Oral Pill Icotrokinra Outperforms Placebo in Hard-to-Treat Ulcerative Colitis

A new once-daily pill for ulcerative colitis has demonstrated the ability to heal the intestinal lining and halt symptoms in patients who previously failed advanced injectable therapies. The results establish a highly effective oral alternative in a field historically dominated by intravenous infusions.[1][2]

The drug, icotrokinra, is the first oral peptide designed to selectively block the interleukin-23 receptor. Until now, targeting this specific inflammatory pathway required regular hospital infusions or subcutaneous injections, which can be burdensome and painful for patients managing chronic digestive diseases.[1][5]

The Phase 2b ANTHEM-UC trial enrolled 252 adults with moderately to severely active ulcerative colitis across 21 countries. The participants had an average age of 41.6 years and had lived with the debilitating condition for an average of nearly eight years.[5]

On endoscopic evaluation at the start of the study, 59% of the participants had a severe endoscopic subscore. The remaining 41% presented with moderate disease activity, and the majority had inflammation limited to the left side of their colon.[5]

The trial cohort represented a notoriously difficult-to-treat population. All participants had a history of glucocorticoid dependence or an inadequate response to first-line therapies, and nearly half had already failed advanced biologic treatments like tumor necrosis factor inhibitors.[5]

Patients were randomly assigned to receive a daily oral dose of 100, 200, or 400 milligrams of icotrokinra, or a visually identical placebo. The primary endpoint measured clinical response at week 12, defined as a significant drop in the modified Mayo score.[4][5]

Week 12 Efficacy and Healing

At 12 weeks, 63% of patients taking the highest 400-milligram dose achieved a clinical response, compared to just 27% of those on a placebo. The 100-milligram and 200-milligram doses also outperformed the placebo, achieving response rates of 55% and 58%, respectively.[1][4]

The findings were published in the October 15 issue of the New England Journal of Medicine. Beyond basic symptom relief, the highest dose group achieved a 30% clinical remission rate, significantly higher than the 11% observed in the placebo arm.[1][4]

The researchers tracked symptomatic remission, which requires a complete halt to rectal bleeding and a normalization of stool frequency. At week 12, 46% of patients on the highest dose achieved this milestone, compared to just 19% of the placebo group.[4]

Objective visual evidence supported the patients' symptom reports. Endoscopic improvement—meaning visible healing of the colon lining on a scope—occurred in 37% of patients on the 400-milligram dose, compared to just 14% of those receiving the placebo.[4]

"Icotrokinra was effective even in hard-to-treat patients who had failed previous drug regimens," said Dr. Maria T. Abreu, executive director of the F. Widjaja Inflammatory Bowel Disease Institute at Cedars-Sinai. Abreu served as the corresponding author for the published study.[3][4]

"The fact that the medicine can be taken orally will help us improve the range of options we have for treating patients," Abreu noted. The oral route could allow gastroenterologists to deploy advanced targeted therapy much earlier in the disease course.[3][4]

Long-Term Durability and Safety

Data presented at the American College of Gastroenterology annual meeting in October showed the benefits held steady over time. During the trial's long-term extension, 72.7% of patients on the 400-milligram dose maintained their clinical response at week 76.[2]

Steroid independence emerged as a major highlight of the extended data. Among the patients who achieved clinical remission during the long-term extension, 97% were able to remain completely free of corticosteroids, avoiding the severe metabolic side effects of long-term steroid use.[2]

Icotrokinra utilizes cyclic peptide technology to survive the harsh, acidic environment of the human digestive tract. This structural design provides the high stability and epithelial permeability required to reach the immune system without being destroyed in the stomach.[5]

The safety profile through week 28 was comparable between the active treatment and placebo groups. Overall adverse events occurred in 60% of the 400-milligram group and 62% of the placebo group, indicating the drug did not add significant baseline toxicity.[4]

The most common mild side effects reported during the trial included upper respiratory tract infections, headaches, and joint pain. These adverse events occurred at similar rates across all dosage levels and rarely led patients to discontinue their treatment.[2]

Serious adverse events were actually lower in the high-dose treatment arm, occurring in 2% of the 400-milligram group compared to 10% of the placebo group. Researchers reported no deaths, serious infections, cancers, or major adverse cardiovascular events among patients taking the active drug.[4][5]

Shifting the Treatment Paradigm

Ulcerative colitis affects an estimated 3.1 million adults in the United States alone. The chronic condition causes severe inflammation and ulcers in the large intestine, leading to frequent bloody diarrhea, abdominal pain, malnutrition, and debilitating joint pain.[3]

"Patients with ulcerative colitis often need to try several treatments before finding one that controls their disease," said Dr. Gil Melmed, director of Inflammatory Bowel Disease Clinical Research at Cedars-Sinai. "It's not unusual for medications that work against one immune-related condition to also benefit patients with another."[3]

The FDA approved icotrokinra for the treatment of moderate to severe plaque psoriasis earlier in 2026. The shared interleukin-23 inflammatory pathway between psoriasis and inflammatory bowel disease made ulcerative colitis a logical next target for the drug's developers, Protagonist Therapeutics and Johnson & Johnson.[2][3]

A larger Phase 3 trial, known as ICONIC-UC, is currently underway to confirm these results in a broader population of adults and adolescents. A separate Phase 2b/3 trial is also actively evaluating the drug's efficacy for Crohn's disease.[2][5]

If the Phase 3 data replicates the Phase 2b success, icotrokinra could fundamentally reshape the standard of care. An effective, safe oral pill would likely become a preferred first-line advanced therapy, pushing cumbersome infusions further down the treatment algorithm.[2]