The inflammatory bowel disease ulcerative colitis is a chronic immune-mediated condition that affects the colon and rectum
Patients experience abdominal pain, weight loss, diarrhoea and bleeding. However, the options for treatment remain limited, relying on anti-inflammatory drugs such as mesalazine, which is usually delivered as a controlled release formulation (so that it reaches the colon intact) or antibodies that interfere with the inflammatory cascade signalling processes.
In the most severe cases, surgery may be required, so more effective drug therapies would be extremely beneficial to patients.
An alternative potential treatment is being developed by InDex Pharmaceuticals. Cobitolimod is a synthetic DNA-based oligonucleotide that acts as an agonist at toll-like receptor 9 (TLR9).
After topical application, it has a local anti-inflammatory effect in the colon, which may lead to mucosal healing and symptomatic relief in colitis patients.1 Activating TLR9 in this way appears to suppress Th17 cells and induces anti-inflammatory IL10+ macrophages and regulatory T-cells, altering the balance of intestinal cytokines.
The clinical effects of its topical application were investigated in 131 patients with moderate-to-severe active ulcerative colitis.2 Subjects were randomised to receive two doses of the drug or a placebo, which was administered topically during lower GI endoscopy at weeks 0 and 4.
Although there was no statistically significant difference between the groups regarding the induction of clinical remission at week 12, 32% of the treated group had symptomatic remission compared with 14% of the placebo group.
Significantly more had mucosal healing, too. The drug was well tolerated.
Despite the underwhelming results, the company pressed on with development, using higher doses and less challenging endpoints.
In a randomised, double-blind, placebo-controlled Phase IIb trial, 213 patients with moderate-to-severe left-sided ulcerative colitis who had not responded well to existing treatments were given rectal enemas of 31, 125 or 250 mg of cobitolimod at weeks 0 and 3, 125 mg at weeks 0, 1, 2 and 3, or a placebo.3
The primary endpoint was clinical remission at week 6. More patients (21%) achieved clinical remission in the 250 mg dose group than the placebo group, in which the response rate was 7%.
There was no significant difference from the placebo in the other dose schedules. It was generally well tolerated; severe adverse events were seen in 4% of all patients, most of which were a worsening of the colitis. A Phase III trial using this higher dose is now being planned.