Patients with Crohn’s disease who previously failed treatment with anti-tumor necrosis factor therapy saw improvement after treatment with an investigational anti-interleukin-6 antibody, according to phase 2 research published in Gut.
While patients achieved significantly greater clinical remission and response rates with the study drug vs. placebo, investigators noted that gastrointestinal perforation and abscess occurred in some patients, and emphasized that careful consideration of these safety concerns in the future clinical development of PF-04236921 (Pfizer) is warranted.
Although antibody-based treatments directed against tumor necrosis factor (TNF) have demonstrated efficacy in moderate-to-severe Crohn’s disease (CD), the treatment is ineffective in many patients.
“Up to 50% of patients experience primary non-response and more than 50% can lose response over time to anti-TNF maintenance therapy,” Silvio Danese, MD, of the Gastrointestinal Lab and IBD Unit at Humanitas Clinical and Research Center and Humanitas University in Milan, Italy, and colleagues wrote. “This leaves a significant unmet need in the treatment of non-responsive patients, particularly after therapy with anti-TNF antibodies.”
In this pair of multicenter phase 2 trials (ANDANTE I and II), Danese and colleagues evaluated the efficacy of PF-04236921, which targets IL-6, a cytokine with multiple pro-inflammatory effects, in patients with CD.
They randomly assigned 249 patients with moderate-to-severe CD for whom at least one anti-TNF therapy failed to receive 10 mg, 50 mg or 200 mg doses of PF-04236921 by subcutaneous injection or placebo on days 1 and 28 of a 12-week treatment period. They discontinued the 200-mg dose due to safety findings in another study, and excluded that group from the primary efficacy analysis.
Patients in the 50-mg group showed significantly greater clinical response rates (defined as 70-point reduction in Crohn’s Disease Activity Index [CDAI]) compared with placebo at weeks 8 (49.3% vs 30.6%, P < .05) and 12 (47.4% vs. 28.6%, P < .05), which served as the primary endpoint. Additionally, 27.4% of patients in this dose group achieved CDAI remission at week 12 compared with 10.9% of the placebo group, a difference of 16.5% (P < .05).
Although researchers noted improvements in CDAI scores for the 10-mg group they were not significant, and this lower dose did not meet the primary endpoint.
After the induction phase, 191 participants entered the 48-week open-label extension study. Across both studies, the most common treatment emergent adverse events and serious adverse events included worsening of CD, abdominal pain and nasopharyngitis, but investigators noted that GI abscesses and perforations emerged as a safety signal, affecting six patients in the induction trial and 10 patients in the extension study.
The investigators said the results are encouraging in the context of treating patients who do not respond to anti-TNF therapies.
“The overall benefit/risk profile for PF-04236921 appears to be acceptable for the continued development of this treatment in this refractory population,” they wrote. – by Alex Young
Disclosures: These studies were funded by Pfizer. Danese reports he is a speaker, consultant and advisory board member for Abbott Laboratories, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Hospira, Johnson and Johnson, Merck & Co, Millennium Takeda, Mundipharma, Novo Nordisk, Nycomed, Pharmacosmos, Pfizer, Schering-Plough, UCB Pharma and Vifor. Please see the full study for all other authors’ relevant financial disclosures.