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 4.9 Years of Treatment

Summary Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Aim To report incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in the tofacitinib UC programme. Methods DVT and PE were evaluated from one phase 2 and two phase 3 induction studies, one phase 3 maintenance study and an ongoing, open‐label, long‐term extension (OLE) study (September 2018 datacut). Data were analysed in induction, maintenance and overall (patients receiving ≥ 1 dose of tofacitinib 5 or 10 mg b.d. in any phase 2, 3 or OLE study) cohorts. Results 1157 patients (2404 patient‐years’ exposure; ≤ 6.1 years’ tofacitinib treatment) were evaluated in the overall cohort. In induction, one placebo‐treated patient had DVT and one had PE; no tofacitinib‐treated patients had DVT/PE. In maintenance, one placebo‐treated patient had DVT and one had PE; no tofacitinib‐treated patients had DVT/PE. In the overall cohort, one patient had DVT (incidence rate [patients with events/100 patient‐years; 95% CI]: 0.04 [0.00‐0.23]); four had PE (0.16 [0.04‐0.41]); all received predominant dose tofacitinib 10 mg b.d.; all had venous thromboembolism risk factors alongside UC. Conclusions In this post hoc analysis of patients with UC, during tofacitinib exposure, one patient had DVT and four had PE, all during the OLE study, on predominant dose 10 mg b.d. (83% of overall cohort patients received predominant dose 10 mg b.d.) with venous thromboembolism risk factors. This analysis is limited by small sample size and limited drug exposure; further studies are needed. ClinicalTrials.gov: NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612.

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“…in any phase 2, phase 3 or OLE study (data as of September 2018; database not locked). Study designs were described previously …”

Section: Methodsmentioning

confidence: 99%

“…Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Tofacitinib safety in UC was evaluated in phase 2 and phase 3 randomised controlled studies, and in an ongoing, open‐label, long‐term extension (OLE) study …”

Section: Introductionmentioning

confidence: 99%

Venous thromboembolic events in the tofacitinib ulcerative colitis clinical development programme

Sandborn

Panés

Sands

et al. 2019

Aliment Pharmacol Ther

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136

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“…The most frequently reported adverse event in [1][2][3][4][5][6][11][12][13][14][15][16]33,34 All adverse events resolved before the completion of the study. No serious adverse events or deaths were reported, and no volunteers had clinically significant laboratory abnormalities.…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

“…Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis, 1-10 psoriatic arthritis, [11][12][13] and ulcerative colitis. [14][15][16] JAK signaling is critical for immune cell activation, proinflammatory cytokine production, and cytokine signaling. 17 Tofacitinib is a potent, selective inhibitor of the JAK family of kinases with a high degree of selectivity against other human kinases.…”

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confidence: 99%

Phase 1 Dose‐Escalation Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Tofacitinib in Japanese Healthy Volunteers

Miyoshi

Krishnaswami

Toyoizumi

et al. 2019

Clinical Pharm in Drug Dev

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The aim of the study was to characterize the pharmacokinetics, safety, and tolerability of tofacitinib, an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis in healthy Japanese volunteers, and to compare these outcomes with those of healthy Western volunteers. Twenty-five volunteers (Japanese, n = 16; Western [white], n = 9) were randomized to receive either 3 escalating single doses of tofacitinib (1, 5, and 30 mg), singledose tofacitinib (15 mg) followed by multiple doses (15 mg twice daily for 5 days), or placebo. No significant differences in systemic exposure to tofacitinib were detected between the 2 ethnicities.Following single tofacitinib 1,5,and 30 mg doses, mean area under the plasma concentration-time curve from time zero to infinity ratio (Japanese/Western) values were 96.6%, 93.5%, and 95.6%, respectively. Similarly, mean maximum observed plasma concentration ratio values were 99.5%, 118%, and 119%, respectively. Mean renal clearance was also similar, ranging across doses from 134 mL/min (5 mg) to 162 mL/min (1 mg) in Japanese volunteers, and 124 mL/min (30 mg) to 160 mL/min (1 mg) in Western volunteers. In both ethnicities, most adverse events were mild. No serious adverse events or deaths were reported. The pharmacokinetics of tofacitinib were well characterized in healthy Japanese volunteers and were similar to those in Western volunteers.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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“…Data for patients with UC were obtained from an 8-week, double-blind, placebo-controlled phase 2 induction study (A3921063, NCT00787202) [21]; two identical, 8-week, double-blind, placebo-controlled phase 3 induction studies (OCTAVE Induction 1 and 2, NCT01465763 & NCT01458951) [12]; a 52-week, double-blind, placebocontrolled phase 3 maintenance study (OCTAVE Sustain, NCT01458574) [12]; and an ongoing, open-label, long-term extension (OLE) study (OCTAVE Open, NCT01470612; data as of November 2017 data cutoff) [22] (Fig. 1).…”

Section: Tofacitinib Uc Studiesmentioning

confidence: 99%

Characterization of Creatine Kinase Levels in Tofacitinib-Treated Patients with Ulcerative Colitis: Results from Clinical Trials

et al. 2020

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Background Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Creatine kinase (CK) levels and CK-related adverse events (AEs) in tofacitinib-treated patients with UC were evaluated. Methods Data were analyzed for three UC cohorts: Induction (phase 2 and 3 induction studies); Maintenance (phase 3 maintenance study); Overall [patients who received tofacitinib 5 or 10 mg twice daily (b.d.) in phase 2, phase 3, or openlabel, long-term extension studies; data at November 2017]. Clinical trial data for tofacitinib-treated patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis are presented for contextualization. Results Week 8 mean change from baseline CK with tofacitinib 10 mg b.d. induction therapy was 91.1 U/L (95% CI, 48.1-134.1) versus 19.2 U/L (8.5-29.9) with placebo. Among patients completing induction with 10 mg b.d. and re-randomized to 52 weeks of maintenance therapy, mean increases from induction baseline to the end of maintenance were 35.9 (8.1-63.7), 90.3 (51.9-128.7), and 115.6 U/L (91.6-139.7), with placebo, 5 and 10 mg b.d., respectively. The incidence rate (unique patients with events per 100 patient-years) for AEs of CK elevation in the tofacitinib-treated UC Overall cohort was 6.6 versus 2.2, 6.5, and 3.7 for tofacitinib-treated patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis, respectively. No serious AEs of CK elevation or AEs of myopathy occurred in UC studies. Conclusions In patients with UC, CK elevations with tofacitinib appeared reversible and not associated with clinically significant AEs. UC findings were consistent with tofacitinib use in other inflammatory diseases.

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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 4.9 Years of Treatment

Cited by 8 publications

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Venous thromboembolic events in the tofacitinib ulcerative colitis clinical development programme

Venous thromboembolic events in the tofacitinib ulcerative colitis clinical development programme

Phase 1 Dose‐Escalation Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Tofacitinib in Japanese Healthy Volunteers

Characterization of Creatine Kinase Levels in Tofacitinib-Treated Patients with Ulcerative Colitis: Results from Clinical Trials

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