Tofacitinib effective as induction, maintenance therapy for ulcerative colitis
A twice-daily oral dose of tofacitinib resulted in higher remission rates compared with placebo in patients with moderate-to-severe ulcerative colitis (UC), with efficacy maintained at 52 weeks, according to the results of three phase III, multicentre, double-blind trials.
Subjects in the OCTAVE Induction 1 and 2* trials (n=598 and 541, respectively) were adults aged ≥18 years with moderate to severely active UC with inadequate response to conventional or tumour necrosis factor antagonist therapy who were randomized to tofacitinib (10 mg twice/day, n=476 and 429, respectively) or placebo (n=122 and 112, respectively) as induction therapy for 8 weeks. [N Engl J Med 2017;376:1723-1736]
Patients who had clinical responses during the induction trials (≥3 point total Mayo score and ≥30 percent decrease from baseline and ≥1 point decrease in rectal bleeding subscore/absolute rectal bleeding subscore of 0 or 1) were eligible for the OCTAVE Sustain** trial (n=593) and were randomized to tofacitinib (5 mg [n=198] or 10 mg [n=197] twice/day) or placebo (n=198) for 52 weeks as maintenance therapy.
At 8 weeks, more patients on tofacitinib in the Induction 1 trial were in remission (total Mayo score ≤2, no subscore >1, rectal bleeding subscore=0) compared with placebo (18.5 percent vs 8.2 percent; p=0.007). Similar results were observed in the Induction 2 trial (16.6 percent vs 3.6 percent of patients on tofacitinib and placebo, respectively; p<0.001).
In the Sustain trial, 34.3 and 40.6 percent of patients on tofacitinib 5 mg and 10 mg, respectively, were in remission compared with 11.1 percent of patients on placebo (p<0.001 for both doses compared with placebo) at 52 weeks. In patients already in remission at Sustain trial entry, sustained and glucocorticoid-free remission was also higher in patients on tofacitinib (35.4 and 47.3 percent in patients on 5 mg and 10 mg tofacitinib, respectively) compared with placebo (5.1 percent; p<0.001 for both comparisons).
In the Induction 1 trial, 3.4 percent of patients on tofacitinib reported severe adverse events compared with 4.1 percent on placebo, while in the Induction 2 trial, 4.2 and 8.0 percent of patients on tofacitinib and placebo, respectively, reported severe adverse events. In the Sustain trial, the proportion of patients with severe adverse events was comparable between groups (5.1, 5.6, and 6.6 percent of patients on tofacitinib 5 mg, 10 mg, and placebo, respectively).
Treatment discontinuation due to adverse events was also comparable between groups in the Induction 1 and 2 trials, and higher in the group on placebo in the Sustain trial.
Seven patients on tofacitinib in the Induction 1 and 2 trials had serious infections compared with none in the placebo group, while in the Sustain trial, the rates of serious infection were comparable between groups (two, one, and two patients on tofacitinib 5 mg, 10 mg, and placebo, respectively).
Herpes zoster infection was more common in the tofacitinib groups in the Induction 1 and 2 trials (five and one, respectively) and in the Sustain trial (three and 10 patients on tofacitinib 5 mg and 10 mg, respectively vs one on placebo).
There were five cases of nonmelanoma skin cancer among patients on tofacitinib and one in a patient on placebo across the three trials.
The researchers acknowledged that the short follow-up duration in the Induction trials posed a limitation. However, an ongoing extension trial may help determine the long-term safety of tofacitinib.
“As compared with placebo, tofacitinib treatment was associated with increased levels of [HDL] and [LDL] cholesterol, more overall infections, and more cases of herpes zoster infection, so the benefit of this therapy comes at a price,” said Dr Sonia Friedman from Harvard Medical School, Boston, Massachusetts, US, in an editorial. [N Engl J Med 2017;376:1792-1793]
“[T]ofacitinib is a new class of therapy that has efficacy,” she said. “Still, on the basis of these results, is tofacitinib a game-changing therapy? Does tofacitinib ... cause side effects that limit its usefulness in patients with [UC]?” she questioned, stating that its role as an essential therapy will only be established in future trials.