Anti-interleukin-6 antibody shows some promise in Crohn's disease

Last Updated: 2018-01-05

By Will Boggs MD

NEW YORK (Reuters Health) - An antibody to interleukin-6 (IL-6) called PF-0423691 appears to induce clinical response and remission in patients with moderate-to-severe Crohn's disease (CD) who are refractory to anti-TNF therapy, according to results from ANDANTE I and II.

IL-6 has multiple pro-inflammatory effects, and a small pilot study of another IL-6 receptor inhibitor, tocilizumab, suggested a clinical benefit in moderate-to-severe CD.

PF-0423691, a monoclonal antibody that binds to human IL-6 with a half-life of 36-51 days, was well tolerated in earlier studies of patients with rheumatoid arthritis or systemic lupus erythematosus.

Dr. Silvio Danese from Humanitas University, in Milan, Italy, and colleagues investigated the effects of PF-0423691 in a 12-week, phase 2 randomized trial of 249 patients with moderate-to-severe CD, followed by an open-label extension to week 76 with 191 patients, of whom 88 had been responders in the double-blind trial.

In the induction study, PF-0423691 50 mg was associated with significantly greater CDAI-70 (i.e., at least a 70-point improvement in Crohn's Disease Activity Index score) response rates at weeks 8 (49.3%) and 12 (47.4%) than was placebo (30.6% and 28.6%, respectively).

The response rates with PF-0423691 10 mg and 200 mg, however, did not differ significantly from those with placebo.

CDAI remission rates with PF-0423691 50 mg at week 12 (27.4%) also were significantly greater than with placebo (10.9%), the researchers report in Gut, online December 15.

While overall adverse event rates were similar for PF-0423691 and placebo, severe adverse event rates were higher with all PF-0423691 doses than with placebo. Moreover, during induction, there were seven serious adverse events of abscess or perforation, all in PF-0423691-treated patients.

"The overall benefit/risk profile for PF-04236921 appears to be acceptable for the continued development of this treatment in this refractory CD population," the researchers conclude. "However, the signals of GI perforation and abscess do require careful consideration and characterization during future clinical development."

Dr. Andrew T. Chan from Massachusetts General Hospital and Harvard Medical School, in Boston, who recently examined the association between IL-6 and the risk of inflammatory bowel disease, told Reuters Health by email, "Given the clear role of the inflammatory cytokine IL-6 in Crohn's disease onset and progression, it was very interesting to see that an agent that specifically targets this pathway may have substantial benefits for Crohn's patients that are difficult to treat, especially those with elevated levels of inflammatory markers."

"With additional trials in larger numbers of patients, agents that target IL-6 may offer a novel treatment option for patients with moderate-to-severe Crohn's disease that have failed other therapies," said Dr. Chan, who was not involved in the new work. "This study provides proof-of-principle of the importance of the IL-6 pathway in onset, development, and progression of Crohn's disease."

PF-0423691 is in phase 2 development in 19 countries for Crohn's disease. Pfizer has discontinued its development as a possible treatment for rheumatoid arthritis and systemic lupus erythematosus.

Pfizer sponsored the trials, employed seven of the authors, and had various relationships with several others.

Dr. Danese did not respond to a request for comment.

SOURCE: http://bit.ly/2m0GzbA

Gut 2017.