IL-23 Inhibitors for Crohn's Disease: What Patients Should Know

For many of us living with Crohn's disease, the search for a treatment that truly works can feel like a long and uncertain road. Anti-TNF therapies transformed care when they arrived, but they do not work for everyone, and some of us lose response over time. That is why the emergence of a new class of biologics - IL-23 inhibitors for Crohn's disease - represents one of the most significant advances in recent years. As of 2025, three IL-23 inhibitors have earned FDA approval for Crohn's disease, and the clinical trial data behind them is genuinely encouraging. Here is what you need to know.

What Are IL-23 Inhibitors and How Do They Work?

To understand why IL-23 inhibitors matter, it helps to understand the molecule they target and how this approach differs from the biologics many of us already know.

The Role of IL-23 in Crohn's Inflammation

IL-23, short for interleukin-23, is a cytokine - a small signalling protein that the immune system uses to coordinate inflammatory responses. In Crohn's disease, IL-23 plays a central role in driving chronic intestinal inflammation. It does this primarily by activating T-helper 17 (Th17) cells and other immune pathways that sustain the kind of ongoing, destructive inflammation that characterizes our disease (6). Think of IL-23 as a persistent alarm signal that keeps certain immune cells in attack mode, even when they should be standing down.

In a healthy gut, IL-23 has legitimate immune functions. But in Crohn's disease, its overproduction helps maintain the cycle of inflammation that damages the intestinal lining and leads to the symptoms we know too well - pain, fatigue, diarrhea, and the complications that follow.

How IL-23 Inhibitors Differ from Anti-TNF and IL-12/23 Biologics

If you have been through anti-TNF therapies like infliximab or adalimumab, you know those drugs work by neutralizing tumor necrosis factor-alpha, a different inflammatory cytokine. IL-23 inhibitors take a more targeted approach by specifically blocking the p19 subunit of the IL-23 molecule (5).

This selectivity is an important distinction. Ustekinumab (Stelara), which many Crohn's patients are already familiar with, blocks both IL-12 and IL-23 through their shared p40 subunit. The newer IL-23 inhibitors leave IL-12 signalling intact and focus exclusively on IL-23. Researchers believe this selective targeting may explain both the improved efficacy and the favorable safety profiles seen in clinical trials - by blocking only the pathway most responsible for chronic gut inflammation while preserving other immune functions (5, 6).

The Three FDA-Approved IL-23 Inhibitors for Crohn's Disease

As part of the evolving landscape of biologic therapies for Crohn's disease, three IL-23 inhibitors have now reached FDA approval, giving patients and gastroenterologists more options than ever before.

Risankizumab (Skyrizi) - Approved 2022

Risankizumab was the first IL-23 inhibitor to receive FDA approval for Crohn's disease in 2022, marking the beginning of this new treatment era. It is administered as an intravenous infusion during the induction phase, followed by subcutaneous injections for maintenance. Risankizumab has since also been approved for ulcerative colitis (2024), making it a versatile option across inflammatory bowel diseases (2).

Mirikizumab (Omvoh) - Approved January 2025 for CD

Mirikizumab earned its Crohn's disease approval in January 2025, based on the Phase 3 VIVID-1 trial. The results were compelling: 53% of patients treated with mirikizumab achieved clinical remission at one year, compared with 36% of those on placebo (2). Like risankizumab, mirikizumab uses an IV induction followed by subcutaneous maintenance dosing. It is also approved for both Crohn's disease and ulcerative colitis.

Guselkumab (Tremfya) - Approved March 2025 for CD

Guselkumab became the most recently approved IL-23 inhibitor for Crohn's disease in March 2025. What sets guselkumab apart is its dosing flexibility: it is the first IL-23 inhibitor to offer both intravenous and subcutaneous induction options, which gives patients and doctors more flexibility in how treatment begins (3). This may be particularly welcome for patients who prefer to avoid infusion centers when possible.

