‘More options’ flood IBD market as rival IL-23 drugs face off with Stelara biosimilar boom

Key Takeaways:

• Three new IL-23 inhibitors have been approved for IBD, threatening Stelara’s long-standing status as the standard of care.
• Decision making between options relies on physician comfort and insurance coverage.

A seismic shift is underway for inflammatory bowel disease therapies as a trio of newly approved interleukin-23 inhibitors are poised to challenge both the resident blockbuster and an avalanche of its biosimilars for market dominance in 2025.

“IL-23 inhibition is a novel mechanism of action compared with anti-integrin or anti-[tumor necrosis factor] agents,” Sunanda V. Kane, MD, professor of medicine in the departments of gastroenterology and hepatology at Mayo Clinic in Rochester, Minnesota, told Healio Gastroenterology. “As a class, there is a lower likelihood of development of neutralizing antibodies, and they have a favorable side effect profile, particularly when compared to anti-TNF agents.”

Stelara (ustekinumab, Janssen), an IL-12/23 inhibitor, has been the standard-bearer for the class since its approval for Crohn’s disease in 2016 and ulcerative colitis in 2019. Since then, Skyrizi (risankizumab, AbbVie) and Omvoh (mirikizumab, Lilly), both specific IL-23p19 inhibitors, have gained FDA approval for both conditions under the IBD umbrella.

Not to be outdone, a third IL-23p19 inhibitor, Tremfya (guselkumab, Johnson & Johnson) was approved for UC in 2024 and just snagged an approval for Crohn’s in March, laying the groundwork for a five-way clash between rival IL-23p19s, an IL-12/23 juggernaut and at least seven ustekinumab biosimilars entering the market this year.

With so many options, the first key question pertains to the eventual pecking order for clinicians hoping to use IL-23 in IBD. There are no easy answers, at least in part because the studies leading to FDA approval pitted the newer medications against placebo or ustekinumab, but not against one another.

“There is danger in comparing results across trials, but we all do it,” Edward V. Loftus Jr., MD, the Maxine and Jack Zarrow Family Professor of Gastroenterology at Mayo Clinic, told Healio Gastroenterology. “We all try to read the tea leaves from the data we have.”

Performance in clinical trials is only one part of the equation when selecting a medication for a particular patient. “The decision on which IL-23 agent depends on accessibility, not access,” Stephen B. Hanauer, MD, the Clifford Joseph Barborka Professor of Medicine at Northwestern University Feinberg School of Medicine, said in an interview. “How quickly can we get the agent into patients without needing to go through a course of steroids? What is the pharma company support? How frequent and convenient are maintenance therapies?”

When making treatment decisions, clinicians must acknowledge one unavoidable reality: “The rebate wags the dog,” Loftus said. “We will see if that changes with more options on the market.”

While it is unclear what will happen when those options hit the market, it is certain that gastroenterologists will have a range of choices in the coming months. Understanding what sets IL-23 inhibitors apart in the IBD management paradigm may hold clues to where each biologic and biosimilar product will fall in terms of uptake and patient satisfaction.

More effective, less risk

“Since IL-23 was first identified as a genetic risk mutation for IBD and psoriasis, research has shown why this target can be so effective,” Hanauer said. “IL-23 is an important regulator of downstream inflammatory responses directed toward the IL-17 pathway and is present within the gut, skin in psoriasis and enthesitis in psoriatic arthritis. Hence, IL-23 is less systemic and more tissue specific than TNF inhibitors.”

This translates into efficacy without the same risk for infections as TNF blockers, according to Hanauer. “In addition, TNF-directed therapy does increase the expression of IL-23 and likely reflects why IL-23-directed therapy is efficacious in patients who have lost response to TNF blockers or who develop paradoxical psoriasis while on TNF blockers,” he said.

Miguel Regueiro, MD, professor of medicine and chief of the Digestive Disease Institute at Cleveland Clinic, explained what he believes is the most important benefit of IL-23 inhibitors: “The efficacy is being realized in all endpoints, but what is most impressive to me is the high steroid-free remission and endoscopic improvement.”

Those improvements have been observed across the IBD patient population, according to Loftus. “The more biologics a patient has been on, the less likely they are to respond to treatment,” he said. “Data for IL-23 inhibitors show that they perform well regardless of whether the patient is biologic-naive or experienced. That has been a nice benefit, so if a patient comes along who has failed previous therapy, I am more likely to go with an IL-23 than ustekinumab.”

Patient experience with biologics is just one factor that a clinician must consider when choosing a therapy. A closer look at some of the trials that led to approval may shed light on other risk-benefit considerations.

What will emerge as the preferred option?

“At least two studies, SEQUENCE and GALAXI, show higher efficacy with the IL-23s than with IL-12/23, with similar safety results,” Regueiro said. “To that end, I see the IL-23s replacing ustekinumab.”

