Xeljanz beats placebo in three ulcerative colitis trials

Xeljanz induced and maintained remission in patients with ulcerative colitis more effectively than placebo in the phase 3 OCTAVE trials published in the New England Journal of Medicine.

Xeljanz (tofacitinib citrate, Pfizer) is an oral, small molecule Janus kinase (JAK) inhibitor, which is approved in many countries as a second-line treatment for moderate-to-severe rheumatoid arthritis, and is currently being investigated as a treatment for inflammatory bowel disease.

“There is still a substantial unmet need for new treatments for patients with ulcerative colitis,” William J. Sandborn, MD, professor of medicine, chief of the division of gastroenterology and director of the University of California San Diego Inflammatory Bowel Disease Center, told Healio Gastroenterology. “A previous phase 2 study had suggested that tofacitinib might be effective for short-term therapy of ulcerative colitis. ... Now we report the findings from three large phase 3 trials, two short-term trials and one long-term trial, demonstrating that tofacitinib 10 mg twice daily is effective for short-term therapy, and that both 5 mg and 10 mg twice daily is effective for long-term therapy.”

Further, most patients in the phase 2 study had not previously failed anti-TNF therapy, but the phase 3 trials showed that “tofacitinib is effective both in patients who have not failed anti-TNF therapy and patients who have failed anti-TNF therapy,” Sandborn added.

These three international, multicenter, randomized, double blind, placebo-controlled trials were conducted from April 2012 through May 2016.

In the OCTAVE Induction 1 and 2 trials, Sandborn and colleagues randomly assigned patients with moderate-to-severe active ulcerative colitis to receive 10 mg tofacitinib twice daily (n = 598) or placebo (n = 541) for 8 weeks. All patients had either failed previous conventional or anti-TNF therapy.

The primary endpoint of remission at 8 weeks, based on Mayo scores, was achieved by 18.5% of the treatment group vs. 8.2% of the placebo group in the first induction trial, a 10.3% difference (P = .007). In the second trial, remission was achieved by 16.6% in the treatment group and 3.6% in the placebo group, a 13% difference (P < .001). Treatment effects were comparable between patients who had and had not been previously treated with an anti-TNF agent. Mucosal healing at 8 weeks also occurred in significantly more patients who received 10 mg tofacitinib vs. placebo in both induction trials (P < .001 for both).

In the OCTAVE Sustain trial, Sandborn and colleagues randomly assigned 593 of the clinical responders from the induction trials to receive 5 mg or 10 mg tofacitinib or placebo for 52 weeks. The primary endpoint of remission at 52 weeks was achieved by 34.3% of patients who received 5 mg tofacitinib, 40.6% of patients who received 10 mg, and 11.1% of patients who received placebo, a 23.2% and a 29.5% difference vs. placebo for each respective dose group (P < .001 for both vs. placebo). Mucosal healing at 52 weeks also occurred in significantly more tofacitinib-treated patients compared with placebo (P < .001 for both dose groups).

These studies “demonstrated induction of clinical remission, clinical response and mucosal healing (flexible sigmoidoscopy improvement) over the short-term, and maintenance of clinical remission, clinical response, and mucosal healing over the long-term,” Sandborn said.

The investigators noted that patients treated with tofacitinib had higher rates of overall and serious infections than the placebo groups in the induction trials, and while they had comparable rates of serious infection in the maintenance trial, they had higher rates of overall infection and herpes zoster infection. Further, adjudicated nonmelanoma skin cancer occurred in five tofacitinib-treated patients and one placebo-treated patient, and adjudicated cardiovascular events occurred in five and zero patients, respectively. Tofacitinib was also associated with higher lipid levels compared with placebo.

Sandborn concluded that “treatment with oral tofacitinib is potentially a new treatment option for patients with moderate to severe ulcerative colitis, pending review by the FDA and other international regulatory bodies.”

In a related editorial, Sonia Friedman, MD, of Harvard Medical School and Brigham and Women’s Hospital Center for Crohn’s and Colitis, characterized this research as “a promising step forward” in the treatment of ulcerative colitis.

The advantages that small-molecule drugs have compared with biologics include their lower cost resulting from easier manufacturing, their lack of immunogenicity, and their ability to be administered orally and bind to specific intracellular targets, she wrote. However, she questioned whether these results indicate that tofacitinib will be “a game-changing therapy,” and whether its side effects may “limit its usefulness” in ulcerative colitis.

“Whether tofacitinib will be an essential therapy for ulcerative colitis remains to be determined in future trials,” she concluded. “Regardless of its eventual place in the treatment algorithm for ulcerative colitis, tofacitinib is a new class of therapy that has efficacy.” – by Adam Leitenberger

Disclosures: This trial was funded by Pfizer. Sandborn reports he has received research grants from Pfizer, and has served as a consultant for Pfizer, and several other researchers report financial relationships with Pfizer. Friedman reports personal fees from Boston University, outside the submitted work.