IL-12/23 Inhibitors Demonstrate Efficacy in IBD With Excellence Safety Profile

Since infliximab was introduced for the treatment of inflammatory bowel disease (IBD) in 1998, “we’ve seen an explosion of different agents with difference mechanisms for the management of ulcerative colitis (UC) and Crohn disease (CD),” Uma Mahadevan, MD, told the attendees at the virtual Advances in Inflammatory Bowel Diseases (AIBD) regional meeting April 16. “What we really have to understand is what is the best therapy for which patient?”

Dr Mahadevan is a professor of medicine at the University of California at San Francisco and codirector of the UCSF Center for Colitis and Crohn’s Disease.

Through multiple studies and trials, the IL-12/23 inhibitor ustekinumab has proved to be a very effective and safe therapeutic agent for the treatment of IBD, she explained, both among patients who are naïve to biologic therapeutics and those who previously used tumor necrosis factor (TNF) inhibitors.

Dr Mahadevan noted that the UNITI-1 and UNITI-2 trials of ustekinumab demonstrated clearly that ustekinumab was superior to placebo for induction of remission in IBD. The UNIFI study in 2019 found that ustekinumab showed efficacy for induction of remission at week 8, with no difference among patients who had had biologic exposure and those who had not. After 1 year, patients continued to experience benefit from ustekinumab.

“Even if a patient has failed an anti-TNF, ustekinumab is a good option” in the induction and maintenance of remission in IBD, she said.

One of ustekinumab’s key advantages is its safety, Dr Mahadevan pointed out. In the PSOLAR study of the safety of ustekinumab in 12,000 patients with psoriasis, researchers found no increased risk of malignancy, major adverse cardiac events (MACE), serious infections, or mortality. “This is very reassuring to us and our patients,” she said. However, she added, a study conducted in France found a 4-fold risk of MACE in patients being treated with ustekinumab who had 2 cardiac risk factors or a history of severe cardiac events after starting.

Although these patients were not in the IBD population, Dr Mahadevan suggested that gastroenterologists take this result into consideration before using ustekinumab among patients with a history of cardiac disease or multiple risk factors.

Ustekinumab now has a history of use in treating IBD. Dr Mahadevan noted that 5-yr safety data from a long-term extension study of ustekinumab in IBD revealed no new deaths, low rates of adverse events and serious adverse events, infections and serious infections. “Only

5.8% of patients who had been treated with ustekinumab over this time developed antidrug antibodies—a very low rate,” she noted, demonstrating a lack of immunogenicity in the IL 12-23 inhibitor compared to that of the anti-TNF agents. Only 6 patients developed malignancies, consistent with the rate expected in the general population.

Patients treated with ustekinumab also have lower rate of tuberculosis and other serious infections compared to patients treated with anti-TNFs.  “The TB issue is very important,” Dr Mahadevan stated. “We know that anti-TNFs increase the risk for TB.” However, the rate of serious infection with ustekinumab was only 1.3 per 100 patient-years (PY) vs 5.75 per 100PY with infliximab and 4.3 per 100PY with adalimumab and etanercept. “This makes ustekinumab a really good choice for patients with IBD who need to start therapy quickly but have

Makes UST a good choice for pts who have IBD and need to start on therapy quickly but have positive QuantiFERON tests.”

Adding an immunomodular to ustekinumab has shown no additional benefit to patients with UC or CD, she added. “I think in my own practice the one exception would be patients who failed multiple agents and have very complex disease,” Dr Mahadevan explained. “In those patients think there is some hesitation in stopping because there may be an independent effect of the IMM as well.” That said, she noted, “the vast majority of my ustekinumab patients are on monotherapy.”

Ustekinumab is not associated with increased rates of congenital anomalies or miscarriage among pregnant women. “The PIANO registry has also confirmed no increased risk with ustekinumab.” Because this therapeutic does cross the placenta more data are needed, Dr Mahadevan said, but available data suggest that ustekinumab can be continued through pregnancy and postpartum without interruption.”

“So when we think about safety in IBD therapies, we know TNF inhibitors are extremely effective, , but they do have injection site or infusion-related reactions, and they carry boxed warnings for serious infections and malignancies,” she said. “When you look at JAK inhibitors such as tofacitinib, you can also see reactivated herpes zoster and elevated cholesterol levels boxed warnings for serious infections, mortality, malignancies, and thrombosis.” Ustekinumab—along with vedolizumab—has no boxed warnings, she noted.

When positioning therapies, the clinician has to weigh the pros and cons and consider factors including speed of onset, overall efficacy, anti-TNF exposure or failure, patient age, comorbidities, and safety for each patient.

Looking ahead, Dr Mahadevan noted that 3 “pure IL-23 inhibitors should be coming to the market soon.” Ustekinumab is an antibody to the P40 subunit of IL 12 and IL 23. However, she commented, “It turns out you don’t really need the IL-12 part; if you have pure antibody to the P19 subunit on IL23, the efficacy is at least as good, and may be better, but this needs to be shown in trials.”

Guselkumab and risankizumab have already been approved for psoriasis and is in trials for IBD, while mirikizumab is in phase 3 trials for both UC and Crohn disease. “By early 2022 one of these should be available for IBD,” she said.

For the present, Dr Mahadevan said, “ustekinumab is clearly effective for induction and maintenance of remission in UC and CD, in both biologic-naïve and biologic-exposed patients, and it has an excellent safety profile. But these novel IL-23 agents coming may be even better.”

--Rebecca Mashaw

Mahadevan U. Optimal and future use of IL-12/23 for the management of IBD. Talk presented at: Advances in Inflammatory Bowel Diseases 2021 regional meeting; April 16, 2021. Virtual.