IL-12/23 and IL-23 Inhibitors for IBD: Stelara, Skyrizi, Omvoh, Tremfya

The IL-23 inhibitors for IBD are a family of biologic drugs that calm inflammation by blocking interleukin-23, a signaling protein that drives the immune response behind Crohn's disease and ulcerative colitis. IL stands for interleukin. Four agents make up this treatment area: ustekinumab, sold as Stelara, plus three newer drugs, risankizumab, sold as Skyrizi, mirikizumab, sold as Omvoh, and guselkumab, sold as Tremfya. They fall into two subclasses that differ in exactly which part of the interleukin machinery they grab, and that difference shapes both how selective they are and how each drug is dosed. Understanding the split helps explain why these medications are often positioned differently from the older anti-tumor necrosis factor biologics.

How Do IL-23 Inhibitors Work: p40 Versus p19

Interleukin-23 is built from two protein subunits, p40 and p19. The p40 subunit is shared with a related cytokine, interleukin-12, while the p19 subunit belongs to interleukin-23 alone. Ustekinumab is an IL-12/23 inhibitor drug because it binds the shared p40 subunit of interleukin-12 and interleukin-23, switching off both pathways at once. The three newer agents are p19 selective IL-23 biologics that bind only the p19 subunit, so they neutralize interleukin-23 while leaving interleukin-12 intact. Risankizumab, for example, is an antibody against the p19 subunit of interleukin-23, and mirikizumab and guselkumab work the same way, with guselkumab described as a dual-acting inhibitor that neutralizes the interleukin-23p19 subunit. Preserving interleukin-12 matters because that cytokine helps coordinate the T helper 1 immune response used to fight intracellular pathogens.

Ustekinumab (Stelara): The IL-12/23 Inhibitor

Ustekinumab was the first biologic in this class approved for inflammatory bowel disease, reaching the market for Crohn's disease in 2016 and ulcerative colitis in 2019. Its Crohn's approval rested on the UNITI program, where intravenous induction produced a week 6 clinical response in about 34 percent of anti-tumor necrosis factor failures versus 21.5 percent on placebo, and subcutaneous maintenance kept 53.1 percent of responders in remission at week 44 compared with 35.9 percent on placebo. For ulcerative colitis, the UNIFI trial enrolled 961 patients and showed clinical remission at week 8 in 15.5 percent of those given the weight-based intravenous dose versus 5.3 percent on placebo, with maintenance remission at week 44 reaching 43.8 percent on the every-8-week schedule. Ustekinumab uses a single intravenous induction infusion followed by subcutaneous injections every 8 or 12 weeks.

The Selective IL-23 Inhibitors: Skyrizi, Omvoh, and Tremfya

The p19 selective agents arrived later and each carries its own trial record. Risankizumab gained a Crohn's disease approval in 2022 on the strength of the ADVANCE and MOTIVATE induction studies, which showed clinical remission at week 12 in roughly 42 to 45 percent of patients versus 20 to 25 percent on placebo. Its later ulcerative colitis indication came from the INSPIRE and COMMAND studies, where intravenous induction produced week 12 remission in 20.3 percent of patients versus 6.2 percent on placebo. Mirikizumab was approved for ulcerative colitis in October 2023 after the LUCENT trials showed week 12 remission of 24.2 percent versus 13.3 percent, and its Crohn's indication followed the VIVID-1 study, which reported clinical remission at week 52 in 45.4 percent versus 19.6 percent on placebo. Guselkumab earned its ulcerative colitis role through the QUASAR program, with week 12 remission of 23 percent versus 8 percent, and its Crohn's indication through the GALAXI-2 and GALAXI-3 trials.

The Stelara, Skyrizi, Omvoh, and Tremfya Difference

The clearest way to see the stelara skyrizi omvoh tremfya difference is by subclass, target, indications, and how induction is delivered. All four use intravenous or subcutaneous induction followed by subcutaneous maintenance, though guselkumab and risankizumab offer route flexibility that the others structure differently. The GALAXI trials confirmed guselkumab uses intravenous induction and subcutaneous maintenance, while risankizumab's ulcerative colitis program combined intravenous induction with subcutaneous maintenance every 8 weeks.

Drug	Target subunit	Approved for	Induction route
Ustekinumab (Stelara)	p40 (IL-12/23)	Crohn's, UC	Intravenous
Risankizumab (Skyrizi)	p19 (IL-23)	Crohn's, UC	Intravenous
Mirikizumab (Omvoh)	p19 (IL-23)	UC, Crohn's	Intravenous
Guselkumab (Tremfya)	p19 (IL-23)	UC, Crohn's	IV or subcutaneous

A Lower Systemic-Infection Signal Than Anti-TNFs

A frequent reason clinicians reach for this class is its safety record. Across inflammatory bowel disease studies of the p19 selective agents, there was no apparent elevation in the risk of infections and no significant signal for cancer or cardiovascular complications. The mechanistic rationale is that leaving interleukin-12 intact preserves the T helper 1 response the body relies on against intracellular pathogens, which is the arm of immunity that broader suppression can weaken. This contrasts with anti-tumor necrosis factor drugs, a class carrying documented risks that include reactivation of tuberculosis and other serious infections. Years of dermatology experience with risankizumab and guselkumab for psoriasis reinforced the picture, showing an excellent long-term safety profile without an obvious rise in infectious, neoplastic, or cardiovascular risk. These agents are not free of risk, and screening still applies, but the systemic-infection signal is comparatively modest.

IL-23 Versus Anti-TNF for Crohn's and Choosing an Agent

When patients and clinicians weigh il-23 vs anti-tnf for crohn's, efficacy in treatment-experienced disease is central. The SEQUENCE trial gave a direct comparison inside the class, testing risankizumab against ustekinumab in Crohn's patients who had already failed at least one anti-tumor necrosis factor drug. Risankizumab was noninferior for clinical remission at week 24 and superior for endoscopic remission at week 48, at 31.8 percent versus 16.2 percent. Head-to-head data against anti-tumor necrosis factor agents remain more limited, so positioning often turns on infection risk, dosing preference, and whether a patient needs Crohn's or ulcerative colitis coverage. The p19 selective agents are frequently favored after anti-tumor necrosis factor failure, and emerging evidence supports first-line use in higher-risk patients. Guselkumab has also shown superiority to ustekinumab across endpoints in the GALAXI Crohn's program.

The interleukin-23 pathway has become one of the most productive targets in inflammatory bowel disease treatment, and the four available drugs give patients and gastroenterologists real choice within a single mechanism. Ustekinumab remains a durable option with the longest track record and coverage of both conditions, while the p19 selective agents refine the approach by sparing interleukin-12 and, in the case of risankizumab and guselkumab, showing measurable advantages over ustekinumab in Crohn's disease. Approvals for these newer drugs have expanded quickly across both Crohn's disease and ulcerative colitis, and their favorable infection profile makes the class a reasonable starting point for many people rather than a reserve after other biologics fail. The right selection still depends on individual disease behavior, prior treatment history, and the practical realities of dosing and route.