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

Remo Panaccione, John D Isaacs, Lea Ann Chen, Wenjin Wang, Amy Marren, Kenneth Kwok, Lisy Wang, Gary Chan, Chinyu Su, Remo Panaccione, John D Isaacs, Lea Ann Chen, Wenjin Wang, Amy Marren, Kenneth Kwok, Lisy Wang, Gary Chan, Chinyu Su

Abstract

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 open-label, 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.

Trial registration: NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612; NCT01262118; NCT01484561; NCT00147498; NCT00413660; NCT00550446; NCT00603512; NCT00687193; NCT01059864; NCT01164579; NCT00976599; NCT01359150; NCT02147587; NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01039688; NCT02187055; NCT00413699; NCT00661661; NCT01710046; NCT00678210; NCT01276639; NCT01309737; NCT01241591; NCT01186744; NCT01163253; NCT01877668; NCT01882439; NCT01976364.

Keywords: Creatine kinase; Inflammatory bowel disease; Safety; Tofacitinib; Ulcerative colitis.

Conflict of interest statement

RP has received consulting fees from AbbVie, Amgen, Aptalis, AstraZeneca, Baxter, Biogen, Bristol-Myers Squibb, Celgene, Centocor, Cubist, Eisai, Elan, Ferring, Gilead, GlaxoSmithKline, Janssen, Merck, Pfizer Inc, Robarts Clinical Trials, Salix, Samsung Bioepis, Shire, Takeda, and UCB; has received research Grants from AbbVie, Ferring, Janssen, and Takeda; has received lectures and/or speaker bureau fees from AbbVie, Aptalis, AstraZeneca, Ferring, Janssen, Merck, Prometheus, Shire, and Takeda; and has received advisory board fees from Abbott, AbbVie, Amgen, Aptalis, AstraZeneca, Baxter, Bristol-Myers Squibb, Celgene, Centocor, Cubist, Eisai, Elan, Ferring, Genentech, GlaxoSmithKline, Janssen, Merck, Pfizer Inc, Salix, Schering-Plough, Shire, Takeda, and UCB. JDI has been a consultant for, and/or has received research Grants or speaker fees from, AbbVie, Amgen, Eli Lilly, Gilead, Merck, Pfizer Inc, Roche, and UCB. LAC has served as a consultant for Pfizer Inc; has received research Grants from BioRad, Pfizer Inc, and PredictImmune; and has received advisory board fees from Gilead and Janssen. WW, AM, KK, LW, GC, and CS are employees and stockholders of Pfizer Inc.

© 2020. The Author(s).

Figures

Fig. 1
Fig. 1
Overview of the tofacitinib UC clinical studies and cohorts included in this analysis. Clinical response in OCTAVE Induction 1 and 2 was defined as a decrease from induction study baseline total Mayo score of ≥ 3 points and ≥ 30%, plus a decrease in rectal bleeding subscore of ≥ 1 point, or an absolute rectal bleeding subscore of 0 or 1. Study A3921139 (OCTAVE Open) is ongoing. Remission was defined as a total Mayo score ≤ 2 with no individual subscore > 1, and a rectal bleeding subscore of 0 b.d. twice daily, N number of patients in each treatment group included in the cohort analysis, UC ulcerative colitis
Fig. 2
Fig. 2
Mean (95% CI) change from induction study baseline CK during the tofacitinib phase 3 UC induction and maintenance phases. For the induction phase, data from the phase 2 induction study (A3921063) are not included b.d. twice daily, CI confidence interval, CK creatine kinase, UC ulcerative colitis
Fig. 3
Fig. 3
Mean (95% CI) change from baseline CK in the RA, Pso, and PsA Overall tofacitinib-treated cohorts. CI confidence interval, CK creatine kinase, PsA psoriatic arthritis, Pso psoriasis, RA rheumatoid arthritis
Fig. 4
Fig. 4
IRs (95% CI) for AEs of CK elevation in the UC Maintenance and Overall cohorts, and the RA, Pso, and PsA Overall cohorts. IRs for AEs of CK elevation in the UC Induction cohort are not shown due to the short duration (8 weeks) of the UC induction studies. For the UC Overall cohort, data from the phase 2 induction study (A3921063) are not included. AE adverse event, b.d. twice daily, CI confidence interval, CK creatine kinase, IR incidence rate, N number of evaluable patients in each treatment group or cohort, n number of unique patients with events, PsA psoriatic arthritis, Pso psoriasis, RA rheumatoid arthritis, UC ulcerative colitis

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Source: PubMed

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