In the SEQUENCE trial, which was published in The New England Journal of Medicine, Peyrin-Biroulet and colleagues compared ustekinumab with risankizumab in a cohort of more than 500 patients with moderate to severe Crohn’s who had demonstrated inadequate response or intolerance to TNF inhibition. Results showed noninferiority of risankizumab compared with ustekinumab as assessed by clinical remission at week 24 and superiority in endoscopic remission at week 48.

Findings from the phase 3 GALAXI trial yielded similar results. In a paper published in the Journal of Crohn’s and Colitis, Panés and colleagues compared rates of endoscopic response and remission, along with clinical remission, for ustekinumab vs. guselkumab among patients with moderately to severely active Crohn’s and inadequate response or intolerance to conventional or biologic therapies. Results showed greater proportions of endoscopic-based efficacy among patients treated with guselkumab compared with ustekinumab at week 48. The results were independent of prior biologic exposure.

“There is a sense that at least two of the IL-23p19 inhibitors might be better than ustekinumab,” Loftus said.

However, this may not hold true for every patient, according to Regueiro. “Of note, for patients who are currently on ustekinumab and doing well, I am not switching to IL-23 unless they lose response to ustekinumab,” he said. “To put it differently, even though the data with IL-23s look superior, a patient doing well on ustekinumab should stay on ustekinumab.”

While results from trials like SEQUENCE and GALAXI can shed light on how the newly approved agents can perform against ustekinumab, no data are available pitting the newer agents against one another, making it difficult to determine whether guselkumab, mirikizumab or risankizumab will emerge as the preferred option. “We do not have head-to-head data with IL-23s and it is not possible to answer this question,” Regueiro said. “Rather, I can say that we will have three good IL-23 options for the treatment of Crohn’s and ulcerative colitis. It is possible that with time we will see nuances between these three, but it will require longer-term post-marketing studies.”

Those studies are sure to come. However, there is still much speculation about what, exactly, will happen in the market once all of the IL-23 biologics have been approved and are available.

Lessons learned from TNF experience

“I do not know what will happen when [the ustekinumab biosimilars] all hit the market, but maybe we can extrapolate from the TNF inhibitor biosimilars,” Regueiro said. “Meaning, certain payers may require the use of a biosimilar prior to a non-biosimilar. However, I would like to be careful in making this statement as I cannot speak for the payers but can only extrapolate what we have seen with the TNF biosimilars.”

Regueiro is not alone in this opinion. “Similar to the introduction of biosimilars to infliximab and adalimumab, it will take some time for third-party payers to sort out priorities that will drive prescribing decisions,” Hanauer said. “Keep in mind that the majority of IL-23 agents are introduced as replacements for marketed drugs that have lost patent protection.”

It is worth noting that ustekinumab initially replaced infliximab as the next generation, according to Hanauer. “Now risankizumab is replacing Humira (adalimumab, AbbVie) and guselkumab is replacing ustekinumab,” he said. “The newer IL-23 agents will be more costly than the biosimilars and it is likely that third-party payers will begin to prioritize ustekinumab biosimilars over more expensive risankizumab and guselkumab.”

Despite these differences in market factors, Hanauer noted that the agents are fairly similar in terms of effectiveness. “While there may be some efficacy benefits, the level of benefit is relatively small,” he said. “The concept of biosimilars is to lower overall costs but, to date, patients do not save on an individual basis.”

Advocacy is likely to play a role in market uptake. “Hopefully, with societies such as AGA recommending interventions with effective agents — such as biologics and advanced small molecules — earlier in the course of disease, there may be the potential to improve long-term outcomes, particularly in Crohn’s disease,” Hanauer said.

How a medication performs in the market is largely out of the control of any individual practitioner. What happens in the clinic is a different story. This will hold true even with several IL-23 inhibitors moving into the rotation.

‘Best option’ for patients and insurers?

As always, explaining the medications to patients in language they can understand is critical. “I describe IL-23 agents as more organ- or tissue-specific agents with comparable or improved effectiveness with less risk of side effects,” Hanauer said. “I also stress a very convenient administration, with subcutaneous administration every other month vs. every few week injections or every 8 week infusions.”

The timing of the conversation can also impact outcomes, according to Kane. “Usually, the discussion is following loss of response to at least one other mechanism of action,” she said. “It is important to understand whether we are talking about ulcerative colitis or Crohn’s disease and if perianal fistulas are in the scenario as well.”

Patients have to be comfortable with subcutaneous administration if they only have experience with infliximab and expectations for therapy are being discussed, according to Kane. “IL-23 agents have a favorable side-effect profile and a lower incidence for neutralizing antibodies, so concomitant immunotherapy is not as necessary as with an anti-TNF,” she said.

