Ulcerative colitis , Two investigational agents, PF-00547659 by Pfizer and GS-5745 by Gilead, show promising results for patients with moderate to severe ulcerative colitis, according to data from two late-breaking abstracts presented at DDW (901a and Tu2056).
A Phase II trial known as the TURANDOT study was designed to determine the optimal dose for PF-00547659, a monoclonal antibody that acts directly on MAdCAM, to induce remission in patients with moderate to severe ulcerative colitis who have experienced treatment failure with at least one prior therapy.
MAdCAM is a cell adhesion molecule expressed mainly by intestinal venules. Its role in the intestinal inflammatory response has been previously demonstrated in animal models, with inhibition resulting in improvement of colitis. A total of 357 patients were enrolled and randomized to one of four doses of the investigational agent (7.5 mg, 22.5 mg, 75 mg, and 225 mg) or placebo, with therapy administered every 4 weeks for a total of three doses.
Results for the primary endpoint of clinical remission at week 12, based on the total Mayo score, and varying secondary endpoints showed that the greatest efficacy signal was derived from the 22.5-mg and 75-mg doses. Clinical remission rates were 16.7% and 15.5% for the 22.5-mg and 75-mg doses, respectively, compared with 2.7% in the placebo group (P < 0.05). The clinical remission rates in the 7.5-mg and 225-mg groups were 11.3% and 5.7%, respectively.
The investigators noted that patients who had experienced previous treatment failure with an anti–tumor necrosis factor agent had poorer responses than those who had not received such therapies. In terms of safety, the findings were unremarkable, and no cases of progressive multifocal leukoencephalopathy occurred.
A multicenter, double-blind, Phase Ib study was conducted in 50 patients with moderate to severe ulcerative colitis to assess the efficacy and safety of GS-5745, an IgG4 monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9). MMP9 is a type IV collagenase that is upregulated in patients with ulcerative colitis and is associated with mucosal injury. Patients were randomized to placebo or varying doses of GS-5745 given intravenously (0.3 mg/kg, 1.0 mg/kg, 2.5 mg/kg, and 5.0 mg/kg at days 0, 7, 14, 21, and 28) or as a once-weekly subcutaneous dose of 150 mg given on days 0, 7, 14, 21, and 28.
Clinical response was 43% for the entire cohort of patients given active treatment compared with 13% in the placebo group. Clinical response rates ranged from 38% to 50% for the varying doses. Remission occurred in 14% of patients given active treatment compared with no patients in the placebo group, and mucosal healing occurred in 33% and 25% of these groups, respectively.
Rates of adverse events and serious adverse events were low in the active treatment group and comparable with rates observed in the placebo group, and only one patient given active treatment discontinued because of an adverse event.