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Treatment with tofacitinib (Xeljanz) proved to be rapidly effective for moderate-to-severe ulcerative colitis (UC), even in patients who previously failed tumor necrosis factor (TNF) inhibition, post hoc analysis of trial data indicated.

While the oral small-molecule JAK inhibitor had greater efficacy than placebo for both induction and maintenance of remission, rates of herpes zoster (serious and non-serious) were numerically higher in tofacitinib recipients, regardless of previous response to TNF inhibition, reported William Sandborn, MD, of the University of California San Diego.

TNF inhibitor failure has been suggested as a predictor of in UC. Patients refractory to this therapy may be and therefore have an unmet need for alternative therapies.

However, "our findings show that tofacitinib induces and maintains clinical response, endoscopic improvement, and remission in patients with and without prior TNF [inhibitor] failure," the team wrote in .

Earlier this year, Sandborn's group reported on the efficacy of tofacitinib versus certain biologics in UC. The current analysis involved participants in the OCTAVE Induction, Sustain, and Open trials. The clinical studies and this follow-up analysis were supported by tofacitinib's manufacturer, Pfizer.

At week 8 (induction) and week 52 (maintenance), tofacitinib showed greater efficacy compared with placebo, regardless of type of non-response to TNF inhibition (primary or secondary owing to loss of efficacy) and number of failed therapies, the authors noted.

During induction, treatment effects were generally similar for patients with previous TNF inhibitor failures and those without failures, and for patients who failed one and two or more TNF inhibitors. During maintenance, treatment effects were numerically higher for 10-mg tofacitinib compared with the 5-mg dose, regardless of previous TNF inhibition failure status.

Also during maintenance, patients with earlier failure showed similar treatment effects for endoscopic improvement and remission with 5-mg tofacitinib whether they had a primary or secondary non-response.

Doubling the dose of tofacitinib generally recaptured clinical response for most patients who lost response with 5 mg by month 2, and this effect was sustained for 3 years.

The Cohorts

Efficacy was assessed in patients from the pooled phase III OCTAVE Induction 1 and 2 studies (n=1,139), the phase III OCTAVE Sustain maintenance study (n=593), and the dose-escalation subpopulation of the open-label, long-term extension OCTAVE Open study (n=59).

Safety was assessed in participants from OCTAVE Sustain, the dose-escalation subpopulation of Open, and the overall cohort, which included patients from OCTAVE Induction 1 and 2, Sustain, and Open (n=1,124).

The number of patients with previous TNF inhibition failure was 583, while those with no failure numbered 541. The dose-escalation subpopulation received tofacitinib 10 mg twice daily in OCTAVE Induction 1 and 2 and OCTAVE Open, and tofacitinib 5 mg twice daily in OCTAVE Sustain.

In the dose-escalation subpopulation, the incident rate of herpes zoster was 5.66 (95% CI 1.17-16.55) in 29 patients with no previous TNF inhibition failure versus 6.66 (95% CI 1.81-17.04) in 28 patients with previous failure.

Asked for his perspective, Edward Barnes, MD, MPH, of the University of North Carolina at Chapel Hill, said it was an important follow-up of data from the OCTAVE program.

"Understanding the efficacy in this population is critical given the current labeling indicating the use of tofacitinib in patients who have had an inadequate response or who are intolerant to anti-TNF therapy," said Barnes, who was not involved in the analysis.

"Additionally, we realize that many of our patients will fall into the category of being non-responders to anti-TNF therapy or intolerant to anti-TNF therapy, so having effective therapies to offer patients in this situation is of great benefit," he added.

Barnes said that the findings reinforce his current clinical practice in large part. "In recent , tofacitinib and ustekinumab were the highest-ranked therapies in patients with UC with prior exposure to anti-TNF therapies. This is also mirrored in the recent for UC, where ustekinumab or tofacitinib are preferred in patients with moderate-to-severe UC and prior exposure to infliximab. Thus, I think this study likely adds to the current literature in terms of our positioning of therapies in UC, particularly in patients who have already experienced a failure of an anti-TNF therapy, and it reinforces some society guidelines."

The network meta-analysis suggested that tofacitinib may be more efficacious than vedolizumab and adalimumab -- but not ustekinumab -- in patients who have previously failed biologics.

Limitations of the studies included the open-label design of OCTAVE Open, the indirect comparison of clinical program safety data with insurance data from a claims database owing to differences in patient populations, and the infrequent evaluation of adverse events of special interest within a relatively short follow-up period of 28 days after last dose.

Additionally, the insurance database only captured the insured population, and safety outcomes are based on diagnosis codes and not medical record review.

Furthermore, TNF inhibition failure status was determined by the investigators, with no definition provided in the protocols. Caution should also be exercised in the interpretation of data for the dose-escalation subpopulation, since patient numbers were low, and also regarding the significance of the observed differences between patients with prior TNF inhibition failures and those without failures for incidence of adverse events, since no statistical testing was performed.

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