Notable news about inflammatory bowel disease (IBD) in 2024 included a study evaluating loss of response to tumor necrosis factor (TNF) blockers, new FDA approvals, problems with placebos, and extended data on a promising new drug.
Top-Down Treatment Beat Step-Up Approach
Clinical trial researchers reported that early and intensive “top down” therapy outperformed conventional “step up” therapy for patients with newly diagnosed Crohn’s disease. The researchers said “top down” therapy should become standard for most patients.
Among the 386 patients randomized in the PROFILE trial, sustained steroid- and surgery-free remission at 48 weeks was significantly more common in the group assigned to top down therapy (immunosuppression with TNF blockers plus an immunomodulator), as compared with those assigned to an accelerated step-up approach with conventional treatment and steroids (79% vs 15%, P<0.0001).
There were fewer adverse events, including disease flares, in the top-down group (168 vs 315), as well as fewer serious adverse events (15 vs 42) and fewer complications requiring surgery (one vs 10), the researchers reported in Lancet Gastroenterology & Hepatology.
Given that most newly diagnosed patients fit the trial’s inclusion criteria — active symptoms, raised C-reactive protein or calprotectin of 200 μg/g or more, plus active inflammation on ileocolonoscopy — “the case appears clear-cut for implementation of top-down treatment as the standard of care for most patients as soon as possible after diagnosis,” concluded Nurulamin Noor, PhD, of the Cambridge University Hospitals NHS Foundation Trust in England, and co-authors.
Most Crohn’s Patients Lost Anti-TNF Response
A population-based observational study in the U.K. showed that approximately two-thirds of patients with Crohn’s disease who initially responded to TNF inhibitors lost response by the third year of treatment.
Fully 60% of patients treated with infliximab (Remicade) and 68% treated with adalimumab (Humira) lost treatment response by year 3, authors of the Personalized Anti-TNF Therapy in Crohn’s Disease (PANTS) study reported in Lancet Gastroenterology & Hepatology.
Higher concentrations of anti-TNF agents at the end of the induction period at week 14 were associated with lower risk for lost treatment response. For infliximab, each 10-fold increase in drug concentration reduced the risk by 55%. For adalimumab, each 10-fold higher drug concentration reduced the risk by 61%, the study found.
“Our observations support the current practice of dose intensification in the setting of low drug concentrations without immunogenicity,” Nicholas Kennedy, MBBS, of the University of Exeter in England, and colleagues concluded. “For some patients who develop treatment failure despite adequate infliximab concentrations after dose intensification, our observations suggest targeting even higher drug concentrations to reach remission.”
New Options Approved for Ulcerative Colitis
In June, the FDA approved risankizumab (Skyrizi) for moderately to severely active ulcerative colitis based on data from the INSPIRE and COMMAND trials.
In the 12-week INSPIRE trial, clinical remission following induction therapy significantly improved with the interleukin (IL)-23 inhibitor, at 24% versus 8% with placebo. And data from COMMAND, a 52-week maintenance study, showed clinical remissions of 41-45% with risankizumab compared with 26% with placebo. The studies also demonstrated endoscopic improvement with the drug. (Risankizumab was approved in 2022 for Crohn’s disease.)
And in September, the FDA expanded the indications for guselkumab (Tremfya) to include moderately to severely active ulcerative colitis based on findings from QUASAR, an ongoing phase IIb/III induction and maintenance program involving patients with inadequate response to conventional drugs, biologics, or a Janus kinase inhibitor.
In the studies, treatment with guselkumab led to significantly higher rates of clinical remission at 44 weeks (45-50% vs 19% with placebo) and higher rates of endoscopic remission at 1 year of maintenance (34-35% vs 15%). Guselkumab is also being evaluated in Crohn’s disease.
End of Intensified Infliximab for Refractory Ulcerative Colitis?
The PREDICT-UC trial showed intensified or accelerated dosing regimens with infliximab did not improve outcomes compared with the standard regimen in patients with steroid-refractory acute severe ulcerative colitis undergoing rescue therapy.
