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SAN DIEGO -- The selective oral JAK1 inhibitor filgotinib was effective in the treatment of moderate-to-severe Crohn's disease in a phase II study, a researcher reported here.

At week 10, 47% of patients randomized to filgotinib were in clinical remission compared with 23% of patients given placebo (P<0.01), said , of Leuven University Hospital in Belgium.

In addition, clinical response was seen in 59% compared with 41% of patients (P<0.05), she reported in a late-breaker session at the annual .

“These results specifically show encouraging data that filgotinib is effective for the treatment of moderate-to-severe Crohn’s disease, and more generally provide evidence that JAK inhibition may be effective for Crohn’s disease,” said , who is the director of the University of California San Diego Inflammatory Bowel Disease Center in La Jolla.

"Crohn's disease is characterized by inflammation and cytokine production, and we know that cytokines signal through the JAK-STAT pathway," she explained. This family of kinases includes JAK1, 2, and 3, as well as tyrosine kinase 2. Inhibition of JAK1 suppresses the signaling of proinflammatory cytokines such as interleukins 2 and 6, while JAK3 inhibition has an effect mainly on the gamma chain interleukins, which are critical for lymphocyte function.

"What we mainly want to avoid is the inhibition of JAK2, because the hormone-like cytokines signal through JAK2 and these are important for hematopoiesis," she said.

Dose selection for the clinical studies of filgotinib for rheumatoid arthritis and Crohn's disease was based on pharmacokinetic and pharmacodynamic assessments that identified 200 mg/day as the likely optimal dose because no additional JAK1 inhibition was seen with higher doses.

Safety and efficacy were previously demonstrated in a phase II study in rheumatoid arthritis.

In the phase II study, known as FITZROY, patients were randomized 3:1 to 200 mg filgotinib or placebo once per day for 10 weeks.

The primary endpoint was remission, defined as a score below 150 on the Crohn's disease activity index (CDAI), at week 10. Response was a decrease of at least 100 points from baseline on the CDAI.

Patients were required to have active Crohn's disease that was confirmed endoscopically, with a baseline CDAI between 220 and 450. The Simplified Endoscopy Score for Crohn's Disease (SES-CD) had to be at least 7.

Exclusion criteria included indeterminate or ulcerative colitis and surgical bowel resection within the past 6 months. Immunomodulator and anti-tumor necrosis factor (TNF) therapies had to be discontinued, but mesalamine and oral steroids in doses below 30 mg/day were permitted.

Baseline features were similar between the active treatment and placebo groups, with a mean age of 35 and a disease duration ranging from 6.8 to 8.8 years. Mean CDAI at baseline was 290, and SES-CD was 15.

Half the patients were on oral steroids, at a mean dosage of 23 mg/day. The majority had previous exposure to anti-TNF therapy.

A total of 40% had levels of C-reactive protein (CRP) above 10 mg/L at baseline. By week 10, CRP levels had normalized in more than twice as many patients in the filgotinib group as in the placebo group (30% versus 14%).

Quality of life, as measured on the Inflammatory Bowel Disease Questionnaire, improved significantly in the active treatment group, with changes of 33.82 points from baseline compared with a change of 17.56 in the placebo group (P=0.0045). The differences were significant for all aspects of the quality-of-life questionnaire, including bowel symptoms, systemic symptoms, emotional status, and social functioning, Vermeire said.

No safety signals were observed, and there were no differences between the groups in infections, gastrointestinal disorders (most often worsening of Crohn's disease), or neurologic symptoms (typically headache).

In addition, no differences were seen for lymphocyte counts, kidney function, or liver function tests, while both groups had increases in mean hemoglobin concentrations.

There was an increase in HDL and no change in LDL, suggesting a favorable lipid profile. "We have also seen this with another JAK inhibitor, tofacitinib [Xeljanz]," she said.

At the end of the 10-week induction phase of the trial, patients were rerandomized to placebo or to 100 or 200 mg of filgotinib for an additional 10 weeks, but those data have not yet been analyzed, she said.

"In conclusion, these week-10 data show that filgotinib was effective in Crohn's disease and showed improvements in quality of life for patients who were either TNF-naive or -failures. The drug was safe and well tolerated, with safety consistent with what has been seen in rheumatoid arthritis. These findings support the further development of the drug in inflammatory bowel disease," she said.

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