Raymond Cross, MD, on Drug Positioning in Crohn's Disease

When choosing therapies for adult patients with luminal Crohn’s disease, the safest agent is the agent that controls the inflammatory bowel disease, Raymond Cross, MD, said at the Advances in Inflammatory Bowel Disease regional meeting September 6 in Los Angeles, California,

Dr Cross is director of the IBD Center at Mercy Medical Center in Baltimore, Maryland, and professor of medicine at the University of Maryland.

He stated that randomized controlled trials, head-to-head trials of active treatments, network meta-analyses, and observational data with longer term follow-up provide sources of information about the efficacy, effectiveness, and safety of interventions. This information will help clinicians choose the treatments that work best for patients in specific circumstances, offering the greatest benefits and the fewest harms.

Dr Cross reviewed several key clinical trials and studies of therapies for Crohn’s disease. A network meta-analysis of 18 randomized clinical trials using surface under the cumulative ranking (SUCRA) showed that for patients naïve to biologic therapy, infliximab and adalimumab ranked highest for inducing clinical remission and endoscopic improvement. In the VERSIFY trial of vedolizumab in Crohn’s disease, endoscopic response rates were greater than endoscopic remission rates, with higher rates of both response and remission in patients who had not been exposed to anti-tumor necrosis factor (TNF) therapies.

The SEAVUE trial, a head-to-head study of the interleukin (IL)12/23 ustekinumab vs the anti-TNF adalimumab, both therapies proved highly effective and showed no differences in safety outcomes among patients with moderate to severe Crohn’s disease. The SONIC trial of infliximab or azathioprine monotherapy vs combination therapy with both drugs proved the superiority of the combination treatment in achieving clinical remission among biologic-naïve patients with Crohn’s.

Dr Cross reviewed the American Gastroenterological Association (AGA) Guideline on positioning therapies among adult outpatients with moderate to severe luminal and fistulizing CD. The AGA Guideline recommends:

• Any anti-TNF or ustekinumab over no treatment
• Vedolizumab over no treatment
• Ustekinumab or vedolizumab over no treatment for patients with primary nonresponse to anti-TNFs
• Ustekinumab, adalimumab, or vedolizumab for patients previously exposed to infliximab who have lost response (over no treatment
• Biologics over thiopurines for induction of remission
• Infliximab + thiopurines over infliximab alone for induction and maintenance of remission

The recent SEQUENCE trial, a head-to-head study of ustekinumab vs risankizumab, an IL-23 inhibitor, found that risankizumab was noninferior to ustekinumab in achieving a Crohn’s Disease Activity Index (CDAI) sore of <150 at week 24, and showed superiority over ustekinumab in achieving endoscopic remission at week 48, Dr Cross reported.

And a recent network meta-analysis showed that among a range of therapies including anti-TNFs, anti-IL012/23 and IL-23, and anti-integrin, all outperformed placebo in inducing and maintaining clinical remission among patients with Crohn’s disease, both biologic-exposed and biologic-naïve, he added.

He further noted the importance of the new PROFILE study presented at ECCO, which showed very high rates of treatment success among patients when they receive effective biologic therapy very quickly after diagnosis in comparison to patients who were treated in a step-up approach beginning with steroids. This top-down approach to therapy appears to work very effectively regardless of the drug chosen, and helps patients attain steroid- and surgery-free maintenance of remission at much higher rates than those on step-up therapy,

In assessing safety, Dr Cross noted that for patients with Crohn’s disease, a meta-analysis of 20 head-to-head safety studies showed that the risk of serious infections associated with advanced therapies varies and “is influenced by treatment effectiveness and “intrinsic immune suppression.” In addition, he stressed, "All of our advanced therapies are actually very safe. And anything that I give a patient will be safer than steroids."

Although ustekinumab may offer net benefit over anti-TNF in patients with Crohn’s disease” in terms of reduced risk of infection. However, he stressed, “’Safer’ biologics such as vedolizumab and ustekinumab are only ‘safer’ if they control disease; you need to choose the right therapy based on disease severity to provide best efficacy.”

The safety pyramid of therapies for Crohn’s disease is topped by vedolizumab, ustekinumab, risankizumab, and the sphingosine 1-phosphate receptor modulators ozanimod and etrasimod, Dr Cross said. Next come the anti-TNFs, then the Janus kinase inhibitors, followed by thiopurines and combination therapy with thiopurines and anti-TNFs. At the bottom lie the corticosteroids.

Dr Cross noted that surgery—or “colorectomab”—is “sometimes the best biologic, for patients with complications.”  It is important to understand therapy-specific safety concerns, but the most important point, he stressed, is that “inadequate treatment is an adverse event. The safest agent is the agent that controls IBD."

Cross R. Drug positioning in Crohn's disease. Presented at: Advances in Inflammatory Bowel Disease regional meeting. September 6, 2024. Los Angeles, California.