It may be impossible to separate the market conversation with the clinical conversation, Kane noted. “Right now, it is the path of least resistance, and it is the patient’s insurance carrier that will decide for me which anti-interleukin I can prescribe,” she said. “These are usually not first-line agents unless there is a contraindication to an anti-TNF, but for Crohn’s disease, I would choose this mechanism of action over an anti-integrin first.”

Physician comfort can also drive clinical decision-making, according to Loftus. “We have all gotten comfortable with risankizumab for Crohn’s over the last few years because it is a good drug, a safe drug and it works in patients who are biologic-naive or if they have previous biologic experience,” he said. “Beyond that, the average provider is going to pick one or two of these drugs and stick with them.”

Patient input can vary. “Some patients will come in with questions and preferences,” Loftus added. “Most patients will just ask for you to recommend the best option.”

But once treatment begins, dosing and delivery can prove tricky for both doctors and patients.

Edge on the competition

“One potential differentiator is that guselkumab is approved for a subcutaneous induction,” Loftus said. “For the other indications, it is IV first and then subcutaneous maintenance. For a busy clinician, that may be a big advantage for guselkumab because you can get the ball rolling to one pharmacy.”

Data are available to help clinicians understand the nuances of induction and maintenance for this new class of drugs.

Findings from the INSPIRE and COMMAND clinical trials, led by Louis and colleagues, were published in JAMA. They showed that risankizumab bested placebo in clinical remission rates as an induction therapy and in maintenance in moderate to severely active UC.

“Here is where it gets complicated,” Loftus said. “With risankizumab, the induction dose in UC is higher than it is for Crohn’s. With Omvoh getting approved for Crohn’s, it is the opposite. We do not understand why that is.”

Then there is the question of IV vs. subcutaneous therapies. AbbVie is currently enrolling patients for subcutaneous induction for risankizumab, but that data may not emerge for some time.

“Even though guselkumab is third to the market, they may have an advantage,” Loftus said. “They anticipated the utility of a subcutaneous administration in advance. They did a regular phase 3 trial of an IV formulation and a subcutaneous study right on the heels of that.”

Sorting out these nuances will benefit clinicians hoping to tailor interventions to each individual patient. But gaps remain in IBD care, even with the advent of IL-23 inhibitors.

Still on the horizon: Precision medicine

Despite the hope associated with IL-23 inhibitors in IBD, Loftus stressed that they may not be ideal for every patient. “Even though these drugs are great, for any given agent or mechanism of action, there are refractory patients,” he said. “A major concern is that we do not know who these patients are in advance because we do not yet have predictive biomarkers.”

Regueiro highlighted this issue as well. “We are still searching for the precision medicine approach,” he said.

A key component of precision medicine pertains to the timing of treatment initiation. “Early intervention, particularly in Crohn’s disease, is still a gap,” Hanauer said. “I emphasize that moderate to severe disease can be diagnosed at presentation and does not require refractoriness. Starting an effective, advanced therapy at diagnosis has the potential to reduce the transmural progression of Crohn’s disease.”

Even with timely intervention, IL-23 inhibitors are not quite miracle drugs.

“As is true with all of our current therapies, we have still not broken the glass ceiling on remission rates and have still not found a cure,” Regueiro said. “Specifically, we are seeing high remission rates with IL-23 inhibitors, but still not in the remission rate of 80% or greater that we strive for.”

In fact, Kane suggested that even the best interleukin inhibitors achieve remission rates closer to 45% or 50%. “These agents are a good choice for combination therapy with another mechanism of action,” she said. “While there are some data for fistula closure, they are not as potent as anti-TNFs. So, there are still significant gaps in treatment options for those who lose response or are nonresponders to this mechanism after failing other biologics.”

Like most clinicians, Regueiro has adopted IL-23 inhibitors as part of his regular practice. “I am pleased with their efficacy and safety,” he said.

However, because of the lack of biomarkers and gaps in understanding of why patients respond to one medication and not another, Loftus believes that managing patient expectations is critical when prescribing IL-23 inhibitors. “If I had to guess, Rinvoq (upadacitinib, AbbVie) is more efficacious for Crohn’s and UC, but maybe these drugs have a better safety profile,” he said. “Like most biologic therapies, these drugs make people feel better for the most part, so they will occupy an important niche for gastroenterologists in the years ahead.”

References:

Louis E, et al. JAMA. 2024;doi:10.1001/jama.2024.12414.

Panés J, et al. J Crohns Colitis. 2025;doi:10.1093/ecco-jcc/jjae190.1091.

Peyrin-Biroulet L, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2314585.

For more information:

Stephen B. Hanauer, MD, can be reached at shanauer@northwestern.edu.

Sunanda V. Kane, MD, can be reached at kane.sunanda@mayo.edu.

Edward V. Loftus, MD, can be reached at loftus.edward@mayo.edu.

Miguel Regueiro, MD, can be reached at regueim@ccf.org.