In Crohn’s, chronic gastrointestinal inflammation is mainly due to imbalance between cytokines. This paper looks at one new agent that targets tumour necrosis factor alpha and its receptors
Division of Gastroenterology
Istituto Clinico Humanitas
IRCCS in Gastroenterology
Division of Gastroenterology
Policlinico Umberto I
Università La Sapienza
Crohn’s disease (CD) is a chronic inflammatory disorder which may involve any part of the gastrointestinal tract. Chronic inflammation is primarily due to an immunological imbalance between pro- and anti-inflammatory cytokines, with a defective apoptosis of lamina propria T-cells. In CD the pattern of cytokines expressed by lamina propria lymphocytes is consistent with a T-helper-1 (Th1) response. Among pro-inflammatory cytokines tumour necrosis factor-α (TNFα) seems to play a central role in the pathogenesis of CD. TNFα is largely produced by monocytes/macrophages, although T- and B-lymphocytes, natural killer cells, mast cells and epithelial cells also produce significant amounts of it.(1,2) The rationale for choosing TNFα as a target for treatment of CD comes from animal models and from the increased concentrations of TNFα found in blood, stool and mucosa (both normal and inflamed) of CD patients. Different efficacy of anti-TNFα inhibitors is based on their nature (humanised or fully human), their avidity and affinity for TNFα, their capacity to bind either soluble and/or membrane TNFα, to fix complement, to mediate antibody-dependent cytotoxicity and to cause T-cell apoptosis (see Table 1).(3,4) Infliximab (a humanised anti-TNFα antibody) was the first TNFα inhibitor approved for the treatment of CD.
Certolizumab pegol (CDP870) is a PEGylated Fab fragment of a humanised anti-TNFα antibody that is administered subcutaneously. The site-specific addition of two molecules of polyethylene glycol to the antibody fragment extends the plasma half-life of CDP870. Compared with other anti-TNFα, CDP870 is the only one that does not mediate apoptosis (see Table 1).(3,4)
In a preliminary phase II trial, 92 moderate-to-severe CD patients were randomised to receive a single intravenous infusion of certolizumab pegol (1.25 mg/kg [n = 2], 5 mg/kg [n = 26], 10 mg/kg [n = 17] or 20 mg/kg [n = 23]) or placebo (n = 24). This trial failed to achieve clinical response and remission at week 4.(5)
In a phase II trial 292 patients with moderately-to-severely active CD were randomised to receive subcutaneous certolizumab pegol at doses of 100 mg, 200 mg, or 400 mg or placebo at weeks 0, 4, and 8. At week 2 all certolizumab pegol doses showed significant clinical benefit over placebo. In a post-hoc analysis in 119 CD patients with elevated C reactive protein (CRP) levels (>10 mg/dl at baseline), any dose of certolizumab pegol showed significant higher response and remission rates vs placebo.(6)
The PRECiSE 1 (Pegylated antibody fRagment Evaluation in Crohn’s dIsease: Safety and Efficacy) study is a phase III RCT designed to assess the efficacy and safety of certolizumab pegol for induction of remission in 662 patients with moderately to severely active CD. All patients were randomised to receive certolizumab pegol 400 mg or placebo at weeks 0, 2, and 4 and then four-weekly through week 24. The clinical response rates at week 6 and at weeks 6 and 26 (co-primary endpoints) showed a modest advantage in certolizumab pegol group with respect to placebo. Serious adverse events were reported in 10% of patients in the certolizumab group with respect to 7% in the placebo group.(7)
The PRECiSE 2 study was designed to assess the efficacy and safety of certolizumab pegol in maintaining clinical response in moderately to severely active CD following induction therapy. Out of 668 adult moderately to severely active CD patients receiving an open induction therapy with certolizumab pegol 400 mg at week 0, 2 and 4, a total of 428 (64%) responded at week 6 and were randomised to maintenance therapy with certolizumab pegol 400 mg (n = 216) or placebo (n = 212) every four weeks through week 24.
The clinical response rates and remission rates at week 26 were significantly higher in the certolizumab pegol group than placebo. Infectious serious adverse events (including one case of pulmonary tuberculosis) were reported in 3% of patients in the certolizumab pegol group with respect to less than 1% in the placebo group.(8)
Of 668 patients enrolled in the PRECiSE 2 study, 474 were infliximab-naive, while 193 had a history of prior infliximab use at baseline. Percentages of CD patients achieving clinical response or remission at week 6 and maintaining them at week 26 were similar in both groups of patients.(9)
Lastly, recent studies suggest that certolizumab pegol 400 mg may improve health-related quality of life in patients with moderate to severe CD.(10)
Taken together, these data suggest that certolizumab pegol would represent an important therapeutic option for CD patients, irrespective of whether they are infliximab-naive or not. ■
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