The randomized placebo-controlled double-blind TURANDOT trial [NCT01620255] substantiated the efficacy and safety of a monoclonal antibody that blocks white blood cell adhesion to gut mucosa in the treatment of moderate to severe ulcerative colitis (UC).

As explained by Walter Reinisch, MD, McMaster University Health Centre, Hamilton, Ontario, Canada, inflammatory bowel disease features translocation of white blood cells into the gut mucosa. An important part of this translocation involves the binding of the α4β7 integrin on some white blood cells to the mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) receptor on endothelial cells [Feagan BG et al. N Engl J Med. 2013; Sandborn WJ et al. N Engl J Med. 2013]. Blocking this binding may be beneficial in inflammatory bowel disease. The fully humanized monoclonal antibody PF-00547659 (PF) targets immunoglobulin G2 MAdCAM-1. The antibody does not hamper the immune function of the central nervous system and does not cross-react with vascular cell adhesion protein 1.

In the TURANDOT trial, 357 patients with moderate to severe UC were randomized to subcutaneously delivered placebo or 7.5-, 22.5-, 75-, or 225-mg doses of PF. Doses were given at 0, 4, and 8 weeks in the 12-week trial, with subsequent 24-month follow-up or enrollment in an open-label extension phase. The researchers reported here on the 12-week treatment.

Patients were aged 18 to 65 years, with biopsy-confirmed UC, Mayo endoscopy subscore ≥ 2, active disease beyond the rectum, Mayo score ≥ 6, and failure on or intolerance to ≥ 1 conventional therapy. Exclusion criteria included enteric infection, use of parenteral steroids with a dose of prednisone equivalent > 20 mg, recent biologic therapy, and any history of anti-integrin therapy. The primary efficacy end point was the proportion of patients in clinical remission at week 12, defined as a total Mayo score ≤ 2 points with no individual subscore > 1 point. There were also several secondary efficacy end points, including the proportion of patients with a clinical response at week 12, defined as a decrease in total Mayo score by ≥ 3 points and ≥ 30% decrease in subscore for rectal bleeding of ≥ 1 point or absolute subscore of ≤ 1.

Baseline demographic and clinical characteristics in the 5 arms were comparable. The primary efficacy end point was met, with improved remission in all PF arms compared with placebo at week 12 and with the differences for 7.5, 22.5, and 75 mg of PF being significant when compared with placebo (all P < .05; Table 1).

In secondary responses, improvements in clinical response at week 12 for all PF doses (7.5 mg, 38.0%; 22.5 mg, 54.2%; 75 mg, 45.1%; 225 mg, 50.0%) were significantly improved (all P < .05) compared with placebo (28.8%). All doses of PF resulted in rates of mucosal healing (endoscopy subscore ≤ 1 point; 7.5 mg, 15.5%; 22.5 mg, 27.8%; 75 mg, 25.4%; 225 mg, 14.3%) that exceeded the rate in the placebo arm (8.2%), with the improvements for 22.5 and 75 mg of PF being significant (both P < .05). These trends in improvement were evident both in treatment-naïve and treatment-experienced patients.

Fecal calprotectin declined in all treatment groups relative to placebo, with the decline being less rapid in the 7.5-mg PF arm. PF doses > 7.5 mg suppressed soluble MAdCAM-1 by >90%. Adverse events were comparable in type and prevalence in the 5 study arms.

The TURANDOT trial met its primary and secondary end points, with no safety issues. Increased remission of symptoms was evident in patients with moderate to severe UC who had failed ≥ 1 treatment before trial enrollment, with the 22.5-mg dose giving the best response.