Janus kinase inhibitor in modern treatment of ulcerative colitis

Introduction: Extraintestinal manifestations (EIMs) in patients with ulcerative colitis (UC) are common. Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC. We evaluated the efficacy of tofacitinib in patients with EIMs, and the impact of tofacitinib on EIMs in patients with UC in the OCTAVE clinical program. Methods: Data from two 8-week induction studies (OCTAVE Induction 1 and 2) and a 52-week maintenance study (OCTAVE Sustain) were analyzed. The effect of tofacitinib on efficacy outcomes stratified by EIM status, proportion of predefined prior and active EIMs at baseline, and change from baseline in EIMs were determined at the end of the treatment period (weeks 8 or 52), or at early termination. Results: At baseline of OCTAVE Induction 1 and 2, and OCTAVE Sustain, 27.0% and 9.0% of patients had a history of EIMs (prior or active), respectively. Patients treated with tofacitinib 10 mg twice daily (BID) achieved remission and had endoscopic improvement in all studies, irrespective of any history of EIMs. A greater proportion of patients had active peripheral arthritis at baseline of OCTAVE Induction 1 and 2 versus OCTAVE Sustain. In OCTAVE Induction 1 and 2, similar proportions of tofacitinib and placebo-treated patients with active peripheral arthritis experienced either no change (81.3% and 85.7%, respectively) or an improvement (15.6% and 14.3%, respectively). By week 52 of OCTAVE Sustain, improvements in active peripheral arthritis were only observed in tofacitinib-treated patients (16.7% and 33.3% with tofacitinib 5 and 10 mg BID, respectively). Conclusion: Any history of EIMs did not influence the efficacy of tofacitinib 10 mg BID for induction or maintenance of UC. The most common active EIM was peripheral arthritis, for which many patients in OCTAVE Induction 1 and 2, and OCTAVE Sustain, reported improvement or no change from baseline with tofacitinib treatment. Clinicaltrials.gov:NCT01465763 ; NCT01458951; NCT01458574

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704 Tofacitinib, an Oral Janus Kinase Inhibitor, in the Treatment of Ulcerative Colitis: An Interim Analysis of an Open-Label, Long-Term Extension Study With up to 5.5 Years of Treatment

The American Journal of Gastroenterology ◽

10.14309/01.ajg.0000592352.44466.21 ◽

2019 ◽

Vol 114 (1) ◽

pp. S413-S414

Author(s):

Gary R. Lichtenstein ◽

Edward V. Loftus ◽

Arif Soonasra ◽

Nervin Lawendy ◽

Gary Chan ◽

...

Keyword(s):

Ulcerative Colitis ◽

Interim Analysis ◽

Kinase Inhibitor ◽

Janus Kinase ◽

Extension Study ◽

Open Label ◽

Janus Kinase Inhibitor

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Tofacitinib, the First Oral Janus Kinase Inhibitor Approved for Adult Ulcerative Colitis

Journal of Pharmacy Practice ◽

10.1177/0897190020953019 ◽

2020 ◽

pp. 089719002095301

Author(s):

Brittany N. Palasik ◽

Hongmei Wang

Keyword(s):

Ulcerative Colitis ◽

Kinase Inhibitor ◽

Safety Data ◽

Janus Kinase ◽

Cytokine Signaling ◽

Efficacy And Safety ◽

Janus Kinase Inhibitor ◽

Multiple Factors ◽

Pharmacokinetic Properties ◽

Inflammatory Bowel

Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) characterized by chronic gastrointestinal inflammation. In most patients, the disease cycles through periods of remission and exacerbations. The complex etiology involves multiple factors including environmental, genetic, and immune causal elements. Janus Kinase (JAK) family is an essential component of a cytokine-signaling cascade partially responsible for the pathogenesis of UC. Treating UC presents difficulties despite various therapeutic options. Medications that block the JAK-signaling pathway can interfere with the inflammatory pathway of UC and possibly reduce symptoms and frequency of exacerbations. Tofacitinib is an oral pan-JAK inhibitor, primarily of JAK1 and JAK3, that was recently approved by the Food and Drug Administration (FDA) for the chronic treatment of UC in 2018. The following review describes the newly approved Janus kinase inhibitor, tofacitinib, including its pharmacokinetic properties, efficacy and safety data, and potential place in therapy.

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Tofacitinib, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis

New England Journal of Medicine ◽

10.1056/nejmoa1112168 ◽

2012 ◽

Vol 367 (7) ◽

pp. 616-624 ◽

Cited By ~ 452

Author(s):

William J. Sandborn ◽

Subrata Ghosh ◽

Julian Panes ◽

Ivana Vranic ◽

Chinyu Su ◽

...

Keyword(s):

Ulcerative Colitis ◽

Kinase Inhibitor ◽

Janus Kinase ◽

Active Ulcerative Colitis ◽

Janus Kinase Inhibitor

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Tofacitinib, an Oral Janus Kinase Inhibitor: Analysis of Malignancy (Excluding Nonmelanoma Skin Cancer) Events Across the Ulcerative Colitis Clinical Program

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa199 ◽

2020 ◽

Author(s):

Gary R Lichtenstein ◽

Gerhard Rogler ◽

Matthew A Ciorba ◽

Chinyu Su ◽

Gary Chan ◽

...

Keyword(s):

Ulcerative Colitis ◽

Skin Cancer ◽

Kinase Inhibitor ◽

Development Program ◽

Clinical Development ◽

Nonmelanoma Skin Cancer ◽

Janus Kinase ◽

Phase 3 ◽

Janus Kinase Inhibitor ◽

Clinical Development Program

Abstract Background Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Here, we performed an integrated analysis of malignancy events from the tofacitinib phase 3 UC clinical development program (excluding nonmelanoma skin cancer [NMSC]). Methods Data (up to May 2019) were pooled from two phase 3 induction studies, a phase 3 maintenance study, and an ongoing, open-label, long-term extension (OLE) study, and analyzed as 3 cohorts: induction (N = 1139), maintenance (N = 592), and overall (induction, maintenance, and ongoing OLE study; N = 1124). Proportions and incidence rates (IRs; unique patients with events per 100 patient-years [PY] of exposure) for malignancies confirmed by adjudication were calculated. Results The overall cohort consisted of patients who received at least 1 dose of tofacitinib at 5 or 10 mg twice daily, for up to 6.8 years, with an exposure of 2576.4 PY. Of the 1124 overall cohort tofacitinib-treated patients, 20 developed a malignancy (excluding NMSC; IR, 0.75; 95% confidence interval, 0.46–1.16), of which 17 occurred in patients treated with tofacitinib 10 mg twice daily; importantly, more than 80% of patients predominantly received this dose. Furthermore, there was no apparent clustering of malignancy types, and IRs were stable over time. Conclusions In the tofacitinib UC clinical development program, malignancy events were infrequent, and rates were comparable with those in the tofacitinib rheumatoid arthritis and psoriatic arthritis clinical development programs, and for biologic UC treatments. ClinicalTrials.gov: NCT01465763, NCT01458951, NCT01458574, and NCT01470612.

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