IL-12/23 and IL-23 Inhibitors

Inflammatory bowel disease (IBD) treatments now include targeted biologic drugs that block specific immune signals called interleukins. IL-12/23 and IL-23 inhibitors calm overactive pathways that drive inflammation in Crohn’s disease and ulcerative colitis. This article explains how ustekinumab, risankizumab, and mirikizumab work, how they are given, and key safety points that matter for patients, families, and care teams.

Key Takeaways

• Ustekinumab blocks both IL-12 and IL-23, while risankizumab and mirikizumab block IL-23 only.

• All three are FDA approved for moderately to severely active Crohn’s disease and ulcerative colitis in adults in the United States. (stelarahcp.com)

• Treatment usually starts with IV infusions, then switches to injections under the skin every 4 or 8 weeks. (ustekinumab.com)

• These medicines often help even when older biologics, such as anti-TNF drugs, have not worked well. (frontiersin.org)

• Main safety concerns are infections, rare allergic reactions, and possible liver irritation with some IL-23 drugs, so TB screening, vaccine review, and lab checks are important. (stelarahcp.com)

What are IL-12/23 and IL-23 inhibitors?

Interleukins are messenger proteins that help immune cells talk to each other. IL-12 and IL-23 are two interleukins that push the immune system toward strong, long-lasting inflammation. They act through specific T cells (Th1 and Th17 cells) that are closely linked to IBD. (pubmed.ncbi.nlm.nih.gov)

• Ustekinumab targets the p40 subunit that IL-12 and IL-23 share. Blocking p40 turns down both IL-12 and IL-23 signals. (en.wikipedia.org)

• Risankizumab and mirikizumab target the p19 subunit, which is unique to IL-23. This is often called “IL-23 selective” blockade. (pubmed.ncbi.nlm.nih.gov)

By turning down these pathways, the drugs reduce gut inflammation, promote healing of the bowel lining, and can lead to symptom control and long-term remission.

When are these medicines used?

These agents are part of the “advanced therapy” group for moderate to severe IBD. They are used when:

• Steroids, aminosalicylates, or thiopurines are not enough, or

• A person has already tried other biologics, such as anti-TNF drugs or vedolizumab, or

• The care team wants to start with a targeted biologic early for high-risk disease. (gastro.org)

Recent American Gastroenterological Association (AGA) guidance:

• In ulcerative colitis, risankizumab is grouped among “higher efficacy” options, while ustekinumab and mirikizumab are classed as “intermediate efficacy” for many patients. (pubmed.ncbi.nlm.nih.gov)

• In both Crohn’s and UC, they are considered reasonable choices after failure of other biologics.

The final choice usually depends on disease type, past medications, other health problems, dosing schedule preferences, and insurance access.

Ustekinumab: the IL-12/23 inhibitor

What it targets

Ustekinumab is a fully human monoclonal antibody that binds the p40 subunit shared by IL-12 and IL-23. This lowers activity of both Th1 and Th17 pathways, which are important in Crohn’s and UC. (en.wikipedia.org)

Who it is for

Ustekinumab is approved for moderately to severely active Crohn’s disease and ulcerative colitis in adults. (stelarahcp.com)

How it is given

• Induction: a single IV infusion, with the dose based on body weight.

• Maintenance: 90 mg injection under the skin every 8 weeks, starting 8 weeks after the infusion. (ustekinumab.com)

Many patients eventually self-inject at home after training.

Effectiveness and safety

Trials and long-term registry data show that ustekinumab can bring many patients into steroid-free remission and maintain benefit for years, including those who previously failed anti-TNF therapy. (frontiersin.org)

In one combined Crohn plus UC analysis:

• Overall infections and serious infections were similar to placebo, and malignancy rates were low but not zero. (stelarahcp.com)

A large real-world cohort found lower serious infection risk with ustekinumab compared with anti-TNF drugs, without loss of effectiveness. (pubmed.ncbi.nlm.nih.gov)

Common side effects include mild upper respiratory infections, fatigue, and injection site reactions.

