Pegylated Anti–Tumor Necrosis Factor for Crohn Disease

Two anti–tumor necrosis factor (TNF) antibodies are FDA-approved for treating patients with Crohn disease. Infliximab is a human/mouse chimeric antibody against TNF, and adalimumab is a fully humanized anti-TNF antibody that can be self-administered subcutaneously (unlike infliximab). To avoid complications that might be associated with complement activation, cellular cytotoxicity, or apoptosis induced by the Fc fragments of these antibodies, researchers developed certolizumab pegol, which is a pegylated humanized Fab′ fragment directed against TNF. In past studies, certolizumab pegol (400 mg subcutaneously, every 4 weeks) was superior to placebo for inducing responses in patients with Crohn disease and elevated baseline C-reactive protein (CRP) levels (≥10 mg/L).

In two industry-sponsored, international, randomized, placebo-controlled trials, researchers provided extended observations of certolizumab for induction of Crohn disease response and for maintenance therapy in patients with successful initial inductions. In the first study, 662 patients with moderate-to-severe Crohn disease received certolizumab or placebo at weeks 0, 2, and 4 and then every 4 weeks through week 26. In the second study, 668 patients initially received certolizumab, and those with responses at week 6 were randomized to maintenance therapy with certolizumab or placebo to week 26. In both studies, other medications were allowed, but steroid doses could not be increased, and patients were ineligible if they had received another anti-TNF agent within 3 months or previously had failed to respond to the first dose of an anti-TNF agent. All patients had baseline Crohn’s Disease Activity Index (CDAI) scores of 220 to 450. Response was defined as reduction in CDAI score of at least 100 points at weeks 6, 26, or both; subanalyses were conducted in patients with baseline CRP levels of at least 10 mg/L. Remission was defined as an absolute CDAI score of 150 points or fewer.

In the first study, response rates at 6 weeks were 35% with certolizumab and 27% with placebo (P=0.02), and response rates at both weeks 6 and 26 were 23% and 16%, respectively (P=0.02). Among patients with baseline CRP levels ≥10 mg/L, certolizumab and placebo response rates at week 6 were 37% and 26%, respectively (P=0.04), and response rates at both weeks 6 and 26 were 22% and 12% (P=0.05). Remission rates were higher with certolizumab than with placebo at both assessed time points in patients with baseline CRP levels ≥10 mg/L and in the entire population, but none of the differences reached statistical significance.

In the second study, among the 428 6-week responders, 63% of certolizumab recipients exhibited continued responses at week 26, compared with 36% of placebo recipients (P<0.001). Among the 213 6-week responders with CRP levels ≥10 mg/L, 62% of certolizumab recipients showed continued responses at week 26, versus 34% of placebo recipients (P<0.001). Response rates were uniformly higher with certolizumab, regardless of concomitant immunosuppressant use or previous infliximab therapy.

In both studies, no striking differences in adverse events were noted between certolizumab and placebo, although one certolizumab recipient in the maintenance study developed pulmonary tuberculosis. Fewer than 10% of all certolizumab-treated patients developed antibodies to certolizumab or new antinuclear antibodies. In the induction study, one 22-year-old patient who had received infliximab previously died from metastatic lung cancer 10 months after withdrawal of certolizumab.