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Xeljanz Induces Remission in Ulcerative Colitis; Modest Results in Crohn’s
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Xeljanz rapidly induced remission in patients with moderate-to-severe ulcerative colitis, according to results from the OCTAVE 1 and 2 trials presented at the European Crohn’s and Colitis Organization’s Congress.
Xeljanz (tofacitinib citrate, Pfizer) is an oral, small molecule Janus kinase inhibitor currently approved in many countries as a second-line treatment for moderate-to-severe rheumatoid arthritis. Researchers are investigating the drug for inflammatory bowel disease, according to a press release.
“We are encouraged by the results from the OCTAVE Induction studies, as they showed that in these trials oral tofacitinib reduced the symptoms of moderate to severe ulcerative colitis and induced remission of the disease,” Geert D’Haens, MD, PhD, professor of gastroenterology at The Academic Medical Center, University of Amsterdam, said in the press release. “What’s more, these results were seen in patients who were previously treated with tumor necrosis factor inhibitors (TNFis) as well as those who had not received treatment with TNFis. And, improvements in symptoms were observed as early as week 2, the first time point it was measured.”
OCTAVE 1 and 2 were identically designed phase 3 studies evaluating the safety and efficacy of tofacitinib for induction of remission in patients with moderately to severely active UC who had previous treatment failure with corticosteroids, azathioprine, 6-mercaptopurine and/or TNFi. Across both treatment cohorts, 53% to 58% had prior TNFi exposure.
In OCTAVE 1, researchers randomly assigned 476 patients to 10 mg tofacitinib twice daily and 122 patients to placebo for 8 weeks. In OCTAVE 2, 429 patients comprised the tofacitinib group and the placebo group was 112 patients.
Remission at week 8 served as the primary endpoint, and mucosal healing at week 8 served as a key secondary endpoint.
In OCTAVE 1, 18.5% of patients who received tofacitinib achieved the primary endpoint compared with 8.2% of those who received placebo (P < .01); in OCTAVE 2, the primary endpoint was achieved by 16.6% of the treatment group vs. 3.6% of the placebo group (P < .001).
Mucosal healing at week 8 was achieved by 31.3% of the OCTAVE 1 treatment group — vs. 15.6% of the placebo group — and 28.4% of the OCTAVE 2 treatment group, compared with 11.6% of the placebo group (P < .001 for all comparisons).
Efficacy was comparable for patients with and without previous exposure to TNFis. Partial Mayo scores improved rapidly and significantly in the treatment groups compared with placebo at weeks 2, 4 and 8 (P < .001 for all).
Safety findings were comparable to those observed in other trials of tofacitinib, and the most common adverse event leading to discontinuation was UC flare, according to the press release.
Adverse event rates were comparable between groups (OCTAVE 1: 56.5% vs. 59.8%; OCTAVE 2: 54.1% vs. 52.7%) and serious adverse event rates were not higher in the treatment groups compared with placebo (OCTAVE 1: 3.4% vs. 4.1%; OCTAVE 2: 4.2% vs. 8%).
The OCTAVE global clinical development program — which is expected to form the approval submission package for the indication of UC — also includes the phase 3 OCTAVE Sustain maintenance trial, the results of which are expected by the end of the year, and the ongoing open-label extension study, OCTAVE Open, according to the press release.
Tofacitinib in Crohn’s disease
Modest results from two other multicenter phase 2b trials of tofacitinib for induction and maintenance in Crohn’s disease were also presented at ECCO.
In the induction trial, patients with moderate-to-severe CD and previous treatment failure were randomly assigned to receive 5 mg tofacitinib (n = 85), 10 mg tofacitinib (n = 86) or placebo (n = 90) twice daily for 8 weeks.
Forty-three percent of the 10 mg group achieved clinical remission at week 8 — the primary endpoint — compared with 43.5% in the 5 mg group and 36.7% of the placebo group. However, researchers did not observe statistical significance in this comparison. Comparable results were observed in patients with and without previous TNFi exposure.
Significantly more patients in the 5 mg group achieved clinical response at week 8 (P < .05), Crohn’s Disease Activity Index scores significantly improved at week 8 in both treatment groups compared with placebo (P < .05) and C-reactive protein levels were significantly decreased at 8 weeks in the 5 mg group (P < .001) and the 10 mg group (P < .0001), compared with placebo.
The researchers concluded that tofacitinib for induction appeared well tolerated in CD patients, small treatment effects were observed, and “a consistent but modest treatment effect ... was demonstrated by secondary clinical endpoints and supported by changes in biomarkers.”
In the maintenance trial, researchers randomly assigned 126 tofacitinib responders from the induction study 5 mg tofacitinib (n = 43), 10 mg tofacitinib (n = 43) or placebo (n = 42) twice daily for 26 weeks. In the 5 mg group, 39.5% achieved clinical response or remission, compared with 55.8% of the 10 mg group and 38.1% of the placebo group; however, although numerically higher in the 10 mg group, the results did not reach statistical significance. C-reactive protein and fecal calprotectin levels were significantly lower at week 26 for the 10 mg group (P < .0001) and fecal calprotectin was significantly lower for the 5 mg group vs. placebo (P < .05).
Tofacitinib appeared to be well tolerated. Adverse events occurred in comparable proportions across groups, the most common of which were GI disorders and infections, although greater rates of infections occurred in the treatment groups.
The researchers concluded that clinical response or remission occurred in greater proportions of the treatment groups, but the results were not statistically significant. However, biomarkers support a treatment effect with the higher dose. – by Adam Leitenberger
Referen ce s :
Sandborn WJ, et al. Abstract OP019. Presented at: ECCO Congress; March 16-19, 2016. Amsterdam.
Panés J, et al. Abstract OP021. Presented at: ECCO Congress; March 16-19, 2016. Amsterdam.
D’Haens, et al. Abstract OP022. Presented at: ECCO Congress; March 16-19, 2016. Amsterdam.
Disclosure: D’Haens reports rants and/or personal fees from MSD, Abbott, GlaxoSmithKline, Shire, Ablynx, AbbVie, Amakem, AM Pharma, BMS, Boehringer Ingelheim, Celgene, Covidien, Ferring, DrFalk Pharma, Celltrion, Centocor/Janssen Biologics, Engene, Galapagos, Hospira, Medimetrics, Millenium/Takeda, Mitsubishi Pharma, Mundipharma, Pfizer, Photopill, Prometheus Laboratories, Receptos, Robarts Clinical Trials, Salix, Sandox, Setpoint, Shire, TEVA and Tillotts. Please see the ECCO disclosures database for all other researchers’ relevant financial disclosures.