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TLR9 activation shows potential as a target for ulcerative colitis and warrants further testing.
Two administrations of cobitolimod 250 mg were well tolerated and efficacious in inducing clinical remission after 6 weeks in patients with moderate-to-severe, left-sided ulcerative colitis, according to findings from a new study.
The topically administered, DNA-based oligonucleotide activates Toll-like receptor (9). Previous research has shown the therapy to be clinically efficacious in patients with moderate-to-severe ulcerative colitis
The goal of this trial, dubbed the CONDUCT study, was to determine the most efficacious dose and dose regiment for further development.
The randomized, double-blind, five-arm, placebo-controlled, dose-ranging phase 2b study was led by Raja Atreya, MD, of the University of Erlangen-Nürnberg, Germany. The team recruited from 91 hospitals or outpatient clinics in 12 European countries patients with moderate-to-severe, left-sided ulcerative colitis, who had experienced inadequate response to conventional or biological therapies.
Patients had a Mayo score of 6-12, a centrally read endoscopic subscore of ≥2, and no individual subscore of <1.
Overall, they included a total of 213 patients, with only 211 receiving treatment. The population was then randomized 1:1:1:1:1 to receive cobitolimod doses of 31 mg, 125 mg, or 250 mg at weeks 0 and 3; 125 mg at weeks 0, 1, 2, and 3; or placebo.
Thus, the primary endpoint sought by the investigators was the proportion of patients achieving clinical remissions at week 6.
Patients were considered to have achieved remission if they had Mayo subscores for rectal bleeding of 0, stool frequency of 0 or 1 (with ≥1-point decrease from baseline), and endoscopy of 0 or 1.
Following week 6 of treatment, a greater proportion of patients who received 250 mg of the investigative drug experienced clinical remission (21%) when compared with the placebo group (7% [OR, 3.8; 80% CI, 1.5-9.5; P = .0.25]).
There were no reported significant differences between the other 3 dose groups and placebo.
Treatment-emergent adverse events occurred in 48% patients in the placebo group, 25% patients in the 31 mg group, 40% in the 2 x 125 mg group, 36% in the 4 x 125 mg group, and 43% in the 250 mg group.
Severe adverse events occurred in 4% of all 211 treat patients. These events included abdominal hernia (7 patients) and wound dehiscence (1 patient).
Furthermore, the investigators noted that 10 patients had a total of 13 serious adverse events, which consisted of worsening of ulcerative colitis (8 events) and pruritus, rash, abdominal hernia, fascia dehiscence, and deep vein thrombosis (1 even each).
“TLR9 activation is a promising novel therapeutic target in ulcerative colitis and warrants further testing, with phase 3 trials of cobitolimod planned,” Atreya and team concluded
The study, “Cobitolimod for moderate-to-severe, left-sided ulcerative colitis (CONDUCT): a phase 2b randomised, double-blind, placebo-controlled, dose-ranging induction trial,” was published online in The Lancet: Gastroenterology & Hepatology.