All three of these medications are now approved for both Crohn's disease and ulcerative colitis, representing a significant expansion of the treatment toolkit available to the IBD community (2).

Landmark Clinical Trial Results

The data behind these approvals is worth understanding, especially the groundbreaking head-to-head trial results that set a new standard for biologic comparisons.

GALAXI-2 and GALAXI-3: Guselkumab vs Ustekinumab Head-to-Head

The GALAXI trials represent a landmark moment in Crohn's disease research. Enrolling 1,048 patients across 257 sites in 40 countries, GALAXI-2 and GALAXI-3 were the first-ever head-to-head comparison of an IL-23 inhibitor against another leading biologic in Crohn's disease (1).

The results were striking. At week 48, guselkumab 200mg achieved a combined clinical remission and endoscopic response rate of 47.3%, compared with 33.7% for ustekinumab (p less than 0.001) (1). This was not just a marginal difference - guselkumab demonstrated superiority across all key endpoints, including endoscopic response, endoscopic remission, deep remission, and clinical remission plus endoscopic response (4). For patients and clinicians accustomed to choosing between biologics based largely on indirect comparisons and clinical experience, having this kind of direct evidence is genuinely valuable.

VIVID-1: Mirikizumab Phase 3 Results

The VIVID-1 trial provided the evidence base for mirikizumab's approval. With 53% of treated patients reaching clinical remission at one year versus 36% on placebo, it demonstrated meaningful and sustained benefit (2). These results are particularly noteworthy because clinical remission - not just symptom improvement - was the primary endpoint, reflecting a higher bar for success.

How the Evidence Compares Across All Three Drugs

A network meta-analysis published in the Annals of Medicine in 2025 attempted to compare all three IL-23 inhibitors, since direct head-to-head trials between all three do not yet exist (5). The analysis found that all three demonstrated considerable effectiveness in inducing clinical remission and promoting endoscopic healing, including in patients who had not responded to anti-TNF therapies.

The comparative picture that emerged suggests each drug may have slightly different strengths: guselkumab appeared to have the highest induction efficacy, risankizumab showed the best endoscopic outcomes with a balanced safety profile, and mirikizumab had the lowest rate of serious adverse events (5). These are indirect comparisons and should be interpreted with caution, but they provide a useful starting framework for discussions with your gastroenterologist.

Safety Profile: What Patients Can Expect

Safety is understandably one of the first questions patients ask about any new biologic. The data here is reassuring.

Common Side Effects

As a class, IL-23 inhibitors have demonstrated favorable safety profiles with low rates of serious infections and malignancies (5). The most commonly reported side effects across trials include upper respiratory infections, injection site reactions, headache, and joint pain - generally mild and manageable.

Long-Term Safety Data

One of the more striking safety findings came from the GALAXI trials. Serious adverse events occurred in only 7% of patients receiving guselkumab 200mg, compared with 12% for ustekinumab and 15% for placebo (1). The fact that the active treatment group had fewer serious adverse events than the placebo group is unusual and noteworthy.

Network meta-analysis data further supports the safety picture, with mirikizumab showing the lowest risk of serious adverse events across both induction and maintenance phases (5). Importantly, no new safety signals have emerged compared to the established profiles from dermatology, where drugs like risankizumab and guselkumab have been used for psoriasis for several years and have longer-term follow-up data (6).

This does not mean these medications are without risk - all immunosuppressive therapies carry some degree of risk, particularly around infections. But the evidence to date suggests that selective IL-23 blockade may offer a more favorable safety-efficacy balance than some older biologic approaches.

Who Might Benefit from IL-23 Inhibitors?

Understanding who is most likely to benefit can help you have a more productive conversation with your care team.

