Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial

Genovese, Mark C.; Fleischmann, Roy; Combe, Bernard; Hall, Stephen; Rubbert-Roth, Andrea; Zhang, Ying; Zhou, Yijie; Mohamed, Mohamed‐Eslam F.; Meerwein, Sebastian; Pangan, Aileen L.

doi:10.1016/s0140-6736(18)31116-4

Cited by 363 publications

(358 citation statements)

References 29 publications

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“…This study was conducted to characterize the effect of hepatic impairment on the pharmacokinetics, safety, and tolerability of a single 15‐mg dose of upadacitinib. The 15‐mg dose of upadacitinib ER formulation administered in this study is 1 of the 2 doses (15 and 30 mg) that were evaluated in phase 3 clinical trials in rheumatoid arthritis and is the dose that optimized efficacy across studies in rheumatoid arthritis patients . In this study, there was no statistically significant difference in upadacitinib C max and AUC in subjects with mild and moderate hepatic impairment compared with subjects with normal hepatic function.…”

Section: Discussionmentioning

confidence: 81%

“…The enhanced selectivity of upadacitinib for JAK 1 may provide an improved benefit‐risk profile . Upadacitinib demonstrated favorable efficacy and acceptable safety profiles in 2 phase 2 studies and in 5 phase 3 studies in subjects with moderate to severe RA . In addition, upadacitinib recently demonstrated favorable efficacy in subjects with Crohn's disease, atopic dermatitis, and ulcerative colitis in phase 2 trials …”

mentioning

confidence: 99%

“…In phase 3 studies in subjects with moderate to severe RA, upadacitinib was evaluated at doses of 15 and 30 mg once daily using the ER formulation. Based on phase 3 results, upadacitinib 15 mg once daily is the optimal dose in RA patients, as it provided maximum efficacy across different studies . The most common adverse events associated with upadacitinib treatment in subjects with moderate to severe RA in phase 3 studies were upper respiratory tract infections and nasopharyngitis.…”

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confidence: 99%

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Characterization of the Effect of Hepatic Impairment on Upadacitinib Pharmacokinetics

Trueman

Mohamed

Tian

et al. 2019

The Journal of Clinical Pharma

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Upadacitinib is a selective Janus kinase 1 inhibitor being developed for the treatment of several inflammatory autoimmune diseases, including rheumatoid arthritis. Upadacitinib is a nonsensitive substrate for metabolism by cytochrome P450 3A enzymes. This open‐label, single‐dose, multicenter study assessed the pharmacokinetics of upadacitinib following oral administration of a single 15‐mg dose of the upadacitinib extended‐release formulation in subjects with mild (n = 6) and moderate (n = 6) hepatic impairment relative to demographically matched healthy subjects (n = 6). Subjects were assigned to 1 of the 3 groups according to the Child‐Pugh classification. Relative to subjects with normal hepatic function, the ratios (90% confidence intervals) of upadacitinib area under the plasma concentration‐versus‐time profile from time 0 to infinity (AUCinf) for subjects with mild and moderate hepatic impairment were 1.28 (0.91‐1.79) and 1.24 (0.87‐1.76), respectively. The central ratios of upadacitinib maximum observed concentration (Cmax) were 1.04 (0.77‐1.39) and 1.43 (1.05‐1.95) in subjects with mild and moderate hepatic impairment, respectively, compared with subjects with normal hepatic function. No clinically significant changes in vital signs or hematology measurements were observed, and no new safety events were identified in this study. These results indicate that mild and moderate hepatic impairment has no clinically relevant effect on upadacitinib pharmacokinetics.

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Section: Discussionmentioning

confidence: 81%

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confidence: 99%

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confidence: 99%

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Characterization of the Effect of Hepatic Impairment on Upadacitinib Pharmacokinetics

Trueman

Mohamed

Tian

et al. 2019

The Journal of Clinical Pharma

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“…Human daily average plasma concentrations (C av ) were used as reported or predicted in the literature for tofacitinib, baricitinib, upadacitinib, and filgotinib and its metabolite, for doses that we determined to be clinically meaningful (ie, tofacitinib 5 mg twice daily [BID], baricitinib 4 mg once daily [QD], upadacitinib 15 mg QD, and filgotinib 200 mg QD). Doses were selected on the rationale that they provided a generally comparable proportion of patients meeting American College of Rheumatology (ACR) response criteria in clinical trial settings . C av as a measure of average daily drug plasma concentration was used as it has been shown to be a predictive exposure metric of the efficacy of tofacitinib and filgotinib, rather than C max or C min .…”

Section: Methodsmentioning

confidence: 99%

Janus kinase inhibitors for the treatment of rheumatoid arthritis demonstrate similar profiles of in vitro cytokine receptor inhibition

