New IL-23 Inhibitors Expand Treatment Options for Crohn’s Disease

The U.S. Food and Drug Administration has approved two new medications for Crohn’s disease, following the results of successful multisite clinical trials conducted in part at the Icahn School of Medicine at Mount Sinai. The therapies fill an important gap in Crohn’s disease treatment.

“Unfortunately, most patients with Crohn’s disease either don’t respond to available medications or lose response over time. That means there’s a real need for new therapies,” says Bruce E. Sands, MD, MS, the Dr. Burrill B. Crohn Professor of Medicine and Chief of the Dr. Henry D. Janowitz Division of Gastroenterology at the Icahn School of Medicine. Dr. Sands served on the steering committee and was a senior author for both studies, which were published in The Lancet.

The classic biologic treatments for Crohn’s disease target tumor necrosis factor (TNF), a key driver of inflammation. Yet in the subset of patients who respond, the drugs often lose efficacy over time. They are also associated with potentially serious side effects, including an increased risk of infections.

Another option, Entyvio® (vedolizumab), which targets α4β7 integrin, is safer but less effective in Crohn’s disease than in ulcerative colitis. The approval of Stelara® (ustekinumab), which blocks interleukin 12 (IL-12) and interleukin 23 (IL-23), was an important advance, but again, a significant number of patients did not respond to it.

The two newly approved drugs target IL-23 alone. “For reasons that aren’t yet clear, the agents directed against IL-23 alone, rather than at both IL-12 and IL-23, seem to be more effective for treating Crohn’s disease,” Dr. Sands says.

Crohn’s Disease Clinical Trials

Two different IL-23 blockers were tested in large global clinical trials focused on patients with moderate-to-severe Crohn’s disease with active inflammation confirmed by endoscopy. The GALAXI-1 trial evaluated Tremfya® (guselkumab) and the VIVID-1 trial examined Omvoh® (mirikizumab). In both studies, about half of the patients had failed one or more advanced therapies.

In the trials, both drugs clearly demonstrated superiority over placebo, with some patients in each trial achieving clinical remission. The trials also compared these medications with ustekinumab, the agent that blocks both IL-12 and IL-23, and found that:

• Guselkumab was associated with superior clinical and endoscopic remission rates when compared with ustekinumab.

• Mirikizumab was associated with a higher rate of clinical remission, though there was no difference in endoscopic outcomes compared with ustekinumab.

The different results may be due to different treatment designs, Dr. Sands says. After the first 12 weeks of the mirikizumab study, responding participants were re-randomized to either a drug or placebo group for the rest of the year. The guselkumab trial used a treat-through design, allowing patients to continue the treatment through the end of the study. “So at the end of the year, what you see is really what you get,” he says.

Both guselkumab and mirikizumab were associated with a very low risk of side effects. They demonstrated their benefit among patients who had not responded to conventional therapies and those who had not been previously treated for Crohn’s disease. “These medications are very safe, and there is no reason not to use them as first-line therapies,” Dr. Sands says.

A Growing Toolkit for Crohn’s Disease Treatment

With more therapies on the market, physicians have more tools—but also more complexity to navigate. Among the biologics now approved for Crohn’s disease, there is a range of dosing schedules and administration methods. Other classes of drugs, including oral medications, have also expanded the treatment options for Crohn’s disease.

“It’s getting harder for gastroenterologists who are not IBD experts to choose,” Dr. Sands says. “We’re always trying to match patient priorities and treatment goals with their disease characteristics. It’s less of a treatment algorithm, and more like a matrix.”

The Mount Sinai Health System has a long history as a leader in treating Crohn’s disease and other forms of inflammatory bowel disease. Indeed, it was Mount Sinai gastroenterologist Burrill B. Crohn, MD, whose seminal 1932 description of noninfectious inflammation in the intestinal tract gave Crohn’s disease its name. Since launching a decade ago, the Susan and Leonard Feinstein Inflammatory Bowel Disease Clinical Center at Mount Sinai has seen approximately 14,000 patients and has been involved in wide-ranging research on Crohn’s disease, ulcerative colitis, and related conditions.

In one line of research, Dr. Sands and his colleagues are exploring therapies that combine the new IL-23 inhibitors with other classes of medications. In a phase 2 study, they found a combination of drugs targeting IL-23 blockers and TNF had added benefit in patients with ulcerative colitis.

“It’s important for us to be involved in research that pushes the paradigm of care,” Dr. Sands says. “This is one more arrow in our quiver as we target these diseases.”