs; Zoltán Szekanecz Journal: Nat Rev Rheumatol Date: 2021-04-08 Impact factor: 20.543
Authors: Taeho Kang; Tuğçe G Erbay; Kane L Xu; Gary M Gallego; Alexander Burtea; Sajiv K Nair; Ryan L Patman; Ru Zhou; Scott C Sutton; Indrawan J McAlpine; Peng Liu; Keary M Engle Journal: ACS Catal Date: 2020-10-27 Impact factor: 13.084
Authors: Josef S Smolen; Li Xie; Bochao Jia; Peter C Taylor; Gerd Burmester; Yoshiya Tanaka; Ayesha Elias; Anabela Cardoso; Rob Ortmann; Chad Walls; Maxime Dougados Journal: Rheumatology (Oxford) Date: 2021-05-14 Impact factor: 7.580
Authors: Gerd R Burmester; Peter Nash; Bruce E Sands; Kim Papp; Lori Stockert; Thomas V Jones; Huaming Tan; Ann Madsen; Hernan Valdez; Stanley B Cohen Journal: RMD Open Date: 2021-05