The Lancet Gastroenterology & Hepatology is one of the world’s most highly regarded scientific journals within the field of gastroenterology. They have a thorough review process where researchers in the field, in our case five people, went through and provided their thoughts on the manuscript prior to deciding whether the manuscript should be accepted for publication. We are delighted that The Lancet Gastroenterology & Hepatology also chose to publish an independent expert commentary on the article (read more here) that was very positive, showing a high level of interest in our data from the scientific community. The publication of our article in this prestigious journal is an additional important validation of the successful results of the CONDUCT study evaluating the TLR9 agonist cobitolimod. In addition, the publication is crucial in informing the larger scientific community of our successful results. We are also very proud to have many of the world’s most eminent gastroenterologists as authors and co-authors of the article.
The study objective was to identify the dose regimen for further development in treatment of patients with left-sided moderate to severe active ulcerative colitis. The 213 patients were divided into four treatment arms receiving different doses of cobitolimod and one arm receiving placebo treatment.
The most important conclusion from the CONDUCT study was that the highest dose of cobitolimod, 2x250mg, met the primary endpoint with a clinically relevant and statistically significant effect (compared to placebo), combined with an excellent safety profile. We were also able to confirm the effect of the highest dose in several clinically relevant secondary endpoints, further strengthening the results. The study therefore fulfilled all objectives and identified the dose to move forward with in phase III.
The regulatory authorities EMA and FDA have their own guidelines for what endpoints they require in phase III clinical studies to obtain market approval for a drug to treat ulcerative colitis. The authorities require the primary endpoint to be a certain score determined by three parts: 1) blood in the patient’s stool, 2) stool frequency, 3) the level of inflammation in the colon when examining the mucosa with a camera during colonoscopy. It was precisely this endpoint that was met in the CONDUCT study.
In addition to meeting the primary endpoint, induction of clinical remission at week 6, several secondary endpoints demonstrated statistically significant effects in the 2x250mg dose group compared to placebo (meeting the predefined exploratory type I error rate of p<0.10).
A statistically significantly higher proportion of patients in the highest dose group achieved symptomatic remission compared with placebo. Symptomatic remission means that the patients no longer have blood in their stool and use the toilet a normal number of times per day. This is an important endpoint to achieve for patients, since bloody diarrhea is the primary reason for their low quality of life. In line with this, we also saw a statistically significant higher reduction in the number of daily toilet visits from when patients entered the study to week 6 for patients treated with the highest dose of cobitolimod (2x250mg) compared with placebo.
We observed a numerically higher portion of patients treated with 2x250mg cobitolimod that experienced endoscopic remission compared to placebo, i.e., the patient had a healed colonic mucosa when examined with a camera during a colonoscopy.
Another secondary endpoint where we observed statistically significant differences between the highest dose group (2x250mg cobitolimod) and placebo was when the physician’s assessment of the patient was included in the definition of clinical remission. In addition to the fact that the patient did not have any blood in their stool, went to the toilet a normal number of times per day and had a healed colonic mucosa, the physician’s assessment of the patient’s general condition was significantly approved.
To measure quality of life, patients filled out a standardized form with questions about their quality of life prior to treatment as well as during the course of the study. This questionnaire, called the Inflammatory Bowel Disease Questionnaire (IBDQ), summarize the patient’s answers in an IBDQ score. This endpoint also showed a numerically larger improvement among patients treated with 2x250mg cobitolimod compared with placebo. In the part of the IBDQ that measures social functions, i.e., how the disease affects the patient’s ability to work and participate in activities and social engagements, we saw a statistically significant improvement from when patients entered the study to week 6 for the group that received 2x250mg cobitolimod, compared with placebo.
CONDUCT was an exploratory study designed to have sufficient statistical power to demonstrate a difference between the groups for the primary endpoint: clinical remission at week 6. The study was not designed to have statistical power to detect differences in the secondary endpoints. With that said, we saw a statistically significant effect in the highest dose group in many clinically relevant secondary endpoints. With more patients in phase III, it will be possible to better study the effect of cobitolimod in the secondary endpoints.
The CONDUCT study demonstrated that the highest dose, 2x250mg cobitolimod, was the most effective. The lower doses did not show a statistically significant difference compared with placebo for the primary endpoint. For some of the secondary endpoints, we could observe a significant effect in the lower doses, for example in the quality-of-life measurement IBDQ and the biomarker calprotectin. However, it is apparent from the overall results that the highest dose, 2×250 mg, shows most promise to proceed with in phase III. It is possible that a high dose is required in the beginning of the treatment to obtain control over the inflammation and to get the patients into remission, which is in line with studies of other drugs for treating ulcerative colitis. It could be the case that with 250mg a threshold is reached where enough receptors are activated to produce an immunomodulatory effect and reduce the inflammation, a threshold that cannot be reached through repeated administrations of lower doses.
The CONDUCT study once again confirmed the excellent safety profile seen in previous studies with cobitolimod. Side effects will always be reported in a clinical trial because patients are required to report everything that takes place during the trial’s course, for example getting a cold or spraining an ankle. In the CONDUCT study, few side effects were reported and there was no difference between the groups receiving cobitolimod and the group receiving placebo.
Results from previous studies evaluating cobitolimod support the results of the CONDUCT study. We have in previous clinical trials with cobitolimod, as in the CONDUCT study, seen a clinically relevant effect in combination with an excellent safety profile. Today, we have data from five placebo-controlled clinical trials evaluating cobitolimod – a major strength.
One difference in the CONDUCT study compared with the previous COLLECT study was that in COLLECT we saw an effect of the lower dose 2x30mg (rounded down from 2×31,2mg). This could be explained by the way cobitolimod was administered, which differed between the studies. In the COLLECT study, cobitolimod was administered via colonoscopy, i.e., an examination of the colon using a tube with a camera inside. Prior to performing a colonoscopy, the colon must be cleaned of feces, mucus and blood with laxatives so that the intestinal mucosa is properly visible during the examination. This meant that the colon was “clean” when cobitolimod was administered during the COLLECT study. In addition, cobitolimod was administered through the tube higher up in the intestine, above the area of inflammation, and was then allowed to flow downwards. Because it is clinically impossible to have a product that requires repeated colonoscopies for administration, in CONDUCT cobitolimod was administered via an enema. An enema is a plastic bottle with a nozzle that is placed in the rectum. The solution inside the bottle is then injected upwards into the colon. Because no bowel cleaning occurred when cobitolimod was administered during the CONDUCT study and the dose was given further down in the colon, the uptake of cobitolimod may have been lower. This could explain why we saw a lower effect with 2x30mg of cobitolimod in the CONDUCT study, and a significant effect of the highest dose, 2x250mg.
This link will take you to The Lancet Gastroenterology & Hepatology’s homepage, where the article can be downloaded for a fee. The Lancet’s terms and conditions state that private pharmaceutical companies are not allowed to distribute the article or make it available on their website.
Yes, the CONDUCT study was presented orally at the two leading gastroenterology conferences in October 2020: United European Gastroenterology Week (UEGW) and American College of Gastroenterology (ACG) Annual Scientific Meeting. UEGW is the largest scientific meeting for gastroenterologists in Europe and the ACG Annual Scientific Meeting is the leading clinical conference for gastroenterologists in the United States. Both meetings were virtual and the presentation slides are available here.