Tofacitinib Shows Promise in Ulcerative Colitis

Diana Phillips

May 05, 2017

Tofacitinib, an oral Janus kinase (JAK) inhibitor, induced and sustained clinical remission for up to 1 year in nearly 41% of patients with refractory moderately to severely active ulcerative colitis in a newly reported phase 3 trial.

The remission rate among patients who received tofacitinib 10 mg twice daily in the Oral Clinical Trials for Tofacitinib in Ulcerative Colitis (OCTAVE) Sustain trial was nearly 30 percentage points higher than in patients who received placebo. William J. Sandborn, MD, from the Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, and colleagues report their findings in an article published in the May 4 issue of the New England Journal of Medicine.

The findings are consistent with those observed in the two phase 3 induction trials (OCTAVE induction 1 and OCTAVE induction 2) from which the maintenance study population was drawn, the authors write.

However, tofacitinib was also associated with multiple adverse events, including increased levels of high-density lipoprotein and low-density lipoprotein cholesterol, more overall infections, and more cases of herpes zoster infection.

The adverse effects could limit tofacitinib's usefulness in some patients, Sonia Friedman, MD, from Harvard Medical School and Brigham and Women's Hospital Center for Crohn's and Colitis, Boston, Massachusetts, writes in an accompanying editorial. Dr Friedman calls the new findings promising, but also points to the need for additional research "to identify the specific subsets of patients who will most likely benefit from this new therapy."

The trials follow successful phase 2 trials in which patients with moderately to severely active ulcerative colitis who received 15 mg tofacitinib twice daily saw a significantly higher response rate at 8 weeks than those who received placebo. Patients also had significantly higher rates of remission at 3-, 10-, and 15-mg doses twice daily than those in the placebo groups.

The OCTAVE Induction 1 and 2 trials comprised, respectively, 598 and 541 patients with moderately to severely active disease that was resistant to conventional therapy or treatment with a tumor necrosis factor antagonist. The OCTAVE Sustain trial enrolled 593 patients who had a clinical response to treatment during the induction trials.

The researchers randomly assigned patients in the Induction trials to receive 10 or 15 mg tofacitinib or placebo twice daily for 8 weeks. They then randomly assigned patients who had a treatment response at week 8 to receive maintenance therapy of either tofacitinib 5 or 10 mg twice daily or placebo for 52 weeks. Most of the patients (88%) in the maintenance trial received the study drug during the induction trial, and 30% were in remission when the maintenance trial began, the authors note.

The primary end point for all three trials was remission based on centrally interpreted Mayo scores and the physician's global assessment. Mayo remission criteria included a total score of 2 or lower, with no subscore greater than 1 and a rectal bleeding subscore of 0.

In both induction trials, the 8-week remission rates were significantly higher in the treatment groups than in the placebo groups. In the Induction 1 trial, 18.5% of patients in the 10-mg treatment group achieved remission at 8 weeks compared with 8.2% of the placebo group (10.3 percentage points difference; 95% confidence interval [CI], 4.3 - 16.3; P = .007). In the induction 2 trial, 16.6% of the patients in the treatment group achieved remission compared with 3.6% of the placebo group (13.0 percentage points difference; 95% CI, 8.1 - 17.9; P < .001).

"In both trials, the treatment effect was similar between those who had received previous treatment with a TNF antagonist and those who had not," the authors note.

The respective remission rates for patients in the Sustain trial who received twice-daily tofacitinib 5 or 10 mg or placebo were 34.3%, 40.6%, and 11.1% (P < .001 for both comparisons with placebo).

In all three trials, the key secondary endpoint of mucosal healing (at 8 weeks for the induction trials and 52 weeks for the maintenance trials) occurred in significantly more intervention than placebo patients.

Similarly, patient-reported quality-of-life outcomes consistent with remission, based on inflammatory bowel disease questionnaire scores, were also significantly more common in the treatment groups than in the placebo groups.

More patients experienced any infections and serious infections in the treatment groups compared with the placebo groups in the induction trials. Similarly, the rates of overall infection observed in the maintenance trial were higher for patients in the treatment groups relative to placebo, although the serious infection rates were similar across the treatment and placebo groups, the authors report.

Six patients overall (five who received tofacitinib and one who received placebo) developed nonmelanoma skin cancer, and five patients (all of whom received tofacitinib) experienced cardiovascular events.

In addition, "the proportion of patients with abnormal lipid and creatine kinase levels was generally larger in the tofacitinib groups than in the placebo groups," the researchers write. Specifically, total cholesterol, low-density lipoprotein, and high-density lipoprotein increased with tofacitinib, reaching a plateau after approximately 4 weeks.

The lipid abnormalities and increased infection rates indicate the benefit of tofacitinib treatment for ulcerative colitis "comes at a price," Dr Friedman writes. "Whether tofacitinib will be an essential therapy for ulcerative colitis remains to be determined in future trials," she stresses. "Only a continued combination of human ingenuity, worldwide cooperation, and enthusiastic funding will allow investigators to further explore the mechanisms by which JAK inhibition ameliorates inflammation in patients with ulcerative colitis and to identify the specific subsets of patients who will most likely benefit from this new therapy."

The results of an ongoing open-label extension trial (OCTAVE Open) "may further elucidate the long-term safety profile of tofacitinib," the researchers write, noting that at this time, treatment risks beyond 1 year in this patient population are unknown.

The OCTAVE studies are funded by Pfizer. The authors have disclosed a variety of financial relationships, including receipt of consulting fees, speaking fees, personal fees, research fees, and other support and serving on advisory boards, with numerous companies. Full disclosures can be found on the journal website. Dr Sandborn reports patents related to topical azathioprine to treat inflammatory bowel disorders, topical formulations of azathioprine to treat inflammatory bowel disorders, the colonic delivery of nicotine to treat inflammatory bowel disease, the use of azathioprine to treat Crohn's disease, azathioprine compositions for colonic administration, the intestinal absorption of nicotine to treat nicotine responsive conditions, the use of topical azathioprine and thioguanine to treat colorectal adenomas, enema and enterically coated oral dosage forms of azathioprine, a pharmaceutical composition for the treatment of inflammatory bowel disease, and an obesity treatment and device. Dr Friedman has disclosed no relevant financial relationships.

N Engl J Med. 2017;376:1723-1736, 1792-1793. Article abstract, Editorial extract

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