"Only two local applications of 250 mg cobitolimod, three weeks apart, led to induction of clinical remission already at week 6 in this moderate-to-severe, treatment-refractory ulcerative colitis patient population," Dr. Raja Atreya of University Hospital Erlangen, in Germany, told Reuters Health by email.
But outside experts warn that the findings may not pan out. "In previous years, many encouraging compounds that showed positive results in phase 1 or 2 studies have not delivered in phase 3 development programs," write Dr. Christopher Ma and Dr. Remo Panaccione of the University of Calgary, in Alberta, Canada, in a linked editorial.
"This risk for cobitolimod is particularly high given that important secondary endpoints, including differences in endoscopic and histological improvement compared with placebo, were not met," they note.
Cobitolimod, a DNA-based oligonucleotide, binds to Toll-like receptor 9 (TLR9) expressed on mucosal immune and epithelial cells and triggers a local anti-inflammatory response. In an earlier study in patients with moderate-to-severe UC, cobitolimod improved symptomatic remission but did not meet the primary endpoint of clinical remission at week 12.
In the current study, Dr. Atreya and colleagues evaluated the efficacy and safety of different dosing regimens of a cobitolimod enema for induction therapy in 211 patients with moderate-to-severe left-sided UC.
The primary endpoint was the proportion of patients with clinical remission at week 6, defined by Mayo subscores for rectal bleeding of 0, for stool frequency of 0 or 1 (with at least a 1-point decrease from baseline), and for endoscopy of 0 or 1 (excluding friability).
Just over a third of patients (37%) were taking concomitant steroids during the study, 23% had previously taken TNF inhibitors, and 15 had taken vedolizumab.
The proportion of patients with clinical remission at week 6 was highest in the cobitolimod group that received two doses of 250 mg (21% vs. 7% of placebo patients, one-sided P=0.025 and two-sided P=0.049), the researchers report in The Lancet Gastroenterology and Hepatology.
Cobitolimod at the other doses (2x31 mg, 2x125 mg, and 4x125 mg) did not outperform placebo.
Symptomatic remission at week 6, a secondary endpoint, was achieved in 35% of patients in the cobitolimod 2x250 mg group versus 21% of patients in the placebo group. Whether this difference was statistically significant depended on the method chosen for comparison. None of the other cobitolimod dose groups differed significantly from the placebo group.
Endoscopic improvement at week 6 did not differ significantly between any cobitolimod dose group versus placebo.
Improvement in total Inflammatory Bowel Disease Questionnaire scores from baseline to week 6 were numerically greater in the cobitolimod 2x250 mg and 4x125 mg groups than in the placebo group, but these differences fell short of statistical significance.
Treatment-emergent adverse events (most commonly, worsening of ulcerative colitis) were less common among patients receiving cobitolimod than among those receiving placebo.
"These promising results warrant further testing," Dr. Atreya said. "Phase-3 trials of cobitolimod are planned."
The editorialists caution, however, that "although a locally delivered gut-restricted treatment might have improved safety compared with systemic drugs, the effect of such a mechanism in controlling extraintestinal manifestations that affect a quarter of patients with ulcerative colitis is unclear."
InDex Pharmaceuticals funded the study and had financial ties to most of the authors, including Dr. Atreya.
By Will Boggs MD
SOURCE: https://bit.ly/37d75rf and https://bit.ly/3o6qzUH Lancet Gastroenterology and Hepatology, online October 5, 2020.
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