Safety Profile of Baricitinib for the Treatment of Rheumatoid Arthritis up to 9.3 Years: An Updated Integrated Safety Analysis

Abstract Background/Aims Baricitinib (BARI) is an oral selective Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of adult patients with moderate-to-severe rheumatoid arthritis (RA). Objective Reporting BARI’s safety profile with data up to 9.3 years of treatment. Methods Pooled data from nine randomized (five Phase 3, three Phase 2, one Phase 1b) and one long-term-extension (LTE) study were assessed. Incidence rates (IR)/100 patient-years at risk (PYR) were calculated for all patients treated with ≥1 dose of BARI (All-BARI-RA). Adverse events (AEs) of interest were assessed in 48-month intervals. Major adverse cardiovascular events (MACE) were adjudicated in five Phase 3 studies and the LTE, and incidence rates evaluated in subgroups of patients aged ≥50 years and presenting with ≥1 cardiovascular risk factor (current smoker, hypertension, high-density lipoprotein cholesterol <40 mg/dL, diabetes, or arteriosclerotic cardiovascular disease). To account for aging of the cohort, a standardized incidence ratio (SIR) for malignancy (excluding non-melanoma skin cancer [NMSC]) was estimated using SEER17, 2013-2017 US population cancer rates, and a standardized mortality ratio (SMR) was estimated using 2019 US population mortality calculated compared to the general US population with the same age distribution. Exposure-adjusted IRs (EAIRs) for deep vein thrombosis (DVT), pulmonary embolism (PE), and DVT and/or PE (DVT/PE) were also calculated for patient groups while receiving BARI 2-mg/4-mg within All-BARI-RA. Results A total of 3770 patients received BARI for 14,744.4 PYE with a median exposure of 4.6 years and a maximum exposure of 9.3 years; 80.5% of PYE were BARI 4-mg and 18.1% of PYE were BARI 2-mg. Overall, EAIRs/100 PYE for any treatment-emergent AE and serious AE (including death) were 22.6 and 7.4. Overall IRs/100 PYR were 2.58 for serious infections; 0.35 for DVT, 0.26 for PE, 0.49 for DVT/PE, 0.51 for MACE, and 0.92 for malignancy; IRs remained stable over time. The IR (95%CI) of MACE for patients aged ≥50 years was 0.68 (0.52, 0.88). In patients aged ≥50 with ≥1 of the cardiovascular risk factors, IR (95%CI) of MACE was 0.77 (0.56, 1.04). The SIR (95%CI) for malignancies excluding NMSC based on the SEER17 standard was 1.07 (0.90, 1.26); the SMR (95%CI) was 0.74 (0.59, 0.92) showing that the incidence of malignancy and death in patients treated with BARI appear similar to the general US population. EAIRs (95%CI) for patients while receiving BARI 2-mg (PYE=2678) and BARI 4-g (PYE=11,872) were DVT 2-mg 0.41 (0.21, 0.73) and 4-mg 0.35 (0.25, 0.48); PE 2-mg 0.26 (0.11, 0.54) and 4-mg 0.27 (0.18, 0.38); and DVT/PE 2-mg 0.49 (0.26, 0.83) and 4-mg 0.51 (0.39, 0.66). Conclusion In this report with 14,744 PYE, BARI maintained a safety profile similar to that previously reported, with no increase of IRs across safety events through exposures up to 9.3 years. Disclosure P.C. Taylor: Consultancies; AbbVie, Biogen, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Fresenius Medical Care, Galapagos NV, Gilead Sciences, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer, Roche, Sanofi, UCB Pharma. Grants/research support; AbbVie, Biogen, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Fresenius Medical Care, Galapagos NV, Gilead Sciences, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer, Roche, Sanofi, UCB Pharma. T. Takeuchi: Consultancies; AbbVie, Asahi Kasei Pharma, Astellas, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly and Company, GlaxoSmithKline, Janssen, Mitsubishi Tanabe Pharma, Nippon Kayaku, Novartis, Pfizer Japan, Taiho Pharmaceutical, Taisho Toyama Pharmaceutical, Takeda, and UCB Japan. Member of speakers’ bureau; AbbVie, Asahi Kasei Pharma, Astellas, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly and Company, GlaxoSmithKline, Janssen, Mitsubishi Tanabe Pharma, Nippon Kayaku, Novartis, Pfizer Japan, Taiho Pharmaceutical, Taisho Toyama Pharmaceutical, Takeda, and UCB Japan. G. Burmester: Consultancies; Eli Lilly and Company, Janssen, Novartis, and Pfizer. Grants/research support; Eli Lilly and Company. P. Durez: Member of speakers’ bureau; Bristol Myers Squibb, Celltrion, Eli Lilly and Company, and Sanofi. J. Smolen: Consultancies; AbbVie, Amgen, AstraZeneca, Astro Pharma, Bristol Myers Squibb, Celgene, Celltrion, Chugai Pharmaceutical, Eli Lilly and Company, Gilead Sciences, GlaxoSmithKline, ILTOO Pharma, Janssen, MedImmune, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, and UCB Pharma. Member of speakers’ bureau; AbbVie, Amgen, AstraZeneca, Astro Pharma, Bristol Myers Squibb, Celgene, Celltrion, Chugai Pharmaceutical, Eli Lilly and Company, Gilead Sciences, GlaxoSmithKline, ILTOO Pharma, Janssen, MedImmune, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, and UCB Pharma. Grants/research support; AbbVie, Amgen, AstraZeneca, Astro Pharma, Bristol Myers Squibb, Celgene, Celltrion, Chugai Pharmaceutical, Eli Lilly and Company, Gilead Sciences, GlaxoSmithKline, ILTOO Pharma, Janssen, MedImmune, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, and UCB Pharma. W. Deberdt: Shareholder/stock ownership; Eli Lilly and Company. J. Zhong: Other; current employee of: IQVIA. J. Ross Terres: Shareholder/stock ownership; Eli Lilly and Company. N. Bello: Shareholder/stock ownership; Eli Lilly and Company. K. Winthrop: Consultancies; AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly and Company, Pfizer, and UCB Pharma. Grants/research support; Bristol Myers Squibb and Pfizer.