In three phase 3 trials involving patients with ulcerative colitis, tofacitinib (an oral, small-molecule Janus kinase inhibitor) was more effective as induction and maintenance therapy than placebo. ...Infections were more common with tofacitinib.
Ulcerative colitis is characterized by an increased frequency of bowel movements and bloody diarrhea, which has a negative effect on quality of life.
1
Current therapies for ulcerative colitis include mesalamine, glucocorticoids, thiopurines, and antagonists to tumor necrosis factor (TNF) and α4β7 integrin.
1
–
5
Many patients do not have a response to these therapies or have a response that is not sustained. Additional treatment options with new mechanisms of action are needed to increase efficacy rates.
The Janus kinase (JAK) family comprises four intracellular tyrosine kinases — JAK1, JAK2, JAK3, and nonreceptor tyrosine-protein kinase 2 — that activate signal transducers and . . .
Tofacitinib in Active Ulcerative Colitis
Patients with ulcerative colitis were assigned to receive one of four doses of tofacitinib or placebo. The highest tofacitinib dose was associated with ...increased response and remission rates, but use of tofacitinib raised cholesterol levels and reduced neutrophil counts.
Ulcerative colitis is a chronic inflammatory disease of the colon.
1
,
2
Patients have intermittent disease flares interspersed with periods of remission.
3
Ulcerative colitis is treated with mesalamine, glucocorticoids, azathioprine, and anti–tumor necrosis factor (TNF) agents (infliximab and adalimumab).
4
–
6
These agents are not universally effective, and some have been associated with serious toxic effects.
7
Additional treatments are needed.
Tofacitinib (CP-690,550) is a selective oral inhibitor of the Janus kinase (JAK) family of kinases, including JAK1 and JAK3, a tyrosine kinase that mediates signal-transduction activity involving the common gamma chain of the surface receptors for multiple cytokines, including interleukins 2, 4, . . .
Tofacitinib is an oral, small-molecule inhibitor of JAK approved in several countries for the treatment of ulcerative colitis (UC). We report integrated safety analyses of tofacitinib-treated ...patients with moderate to severe UC.
Patients receiving placebo or tofacitinib (5 or 10 mg) twice daily were analyzed as 3 cohorts: induction (phase 2 and 3 induction studies, n = 1220), maintenance (phase 3 maintenance study, n = 592), and overall (patients receiving tofacitinib 5 or 10 mg twice daily in phase 2, phase 3, or open-label, long-term extension studies, n = 1157; 1613 patient-years’ exposure). Incidence rates (IRs; patients with events per 100 patient-years of exposure) were evaluated for select adverse events.
In the maintenance cohort, IRs for select adverse events were similar among treatment groups, except for a numerically higher IR of herpes zoster infection among patients who received tofacitinib 5 mg twice daily (2.1; 95% CI, 0.4–6.0) and statistically higher IR among patients who received tofacitinib 10 mg twice daily (IR, 6.6; 95% CI, 3.2–12.2) vs placebo (IR, 1.0, 95% CI, 0.0–5.4). For the overall cohort (84% received average dose of tofacitinib 10 mg twice daily), IRs were: death, 0.2 (95% CI, 0.1–0.6); serious infections, 2.0 (95% CI, 1.4–2.8); opportunistic infections, 1.3 (95% CI, 0.8–2.0); herpes zoster infection, 4.1 (95% CI, 3.1–5.2); malignancy (excluding non-melanoma skin cancer), 0.7 (95% CI, 0.3–1.2); non-melanoma skin cancer, 0.7 (95% CI, 0.3–1.2); major adverse cardiovascular events, 0.2 (95% CI, 0.1–0.6); and gastrointestinal perforations, 0.2 (95% CI, 0.0–0.5).
In safety analyses of patients with moderate to severe UC treated with tofacitinib, we observed a dose relationship with herpes zoster infection. Although follow-up time was relatively short, the safety profile of tofacitinib for patients with UC appeared similar to that reported for patients with rheumatoid arthritis and for patients with UC treated with biologic agents, except for the higher IR of herpes zoster infection. ClinicalTrials.gov, no: NCT00787202, NCT01465763, NCT01458951, NCT01458574, and NCT01470612.
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.
The OCTAVE clinical program included Phase 3 induction (OCTAVE Induction 1&2, NCT01465763 and NCT01458951) and maintenance (OCTAVE Sustain, NCT01458574) studies, and an open-label, long-term ...extension study (OCTAVE Open, NCT01470612).1,2 Stool frequency (SF) and rectal bleeding (RB) are important patient (pt)-reported outcomes (PROs) in measuring UC disease activity and treatment effect. OCTAVE Open data are from the final analyses (Aug 2020). a.Pts were eligible to enroll in OCTAVE Sustain if they had achieved clinical response upon completion of OCTAVE Induction 1 or 2; these pts were re-randomized to receive PBO, tofacitinib 5 mg BID, or tofacitinib 10 mg BID (with a 1:1:1 allocation ratio) in OCTAVE Sustain; b.Pts in remission (total Mayo score ≤ 2, no individual subscore > 1, RBS of 0) at Wk52 of OCTAVE Sustain (central read) received tofacitinib 5 mg BID per protocol in OCTAVE Open; c.Data from OCTAVE Open are reported up to M48, as follow-up data were limited (≤ 40 pts) at M60 and beyond. BID, twice daily; FAS, full analysis set; M, Month; N, number of randomized pts in the total population; n, number of pts with the specified response within the given category; PBO, placebo; pts, patients; RBS, Mayo rectal bleeding subscore; SFS, Mayo stool frequency subscore; UC, ulcerative colitis; Wk/wk, Week/week Figure omitted.
The article “Characterization of Creatine Kinase Levels in Tofacitinib–Treated Patients with Ulcerative Colitis: Results from Clinical Trials”, written by Remo Panaccione, John D. Isaacs, Lea Ann ...Chen, Wenjin Wang, Amy Marren, Kenneth Kwok, Lisy Wang, Gary Chan and Chinyu Su, was originally published electronically on the publisher’s internet portal on 20 August 2020 without open access.
PDF