In 138 adult patients randomized to a first dose of 10 mg/kg or 5 mg/kg, there was no significant difference in the proportion of those who had a clinical response by day 7 (65% vs 61%; risk ratio adjusted for thiopurine treatment history 1.06, 95% CI 0.94-1.20, P=0.32), the researchers reported in Lancet Gastroenterology & Hepatology.
At day 14, there was still no significant difference in the rate of clinical response among patients who received a second dose of the intensified 10 mg/kg regimen (74%), those who received a 10 mg/kg dose after receiving a 5 mg/kg dose (accelerated group; 73%), and those who received a second 5 mg/kg dose (standard group; 68%, P=0.81).
There were also no significant differences in additional longer-term endpoints including clinical remission, steroid-free remission, endoscopic remission, or rates of colectomy at 3 months, the study found.
“The PREDICT-UC study potentially signals the end of accelerated or intensified dosing strategies for infliximab as rescue therapy for acute severe ulcerative colitis, which should prompt new strategic approaches,” Saurabh Kedia, MD, and Vineet Ahuja, MD, of the All India Institute of Medical Sciences in New Delhi, said in an editorial accompanying the study.
Rethinking Placebos in IBD Clinical Trials
Patients with IBD assigned to placebo in clinical trials were shown to be at significantly higher risk for potential harms, according to two systematic reviews published in Lancet Gastroenterology & Hepatology.
In one review and meta-analysis of 47 induction therapy trials that included approximately 21,000 adults with moderate to severe IBD, risk of worsening disease activity was significantly lower in the treatment versus placebo groups (4.2% vs 8.5%; HR 0.48, 95% CI 0.40-0.59), the researchers reported.
Patients who received active treatment were also significantly less likely than those who received placebo to experience serious adverse events (4.8% vs 7.2%; HR 0.69, 95% CI 0.59-0.80) or venous thromboembolism (0.2% vs 0.4%; HR 0.45, 95% CI 0.21-0.94), the analysis found.
Results were similar in a second meta-analysis in the same journal looking at 45 maintenance therapy trials with approximately 16,500 patients. The harms associated with placebo were likely due to a lower risk of adverse outcomes in patients receiving an active drug, rather than a true increase in risk associated with receiving placebo, Alex Ford, MD, of St. James University Hospital in Leeds, England, and co-authors noted.
However, they added: “The results of this meta-analysis should prompt reflection on the current clinical trial model in IBD, encouraging critical thinking about possible strategies to minimize placebo exposure. Alternative trial designs should be considered for future novel drugs for IBD.”
Extended Benefit With Tulisokibart
Long-term data from two clinical trials showed the investigational monoclonal antibody tulisokibart continued to maintain clinical and endoscopic improvements at nearly 1 year in patients with IBD.
In an extension of the phase II ARTEMIS-UC trial, 48% of patients with ulcerative colitis who received 250 mg of intravenous tulisokibart were in clinical remission at 50 weeks. In the phase II APOLLO-CD trial, 56% of patients with Crohn’s disease who received 250 mg of tulisokibart achieved clinical remission at week 50.
The percentage still in clinical remission was lower in patients who received 100 mg of the drug: 32% of patients with ulcerative colitis and 42% of Crohn’s patients. The findings were presented at the United European Gastroenterology Week in Vienna.
Tulisokibart will advance to phase III trials for ulcerative colitis and Crohn’s disease, according to the researchers.
Other Notable IBD News in 2024
Allele May Heighten Risk of Severe Ulcerative Colitis
IBD Surgery Linked to Improved Patient-Reported Pain, Physical Health
Guselkumab Continues Winning Streak in Crohn’s Disease
Switching Twice With Infliximab Biosimilars Not Linked With IBD Flare Risk
Risankizumab Beats Ustekinumab for Previously Treated Crohn’s
History of IBD Linked to Severe Outcomes in Patients Hospitalized for COVID
Telehealth Option Increased IBD Clinic’s Patient Retention
TNF Inhibitors for IBD Linked to Kidney Function Declines
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