IL-23–only inhibitors: risankizumab and mirikizumab

Risankizumab (Skyrizi)

Target and approvals

Risankizumab blocks the p19 subunit of IL-23, leaving IL-12 signaling intact. (pubmed.ncbi.nlm.nih.gov)
It is FDA approved for moderately to severely active Crohn’s disease and ulcerative colitis in adults, in addition to psoriasis and psoriatic arthritis. (skyrizihcp.com)

Dosing pattern

• Induction: 3 IV infusions at weeks 0, 4, and 8

• 600 mg each for Crohn’s

• 1200 mg each for UC (skyrizihcp.com)

• Maintenance: injections under the skin (180 or 360 mg) every 8 weeks. (skyrizihcp.com)

Safety highlights

Risankizumab can increase infection risk and has specific warnings about:

• Serious infections and tuberculosis

• Rare drug-related liver injury reported in IBD trials (skyrizihcp.com)

Before starting, clinicians screen for TB, review infection history, and update vaccines, avoiding live vaccines during treatment. (accp1.org)

Mirikizumab (Omvoh)

Target and approvals

Mirikizumab also targets IL-23 p19. (investor.lilly.com)
It is approved in the United States for moderately to severely active ulcerative colitis and Crohn’s disease in adults. (investor.lilly.com)

Dosing pattern

• UC induction: 300 mg IV at weeks 0, 4, and 8

• UC maintenance: 200 mg injected under the skin every 4 weeks

• Crohn induction: 900 mg IV at weeks 0, 4, and 8

• Crohn maintenance: 300 mg injected under the skin every 4 weeks (omvoh.lilly.com)

Maintenance doses are given as two quick injections each month.

Effectiveness and safety

In the LUCENT ulcerative colitis program, mirikizumab produced sustained clinical remission, bowel healing, and steroid-free remission, with benefits maintained up to four years in extension studies. (investor.lilly.com)

Phase 3 Crohn’s trials showed over half of patients in clinical remission at one year, with endoscopic improvement, including in many who had tried other biologics. (wsj.com)

Common side effects include upper respiratory infections, injection site reactions, joint pain, rash, and headaches. Liver enzymes and bilirubin are checked before starting, and there is a standard infection warning similar to other biologics. (drugs.com)

Comparing ustekinumab, risankizumab, and mirikizumab

Safety basics and monitoring

Across this class, key safety steps are similar:

• Screen for infections, especially tuberculosis, before starting.

• Avoid live vaccines during treatment. Vaccines such as flu shots and COVID-19 vaccines that are not live are usually allowed and encouraged. (ustekinumab.com)

• Watch for symptoms like fever, cough, shortness of breath, painful skin lesions, or burning with urination, and seek prompt medical review if they appear. (skyrizi.com)

• Ustekinumab trials show low but present rates of certain skin and other cancers, so routine cancer screening and skin checks remain important. (stelarahcp.com)

• For IL-23 inhibitors, clinicians may monitor liver enzymes, especially in Crohn’s disease, because rare drug-induced liver injury has been reported. (skyrizihcp.com)

Decisions to start, continue, or switch these medicines are usually made by a gastroenterologist who considers disease severity, prior treatments, infection risk, pregnancy plans, and patient preferences.

FAQs

How fast do IL-12/23 and IL-23 inhibitors start to work?

Some people notice symptom improvement within a few weeks, but full benefits often take 8 to 12 weeks or longer, especially for healing seen on endoscopy. Steroids are sometimes used at the start while the biologic takes effect. (frontiersin.org)

Can these drugs be combined with other IBD medicines?

They are often used along with 5-ASA, low-dose steroids during induction, or some immunomodulators, though many patients take them as biologic monotherapy. The exact combination depends on prior drug history, side effect risks, and guideline-based practice.

Are IL-23–only drugs safer than ustekinumab?

IL-23–only agents were designed to be more selective, but so far, trials and early real-world data show broadly similar safety signals, mainly related to infections. Long-term comparisons are still being studied, so experts focus more on overall efficacy, personal risk factors, and comfort with each drug. (pubmed.ncbi.nlm.nih.gov)