Ustekinumab, the only interleukin (IL) 12/23 inhibitor currently approved for the treatment of inflammatory bowel disease (IBD), has proved efficacious and very safe, but new IL 23 blockers coming to market in the near future may prove even better at treating ulcerative colitis (UC) and Crohn disease (CD), explained Bruce Sands, MD, MS, at the Advances in Inflammatory Bowel Disease virtual regional meeting on September 11.

Dr Sands is chief of the Dr Henry D Janowitz division of gastroenterology and the Dr Burrill B Crohn Professor of Medicine at the Icahn School of Medicine at Mount Sinai in New York.

Ustekinumab, he explained, binds with high affinity to the p40 subunit of IL-12 and IL-23, blocking the inflammatory pathway. In the UNITI-1 trial of patients with Crohn disease who were refractory to anti-tumor necrosis factor (TNF) therapies, one-third of patients achieved clinical response during the 8-week induction period, while in UNITI-2, in which participants had failed prior conventional therapies but were most anti-TNF naïve, almost 58% achieved clinical response during induction, Dr Sands said. Over the extension period of 44 weeks, approximately 60% of all patients achieved clinical response and the majority of these participants were in remission.

“Mucosal healing is much harder to achieve,” Dr Sands said, with just 17% of patients meeting this endpoint.

However, he noted, “The real world looks a bit better,” as in a Canadian study in which 50% of participants with CD achieved steroid-free clinical and objective response as measured by endoscopy or radiology. Approximately one-quarter of the patients maintained remission beyond 6 months.

Ustekinumab also has shown positive results in fistula resolution among patients with perianal Crohn disease. After the 8-week induction period, almost 25% of patients with fistulizing CD at baseline in CERTIFI, UNITI-1, and UNITI-2 trials had a combined 100% resolution of fistulas.

About 1/3 of patients with CD in another cohort demonstrated fistula response with ustekinumab. However, Dr Sands noted, “We don’t have a dedicated RCT to fully evaluate ustekinumab for fistulizing disease.”

Among patients with UC in the UNIFI trial of ustekinumab, approximately 12% of those who had failed anti-TNF therapy achieved clinical remission, while 18% to 20% of the anti-TNF naïve achieved remission. Endoscopic improvement was found in 26% to 27% of participants, while 51% to 62% demonstrated clinical response.

UNIFI was the pivotal program for IBD to include a new endpoint of histoendoscopic mucosal healing, Dr Sands explained, which incorporates “an endoscopic subscore of 0 or 1 and from 0 to less than 5% of neutrophils in epithelium, no crypt destruction, and no erosions, ulcerations or granulations.” By this measure, 46% of patients achieved histoendoscopic mucosal healing by week 44, while 59% of patients showed histoendoscopic improvement. “In maintenance,  clinical remission, steroid-free remission, clinical response, endoscopic improvement, histologic improvement, and toendoscopic improvement, were all superior to placebo,” he said.

He added that both ustekinumab and tofacitinib are effective among patients with UC who have a prior anti-TNF failure and anti-integrin failure. “Whether you treat with tofacitinib or ustekinumab, the outcomes are quite similar,” Dr Sands noted. “However, the safety of ustekinumab appears to be superior.”

This safety advantage also appeared in the results of the SEAVUE study, comparing ustekinumab and adalimumab for induction and maintenance among patients with CD naïve to anti-TNFs who had failed or were intolerant to conventional therapy. “There was no significant difference at week 52 in clinical remission,” Dr Sands stated. “What you do find at week 52 is Simple Endoscopic Score for Crohn Disease (SES-CD) score changes from baseline with ustekinumab. Also, there were more opportunistic infections with adalimumab, consistent with what we know about side effect profile of anti-TNFs.”

He added, “This is an important study as first head-to-head of 2 biologic agents; both were highly effective.”

New evidence indicates that ustekinumab is effective in treating extraintestinal manifestations (EIMs), Dr Sands said. “Ustekinumb seemed to show benefit among patients with rheumatologic, dermatologic, or ocular EIMs in two-third of patients” in one study.

In addition, he said, “We really do not see any difference in MACE [major adverse cardiovascular events] with ustekinumab, and there is no increase in malignancies based on long-term data.”

The STARDUST trial of ustekinumab in the management of moderate to severe CD tested whether patients randomized to a treat-to-target arm with maintenance dose adjustments showed greater improvements than patients receiving standard of care. The results showed little difference between the groups, Dr Sands stated. “At this moment, treat to target is not a thing we engage in based on evidence with ustekinumab in Crohn’s disease.”

Dr Sands explained, “When we use ustekinumab, we are actually blocking both IL 12 and IL 23; but now we have anti-p19 agents that are very specific for blocking IL 23. In theory, blocking the p19 subunit would be superior to blocking p40 because it doesn’t block IL 12, and blocking IL 12 is associated in some genetic cases with increased risk of a number of serious and opportunistic infections.”

Four new agents are in clinical trials now that target the p19 subunit, Dr Sands stated. Brazikumab, mirkizumab, rizankizumab, and guselkumab all have shown promising results in Crohn disease. In addition, oral agents are being developed including a TYK2 inhibitor.

 “There’s also a theoretical benefit to blocking IL 23, in preventing cancer formation as well as growth and metastatis,” Dr Sands said, “which may be very relevant to our patients, especially with colonic IBD who are at risk for colon cancer.”

--Rebecca Mashaw

Sands, BE.  Optimal use and future use of anti-IL 12/23 agents in the management of IBD. Presented at: Advances in Inflammatory Bowel Diseases regional meeting. September 11, 2021. Virtual.