Bruce Sands, MD, on IL-12/23 and IL-23 Inhibitors for IBD

Interleukin (IL)-12/23 and -23 inhibitors are effective options as first or second-line therapies, and are safer than anti-tumor necrosis factor (TNF) agents for many patients with inflammatory bowel disease (IBD), Bruce Sands, MD, said in his presentation at the Advances in Inflammatory Bowel Diseases virtual regional meeting on August 27.

Dr Sands is the Dr. Burrill B. Crohn Professor of Medicine at the Icahn School of Medicine at Mount Sinai in New York City.

He explained, “IL-23 is a key cytokine that shapes the TH-17 response; TH-17 are the effector cells that are critical for development of IBD.”

Ustekinumab, which is approved for both Crohn disease (CD) and ulcerative colitis (UC), blocks the p40 subunit present in both IL-12 and IL-23, Dr Sands explained. The UNITI 1 and 2 trials of ustekinumab among patients with CD found that among patients refractory to anti-TNFs, 37.8% demonstrated a clinical response to ustekinumab at week 8 and 20.9% rate of clinical remission. UNITI 2, which included mostly patients who were naïve to anti-TNFs, showed a 57.9% rate of clinical response and a 40.2% rate of clinical remission after 8 weeks. Both cohorts received either a loading dose of 130 mg or the approved dose of 6 mg/kg.

The STARDUST trial compared a treat to target approach using dose escalation or shortening of dosing intervals with ustekinumab to standard of care among patients with CD. Although the study did not achieve its the primary endpoint of endoscopic response as evidenced by improvement of ≥50% in the Simple Endoscopic Score-Crohn Disease (SES-CD) at week 48, the treat to target results showed numerical superiority to the standard of care. The nonresponder imputation group did demonstrate statistical significance of almost 10% over standard of care.

The UNIFI study of ustekinumab for induction in UC investigated a wide range of outcomes, including clinical remission, endoscopic improvement, clinical response, histo-endoscopic healing, a new measure that combined endoscopy subscores with histologic improvement, among both biologic-naïve and biologic-experienced patients. Dr Sands observed that “across this wide range of outcomes and regardless of the patient population, ustekinumab was effective for induction in ulcerative colitis.”

“What if a patient doesn’t respond at week 8 after their induction dose, how do they respond at week 16?” Dr Sands asked. Further study of ustekinumab demonstrated that 77.6% of patients achieved clinical response within 16 weeks—56.5% at week 8 plus an additional 21.1% at week 16. “That may mean that we should not give up after the 8-week timepoint.”

Ustekinumab is also effective as maintenance therapy, he continued, based on the UNIFI results  at week 44. “It may be especially important to dose patients who had prior biologic failure every 8 weeks” rather than 12 weeks. He noted that biologic-naïve patients in UNIFI sustained remission at about the same rates at both 8- and 12-week dosing, but among patients who had a biologic failure, 39.6% dosed at 8 weeks sustained vs just 22.9% dosed at 12 weeks. In addition, “The durability of efficacy is quite good in ulcerative colitis,” as assessed by corticosteroid-free remission over 3 years of more than 55% in the overall UC patient population.

“The totality of evidence suggests you don’t need to use combination therapy with concomitant immunomodulators when treating with ustekinumab,” due to the very low rate of immunogenicity. The role of therapeutic drug monitoring for ustekinumab in UC is not as clear as with anti-TNFs, he explained, because “no factors seem to have adequate predictive accuracy for an individual patient. At this point, we don’t have a way of picking the winners.”

Dose intensification may be effective for some patients, Dr Sands said, according to results of single-center study that showed higher response rates among patients with UC. Ustekinumab may also be effective for some extraintestinal manifestations, including arthralgia, psoriasis, psoriatic arthritis, pyoderma gangrenosum, and erythema nodosum, and it has shown promising results with apthous stomatitis and uveitis, he stated. However, it does not appear effective for axial spondyloarthritis.

One of the major advantages of ustekinumab is its safety, Dr Sands explained. “The risk of infection is quite low, and in fact is quite similar to placebo,” he said. “There is no increased risk of malignancy in various data sets.” Its long-term safety data in IBD shows no association with major adverse cardiovascular events.

Newer agents in this class include risankizumab, mirikizumab, and guselkumab, Dr Sands explained. These agents only block IL-23 rather than both IL-12 and IL-23, and primarily inhibit the p19 subunit in IL-23. “There are immunologic reasons why this may be a superior modality,” he stated.

In the ADVANCE and MOTIVATE induction trials of risankizumab for Crohn disease, “the efficacy is quite good, with endoscopic response rates among about one-third of the patients overall—about as good as any agent for Crohn’s disease,” he said. The FORTIFY trial in CD demonstrated good maintenance data, he noted, and found that rerandomization of responders achieves clinical remission in more than half of patients and deep remission in nearly one-third.

The GALAXI study of guselkumab showed similar efficacy in induction at week 12. Dr Sands added, “Interestingly, there seems to be a referenced, although this is not fully powered for comparison, seeming to show nearly 10% superiority of guselkumab over ustekinumab. This seems to be especially more effective when we look at endoscopic responses.”

Mirikizumab is the first of these agents to be studied in UC, Dr Sands pointed out. The LUCENT 1 trial demonstrated that it is effective for induction at week 12 even among patients who had failed with a previous biologic, although this was not statistically significant. The LUCENT 2 maintenance data at week 52 showed good sustained clinical, endoscopic, and mucosal remission. Guselkumab has also been trialed in UC and shows similar data to that of mirikizumab, Dr Sands added.

Risankizumab “is very superior in CD” among patients who have been exposed to biologics, he said, while among patients with UC who have been exposed to a biologic, the JAK inhibitors are most effective but ustekinumab also appears very effective.

—Rebecca Mashaw

Reference:
Sands, BE. IL-12/23 and IL-23. Presented at: Advances in Inflammatory Bowel Diseases regional meeting. August 27, 2022. Virtual.