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Safety Profile of Baricitinib in Patients with Active Rheumatoid Arthritis with over 2 Years Median Time in Treatment

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Smolen JS1, Genovese MC1, Takeuchi T1, Hyslop DL1, Macias WL1, Rooney T1, Chen L1, Dickson CL1, Riddle Camp J1, Cardillo TE1, Ishii T1, Winthrop KL1. J Rheumatol. 2018 Sep 15. pii: jrheum.171361. doi: 10.3899/jrheum.171361. [Epub ahead of print]

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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. This work was funded by Eli Lilly and Co., which manufactures baricitinib, and Incyte Corp. A related abstract and poster by all of the authors were presented at the 2017 American College of Rheumatology/ Association of Rheumatology Health Professionals Annual Meeting, November 3-8, San Diego, California, USA: "Safety Profile of Baricitinib for the Treatment of Rheumatoid Arthritis up to 5.5 Years: An Updated Integrated Safety Analysis." 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. Address correspondence to Prof. Dr. J.S. Smolen, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, Austria. E-mail: josef.smolen@meduniwien.ac.at. Full Release Article. For details see Reprints and Permissions at jrheum.org. Accepted for publication July 1, 2018.

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.