Dowty

Lin

Jesson

et al. 2019

Pharmacology Res & Perspec

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Janus kinase (JAK) inhibitors have emerged as an effective class of therapies for various inflammatory diseases such as rheumatoid arthritis (RA). JAK inhibitors function intracellularly by modulating the catalytic activity of JAKs and disrupting the receptor‐mediated signaling of multiple cytokines and growth factors, including those with pro‐inflammatory activity. Understanding the inhibition profiles of different JAK inhibitors, based on the associated cytokine receptors and downstream inflammatory pathways affected, is important to identify the potential mechanisms for observed differences in efficacy and safety. This study applied an integrated modeling approach, using in vitro whole blood cytokine inhibition potencies and plasma pharmacokinetics, to determine JAK‐dependent cytokine receptor inhibition profiles, in the context of doses estimated to provide a similar clinical response in RA clinical trials. The calculated profiles of cytokine receptor inhibition for the JAK inhibitors tofacitinib, baricitinib, upadacitinib, and filgotinib and its metabolite, were generally similar when clinically efficacious doses for RA were considered. Only minor numerical differences in percentage cytokine receptor inhibition were observed, suggesting limited differentiation of these inhibitors based on JAK pharmacology, with each showing a differential selectivity for JAK1 heterodimer inhibition. Nevertheless, only robust clinical testing involving head‐to‐head studies will ultimately determine whether there are clinically meaningful differences between these JAK inhibitors. Furthermore, ongoing and future research into inhibitors with alternative JAK selectivity remains of clinical importance. Thus, all JAK inhibitors should be characterized via thorough preclinical, metabolic and pharmacological evaluation, adequate long‐term clinical data, and when available, real‐world experience.

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“…Upadacitinib is being developed for the treatment of rheumatoid arthritis (RA) as well as for other immune‐mediated inflammatory diseases. In subjects with moderate to severe RA, upadacitinib demonstrated favorable efficacy and acceptable safety profiles, including in 2 phase 2 studies and in 5 phase 3 studies . Additionally, upadacitinib recently demonstrated favorable efficacy in subjects with ulcerative colitis, Crohn disease, and atopic dermatitis in phase 2 studies .…”

mentioning

confidence: 99%

Characterization of the Effect of Renal Impairment on Upadacitinib Pharmacokinetics

Mohamed

Trueman

Tian

et al. 2019

The Journal of Clinical Pharma

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Upadacitinib is a novel selective Janus kinase 1 inhibitor developed for treatment of rheumatoid arthritis and other autoimmune diseases. The objective of this study was to assess the pharmacokinetics and safety of a single upadacitinib dose in subjects with normal renal function and in subjects with renal impairment. A total of 24 subjects between the ages of 18 and 75 years were assigned to 1 of 4 renal function groups based on estimated glomerular filtration rate (normal, mild, moderate, severe; N = 6/group). A single 15‐mg dose of upadacitinib extended‐release formulation was administered under fasting conditions. Serial plasma and urine samples were assayed to evaluate the effect of renal impairment on upadacitinib exposure through regression analysis and analysis of covariance. The primary analysis was the regression analysis of upadacitinib exposures versus estimated glomerular filtration rate. The point estimates for upadacitinib plasma exposure ratios (90% confidence interval [CI]) in subjects with mild, moderate, and severe renal impairment were 1.18 (90%CI, 1.06–1.32), 1.33 (90%CI, 1.11–1.59), and 1.44 (90%CI, 1.14–1.82) for area under the plasma concentration–time curve and 1.06 (90%CI, 0.92–1.23), 1.11 (90%CI, 0.88–1.40), and 1.14 (90%CI, 0.84–1.56) for maximum observed plasma concentration, respectively, relative to subjects with normal renal function based on the regression analysis. The analysis of covariance categorical analysis provided consistent results. Upadacitinib was well tolerated by all subjects, and no safety issues were identified in subjects with renal impairment. Renal impairment has a limited effect on upadacitinib pharmacokinetics. This is in agreement with the known limited role of urinary excretion in upadacitinib elimination. Based on the limited impact on exposure, no dose adjustment is necessary for upadacitinib in subjects with impaired renal function.

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Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial

Cited by 363 publications

References 29 publications

Characterization of the Effect of Hepatic Impairment on Upadacitinib Pharmacokinetics

Characterization of the Effect of Hepatic Impairment on Upadacitinib Pharmacokinetics

Janus kinase inhibitors for the treatment of rheumatoid arthritis demonstrate similar profiles of in vitro cytokine receptor inhibition

Characterization of the Effect of Renal Impairment on Upadacitinib Pharmacokinetics

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