After Anti-TNF Failure

For many Crohn's patients, the journey to an IL-23 inhibitor begins after anti-TNF therapies have stopped working or were not effective in the first place. This is a common clinical scenario, and the good news is that IL-23 inhibitors have shown meaningful efficacy in this population. The network meta-analysis confirmed considerable effectiveness in patients refractory to anti-TNF therapies (5), and the GALAXI trials specifically included patients with prior biologic exposure.

As a First-Line Biologic

There is growing evidence and clinical interest in using IL-23 inhibitors as first-line biologics, rather than reserving them only for patients who have already failed anti-TNF therapy (6). The strong efficacy data and favorable safety profiles make a compelling case for this approach, though treatment guidelines are still evolving.

Personalized Treatment Considerations

No single IL-23 inhibitor is universally "best" - the right choice depends on your individual disease characteristics, treatment history, and lifestyle preferences. Based on current evidence, some general considerations may help guide the conversation:

• Guselkumab may be particularly suitable for patients seeking the strongest head-to-head efficacy data and dosing flexibility (IV or subcutaneous induction)
• Mirikizumab may appeal to patients and clinicians who prioritize the lowest rates of serious adverse events
• Risankizumab offers balanced efficacy and safety with the longest track record as the first-approved IL-23 inhibitor for Crohn's

Your gastroenterologist will also consider factors like insurance coverage, infusion access, and how each option fits alongside your other medications. The important thing is that you now have three strong options in this class where, just a few years ago, there were none.

Questions to Ask Your Gastroenterologist About IL-23 Inhibitors

If IL-23 inhibitors have caught your attention, bringing specific questions to your next appointment can make for a more focused and productive conversation. Here is a practical checklist to consider:

• Am I a candidate for an IL-23 inhibitor? Your gastroenterologist can assess whether your disease type, severity, and treatment history make you a good fit.
• How would this compare to my current treatment? If you are on an anti-TNF or ustekinumab, ask about the potential advantages and risks of switching.
• What does the dosing schedule look like? Understand the difference between IV induction and subcutaneous maintenance, and whether IV or subcutaneous induction is available for the drug being considered.
• What does my insurance cover? Coverage can vary significantly between the three options. Ask about patient assistance programs if cost is a concern.
• What monitoring will I need? Regular bloodwork and endoscopic monitoring are typically part of biologic therapy - ask what the schedule looks like.
• How long until I might see results? Understanding the expected timeline for response can help manage expectations and recognize when a treatment is or is not working.
• What happens if this one does not work? Knowing the plan for next steps can provide peace of mind before you start.

Treatment decisions are always a partnership between you and your care team. The goal is shared decision-making that takes into account not just the clinical evidence but also your individual disease characteristics, treatment history, lifestyle, and personal preferences. With three IL-23 inhibitors now available, there is more room than ever to find an approach that fits your life.

Living with Crohn's disease means adapting, advocating, and staying informed. The arrival of three IL-23 inhibitors in a relatively short span is genuinely good news for our community - more tools, more evidence, and more reasons to feel hopeful about the direction treatment is heading.

References

1. Danese, S., et al. GALAXI-2 and GALAXI-3: 48-week results from two phase 3 trials of guselkumab for Crohn's disease. The Lancet, 2025. Read study
2. Anti-IL-23s reporting for duty: A new line of defense in Crohn's, UC. Healio, 2025. Read article
3. FDA Approves Guselkumab for Adult Patients With Crohn Disease. AJMC, 2025. Read article
4. Guselkumab Demonstrates Superior Efficacy in Landmark Clinical Trials. Mount Sinai, 2025. Read article
5. Wang, Y., et al. Efficacy and safety of IL-23p19 and IL-12/23p40 inhibitors in moderate-to-severe Crohn's disease: a systematic review and network meta-analysis. Annals of Medicine, 2025. Read study
6. New Interleukin-23 Antagonists' Use in Crohn's Disease. PMC, 2025. Read study
7. New IL-23 Inhibitors Expand Treatment Options for Crohn's Disease. Mount Sinai Reports, 2026. Read article