Anti-IL-6 antibody shows promise in refractory Crohn’s disease
The anti-interleukin 6 (IL-6) humanized IgG2 monoclonal antibody PF-04236921 drives clinical response and remission in patients with moderate-to-severe Crohn’s disease (CD) who had failed anti-tumour necrosis factor (TNF) therapy, according to the ANDANTE* I and II extension study.
“CD has no known cure … 50 percent of patients experience primary nonresponse [to anti-TNF therapy] and more than 50 percent can lose response over time to anti-TNF maintenance therapy,” said the researchers.
“The outcomes with PF-04236921 are particularly encouraging in the context of a very difficult-to-treat population: in addition to inadequate response to one or more prior anti-TNF therapies, patients had a median disease duration of approximately 10 years and many had undergone previous resection,” they added.
The multicentre, double-blind, phase II trial involved 247 patients with confirmed CD (CDAI** score 220–450), CRP*** ≥5 mg/L, and inadequate response to anti-TNF agents (failed ≥1 therapy). During the 12-week induction phase, patients were randomized 1:1:1:1 to receive subcutaneous injection of PF-04236921 10, 50 or 200 mg, or placebo on days 1 and 28. Eligible patients who completed the induction study entered the open-label extension phase, during which they received PF-04236921 50 mg Q8W up to six doses and were further followed up for 28 weeks. [Gut 2017;doi:10.1136/gutjnl-2017-314562]
The primary endpoint of clinical response rates based on CDAI-70 were significantly higher with PF-04236921 50 mg than with placebo at 8 weeks (49.3 percent vs 30.6 percent; p<0.05) and 12 weeks of induction (47.4 percent vs 28.6 percent; p<0.05).
CDAI remission rates were also significantly higher at week 12 in the PF-04236921 50 mg vs the placebo arms (27.4 percent vs 10.9 percent; p<0.05).
“Separation from placebo was observed as early as week 4, particularly for CDAI-70 response and remission,” observed the researchers. “The changes in continuous CDAI score are supportive of the rapid onset of action with separation from placebo as early as week 4 and maintained through week 12.”
Although patients receiving the 10 mg dose showed numerical improvements in CDAI score compared with those on placebo, the difference was not significant. The 200 mg dose was discontinued and excluded from primary efficacy analysis due to safety findings in a separate study.
Among the 191 patients enrolled in the open-label extension study, 46 percent were CDAI responders at study entry. Of the responders who had been on active therapy (n=65), the response rates were 40 percent and the remission rates were 32 percent by week 48 of this study phase.
“[T]he loss of response over time in more than half of the patients did not appear to be associated with decrease of drug levels and/or with occurrence of antidrug antibodies, as has been commonly observed for other anticytokine therapies,” the researchers pointed out. “Maintenance for patients induced on anti-IL-6 therapy is impacted by attenuation of unknown cause and will require development of new optimization of treatment strategies that could include high(er) dose and/or longer duration of induction or alternate drug combinations in order to avoid immunological breakthroughs.”
For both the blinded induction and open-label studies, the most common treatment-emergent or serious adverse events with PF-04236921 included worsening CD, nasopharyngitis, and abdominal pain.
“[I]n light of the limited therapeutic options available to difficult-to-treat patients with CD … the present study suggests that targeting IL-6 may provide a further therapeutic option for this population,” said the researchers. “However, the signals of gastrointestinal perforation and abscess do require careful consideration and characterization during future clinical development.”