When a 23-year-old man with ulcerative colitis (UC) presented with 12 loose, bloody stools per day while on a prednisone taper and showed no improvement after 3 days of hospitalization and IV steroid treatment, he was enrolled in a randomized clinical trial of a new agent called cA2. By day 5, the patient had 3 normal stools per day without blood and was able to be discharged home.

The year was 1994. The investigational agent is now called infliximab. And the patient was one of the first in the United States to receive this treatment, recalled his physician, Bruce E. Sands, MD, MS, FACG, in his keynote J. Edward Berk Distinguished Lecture at the American College of Gastroenterology Scientific Meeting on October 25 in Charlotte, North Carolina.

Dr Sands is 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 at Mount Sinai in New York.

“Every new drug starts life as an investigational agent,” Dr Sands emphasized. “Every new drug class has the potential to treat a patient who has not responded.”

However, he noted, “there’s a growing problem of loss of response and therapeutic plateau,” and further, not all new agents succeed.

Dr Sands stressed the importance of making the best use of the existing armamentarium of therapies for inflammatory bowel disease. He advised, “Follow the evidence. Use effective therapy early. Use therapeutic drug monitoring wisely. And treat to target, with short-term, intermediate, and long-term therapeutic goals.”

Since 2018, the Janus kinase (JAK) inhibitors tofacitinib and upadacitinib and the sphingosine 1-phosphate (S1P) receptor modulator ozanimod have been approved for treatment of UC, with another S1P receptor modulator, etrasimod, poised to join the list of new therapies in the near future. For Crohn disease, the anti-IL-23/p19 agent, risankizumab, is now available, Dr Sands noted.

He reviewed the results of the U-ACCOMPLISH and U-ACHIEVE trials of upadacitinib induction therapy among patients with moderate to severe UC, which showed rates of clinical remission from 26% to 33% at week 8 and clinical response of 73% to 74%. Endoscopic improvement rates ranged from 36% to 44% and histoendoscopic mucosal improvement was achieved by 30% to 36% of patients.

Dr Sands commented that while an increased risk of herpes zoster and slightly higher rates of neutropenia and creatinine phosphokinase elevation were seen among the adverse events (AEs) associated with upadacitinib, these trials did not show higher risks of major cardiac adverse events. A heightened risk of cardiac events seen in trials of tofacitinib among patients with rheumatoid arthritis led the US Food and Drug Administration to place a black box warning on all JAK inhibitors, and to require that patients with IBD show no response or lose response to anti-tumor necrosis factor (TNF) agents before they can be treated with JAKs.

Where tofacitinib and upadacitinib function to inhibit the JAK-STAT signaling pathways, S1-P receptor modulators function to ‘blind’ leukocytes so they are unable to exit lymphoid tissues and migrate to sites of inflammation, perpetuating the inflammatory process, Dr Sands explained. In the TRUE NORTH trial, more than 18% of patients with moderate to severe UC showed clinical remission at week 10, while almost 48% showed clinical response during the induction phase. At week 52 of the maintenance trial, 60% showed continued clinical response and almost 52% maintained clinical remission.

Dr Sands also noted that while patients who were naïve to biologics achieved higher rates of response and remission than those who had been exposed to biologics previously, more than 55% of patients who had been exposed to anti-TNFs still achieved and maintained clinical response at week 52 and some 30% maintained clinical remission.

He related the results of a network meta-analysis showing that for patients with UC not exposed to biologics, the newer therapies, including anti-TNFs, anti-integrins, and S1P receptor modulators, ranked very similarly for intent-to-treat maintenance efficacy. However, when assessing the same measure among patients who had been exposed to biologics and therefore were eligible for treatment with JAK inhibitors, upadacitinib outperformed the others by a significant margin.

For Crohn disease, Dr Sands explained, the anti-p19/IL-23 agents show promise. In the ADVANCE and MOTIVATE trials for risankizumab,  patients with moderate to severe Crohn disease achieved clinical remission rates who had not responded or tolerated biologic or conventional therapies achieved clinical remission rates of 19% to 25%, while the FORTIFY maintenance trial showed clinical remission rates as high as 55% at an 180mg dose of risankizumab.

Dr Sand also reported on the GALAXI 1 trial of guselkumab induction therapy among patients

with moderate-to-severe Crohn disease, where patients who had failed with previous conventional therapies achieved remission rates as high as 65% and biologic-experienced patients achieved remission rates of 52%. Other p19 inhibitors such as mirikizumab are also being studied.

Combination therapy is already accepted practice in IBD care, Dr Sands stated, as in the use of immunomodulators with anti-TNFs. The next step is likely to be in combining biologics, taking advantage of their varying mechanisms of action to maximize outcomes for patients. The EXPLORER study is investigating a triple combination therapy of vedolizumab IV, adalimumab SC, and oral methotrexate over a 26-week treatment period to induce endoscopic remission in Crohn disease, followed by vedolizumab IV monotherapy for 78 weeks.

VEGA is a Phase 2a proof-of-concept study investigating the efficacy of guselkumab and golimumab in combination vs guselkumab or golimumab monotherapy in adults with moderately-to-severely active UC. The trial is designed to determine if the combination of an anti-TNF and anti-IL-23 provides an advantage due to the difference in their mechanisms of action.

With all the advances that have been seen in developing therapies for IBD, it’s still not enough, Dr Sands said. He noted that about half of all patients with UC or Crohn disease have difficulty achieving or maintaining remission. The key will likely lie in the advance of precision medicine. “Right now, we treat all our patients the same,” he said. What is needed is a way to determine which patients will respond best to which treatments.

To achieve these goals, he said, clinical trials are essential, yet the enrollment of patients in clinical trials for IBD therapies has dropped dramatically. He called on the attendees to encourage their patients to participate in clinical trials so that new individual treatments and combination therapies can be adequately investigated and provide even more opportunities for successful outcomes for patients with IBD.

Sands, BE. The promise and progress of new approaches to treating the inflammatory bowel diseases. J. Edward Berk Distinguished Lecture. Presented at: American College of Gastroenterology Scientific Meeting; October 25, 2022.