Earlier Is Better: Optimal Use of Anti-IL 12/23 Agents

In clinical trials, the anti-interleukin (IL) 12/23 inhibitor ustekinumab demonstrated “quite substantial results” in both induction and maintenance of remission among patients with inflammatory bowel disease, according to David T. Rubin, MD, who spoke at the Advances in Inflammatory Bowel Disease 2021 virtual regional meeting on March 6, 2021.

Dr Rubin is the Joseph B Kirshner Professor of Medicine and chief of the section of Gastroenterology, Hepatology, and Nutrition at the University of Chicago

He explained that ustekinumab, an anti-p40 agent, “knocks out both IL 12 and IL 23,” which share several proteins. The UNITI-1 trial, of patients previously exposed to anti-tumor necrosis factor (TNF) biologics, and UNITI-2, of patients who were anti-TNF naïve, “informed the decision to use an IV-loading dose that is weight-based and the maintenance dosing that in the US is 90mg every 8 weeks.” These trials showed that every 8-week dosing is more likely to achieve endoscopic healing among patients with Crohn disease.

Dr Rubin noted that “as we’ve seen in many therapies for IBD, when patients have not already failed other biological therapies—and frankly other treatments—they tend to have higher remission rates and higher response rates,” which was also true in the UNITI trials.

For the STARDUST trial, Dr Rubin stated, “the hypothesis was that treat-to-target is more successful than standard of care in obtaining endoscopic improvement at week 48,” he stated. “The objective was to investigate the benefits of treat-to-target with ustekinumab combined with early endoscopic assessment compared with a clinically-driven standard-of-care approach.”

This randomized trial of adult patients with Crohn disease used endoscopy at week 16 as a decision point for dose-adjustment of ustekinumab. This was followed by “regular assessment of biomarkers such as fecal calprotectin and C-reactive (CRP) protein, and clinical symptoms” as assessed according to the Crohn Disease Activity Index (CDAI). Based on these assessments the dose of ustekinumab was adjusted to reach the target.

Despite the treat-to-target strategy, the STARDUST trial found no statistical significance in the NonResponder Imputation analysis, Dr Rubin said. However, it did meet the endoscopic endpoint and dose adjustments in intervals to standard of care.

“This is a really an important advance in our field to understand this further,” Dr Rubin said.

“So what’s the benefit?” he asked. “Baseline CRP levels were inversely associated with ustekinumab concentrations at week 8 and even more dramatically at week 16; as doses went up we were more likely to be able to control the inflammation.”

Ustekinumab has also demonstrated effectiveness in perianal disease, Dr Rubin noted. Post-hoc analysis of the UNITI trials suggests ustekinumab performs better than or equal to 50% reduction in fistula drainage in perianal disease.

In a study conducted at the University of Chicago predominantly among patients with Crohn disease, Dr Rubin found that about 20% of patients needed dose escalation. In addition, shorter intervals improved clinical and biological indices of disease activity.

One of the greatest advantages of ustekinumab is its very low immunogenicity, he continued.

In a 1-year maintenance study only 3 of 127 patients with Crohn disease (2.4%) treated with 90 mg of ustekinumab at 8-week intervals developed antidrug antibodies. In the open-label long-term extension study, just 2 of 82 (2.4%) patients developed antibodies over the 3-year period.

“This may also let us do intermittent therapy with this drug” in which patients could come off ustekinumab if needed and then go back on without immunogenicity issues arising.

In a systematic review and meta-analysis ustekinumab was ranked highest, along with adalimumab, for induction of remission in anti-TNF-exposed patients. Ustekinumab also had the lowest risk of serious adverse events and infection.

These results were supported by those of a prospective observational study of patients with Crohn disease who had been exposed to anti-TNFs and then were switched to ustekinumab or vedolizumab. These patients were assessed at weeks 0, 12, 24, and 52 for steroid-free clinical remission, biochemical remission, and drug survival (staying on drug), the patients on vedolizumab “did less well than patients who were treated with ustekinumab, suggesting that ustekinumab may be a better option for patients with Crohn disease who have failed with anti-TNFs.”

Ustekinumab is also approved for moderate to severe ulcerative colitis (UC). “Unique to the UNIFI trial, across all of our IBD studies, is the incorporation of a novel endpoint called histoendoscopic mucosal healing,” Dr Rubin explained. The endoscopic subscore of 0 or 1 plus the histologic finding of less than 5% neutrophils were combined to result in histoendoscopic mucosal improvement or healing.” More than 45 of patients at who achieved this new endpoint at week 8 were more likely to maintain that improvement at 1 year. “This is clearly an interesting and important endpoint.”

Patients with UC quickly improve with ustekinumab, Dr Rubin said. “This is rapidly acting therapy; bleeding stops and stool frequency improves within 2 weeks in many patients.”

There are long-term safety and efficacy data for ustekinumab in the treatment of UC, as well, he continued. The long-term extension of the UNIFI trial over 2 years showed that efficacy was maintained, with symptomatic and partial Mayo remission sustained through week 92. No new safety signals were found.

A number of real-world studies demonstrated “quite significant 3-month and even 12-month clinical remission results, in a population that had almost all failed biologic therapies along the way.”

Dr Rubin briefly reviewed trial data on IL-23 inhibitors in development, including brazikumab, mirikizumab, and risankizumab, all of which show significant promise in treatment of both IBD and psoriasis.

Ustekinumab is an effective agent in the treatment of UC and Crohn disease, Dr Rubin concluded. “It has favorable safety and low immunogenicity, and certainly should be considered for treatment of patients with both IBD and skin problems, either primary or secondary to their IBD.”

Anti-TNF naïve patients tend to demonstrate the greatest response to ustekinumab in rapid induction of remission of IBD and in maintaining remission, he added. “Earlier works better.”

--Rebecca Mashaw

Rubin DT. Optimal use of anti-IL12/23 inhibitors. Presented at: Advances in Inflammatory Bowel Diseases 2021 regional meeting. March 6, 2021. Virtual.