DAY 2: The Latest Clinical Trial Findings In IBD

Dr. Millie D. Long of the University of North Carolina, Chapel Hill, NC, presented efficacy and safety results from AFFIRM, a phase 3 study of subcutaneous risankizumab induction and maintenance in patients with moderately to severely active Crohn's disease (CD). Risankizumab is a high-affinity humanized IgG1 monoclonal antibody that selectively targets the p19 subunit of interleukin-23 (IL-23) and blocks its interaction with the IL-23 receptor. Intravenous risankizumab is currently approved for induction. AFFIRM evaluated subcutaneous induction as an alternative route that would give patients more flexibility.
Patients with moderately to severely active CD, defined as a baseline Crohn's Disease Activity Index (CDAI) score of 220 to 450, were randomized to risankizumab (n=191) or placebo (n=98) for induction. Corticosteroids and other concomitant medications were kept stable for the first 12 weeks. For maintenance, patients with a clinical response continued their assigned treatment, and rescue therapy was allowed at any time after week 12. The co-primary endpoints were CDAI clinical remission and endoscopic response at week 12. Other efficacy endpoints included CDAI clinical remission and endoscopic response at week 24, as well as endoscopic remission and ulcer-free endoscopy at weeks 12 and 24. The study population was difficult to treat, with long disease duration, baseline CDAI scores above 300 and extensive treatment experience. About two-thirds of patients had failed at least one advanced therapy, including JAK inhibitors. Subcutaneous risankizumab met both co-primary endpoints. For clinical remission at week 12, the difference from placebo was 26.6% overall and 45.8% in patients who had never received an advanced therapy. For endoscopic response, the difference from placebo was 29.4% overall and 46% in advanced therapy-naive patients. Risankizumab also improved all secondary endpoints, with larger differences from placebo in advanced therapy-naive patients. Among patients who responded during the first 12 weeks, 75% achieved clinical remission at week 24. Treatment-emergent adverse events were consistent with the known safety profile of risankizumab.

Dr. David T. Rubin of University of Chicago Medicine, Chicago, IL, shared results from a post hoc analysis of the phase 3 GALAXI and GRAVITI trials of guselkumab in patients with moderately to severely active Crohn's disease (CD). Guselkumab is a dual-acting IL-23p19 subunit inhibitor that also binds the CD64 receptor on IL-23–producing immune cells. GALAXI compared intravenous guselkumab with placebo or ustekinumab, and GRAVITI compared subcutaneous guselkumab with placebo. This analysis followed patients from both trials who had a non-passable stenosis at baseline through week 96. Stenosis status was determined by the narrowing component of the Simple Endoscopic Score for Crohn's Disease (SES-CD). The analysis included 265 patients who received placebo, 401 on guselkumab 100 mg subcutaneous maintenance, 411 on guselkumab 200 mg subcutaneous maintenance, and 291 who received ustekinumab. The number of patients with stenoses and the SES-CD stenosis status were comparable across the four groups. Most patients had no prior surgery, and most stenoses were located in the ileum or right colon. In GALAXI, the proportion of guselkumab-treated patients with a persistent non-passable stenosis fell from 65% at week 12 to 54% at week 48 and 44% at week 96. GRAVITI showed the same trend, though it was less pronounced. Ustekinumab had no significant effect on stenosis persistence. Resolution of stenosis, defined as a narrowing grade of 0, increased from week 12 to week 96 with guselkumab and increased less with ustekinumab.
The investigators also explored whether the stenoses were inflammatory or fibrotic, using a gene correlation network analysis based on single-cell RNA sequencing. In patients whose ileal stenosis improved with guselkumab, expression of fibrosis- and inflammation-associated genes decreased, while expression of healing markers increased. Dr. Rubin concluded that guselkumab may improve endoscopic intestinal stenosis while inducing early changes in stenosis-associated biology.

Dr. David Dulaney of the San Antonio Uniformed Services Health Education Consortium in San Antonio, TX, presented real-world outcomes with upadacitinib, a Janus kinase (JAK) inhibitor, in patients with isolated ileal Crohn’s disease (CD). The study evaluated the drug’s effectiveness in the US Department of Defense Military Health System (MHS), a global health system that serves 9.5 million active-duty service members, retirees, and family members. The investigators performed a retrospective cohort analysis using the MHS Data Repository. They included patients who started upadacitinib for inflammatory bowel disease (IBD) from 2020, and specifically for CD after its 2023 approval, through 2026. All patients had at least 6 months of follow-up. Outcomes included clinical response, clinical remission, endoscopic response, endoscopic remission, and deep remission at 6 months, as well as healthcare utilization. About 40% of the cohort had coexisting perianal disease, a much higher rate than in other populations. This may reflect differences in prior therapies and in how patients were transitioned between therapies. Average disease duration was 3.1 years, and most patients were treatment experienced, primarily with anti-TNF-alpha agents. At 6 months, 81% of patients had a clinical response and 50% were in clinical remission. Endoscopic response was achieved in 58%, endoscopic remission in 54%, and deep remission in 42.5%. Corticosteroid use dropped from 86% at baseline to 15% after 6 months of upadacitinib. Emergency department visits and hospitalizations also decreased, although IBD-related surgeries increased.

Dr. Marla C. Dubinsky of the Icahn School of Medicine at Mount Sinai in New York, NY, presented results from a post hoc analysis of the LIBERTY-CD and LIBERTY-UC studies. The design of these studies allowed investigators to ask what happens when infliximab treatment is interrupted. In both trials, patients received intravenous infliximab induction for 10 weeks. A subset were then randomized to placebo through week 22, after which subcutaneous infliximab was resumed for maintenance. The average interval between the last infliximab dose and reintroduction was 16 weeks, or about 4 months. A key concern with reintroducing a biologic after a drug holiday is that patients may have developed antidrug antibodies (ADAs). The investigators therefore tracked ADA status during the holiday, from week 10 to week 22, and assessed how ADA positivity affected response after infliximab was restarted. Patients who were ADA positive during the holiday (n=37 CD, n=71 UC) and those who were ADA negative (n=14 CD, n=6 UC) had similar rates of clinical remission and response after reintroduction. Patients who restarted infliximab at 240 mg “caught up” to the response seen in patients without a treatment interruption within 8 weeks. ADA status also had no effect on C-reactive protein, fecal calprotectin, or serum infliximab levels after reinitiation. Dr. Dubinsky concluded that restarting infliximab subcutaneously after a treatment holiday achieves consistently high drug concentrations that prevent antibodies formed after intravenous induction from affecting outcomes.

Dr. Maria T. Abreu of Cedars-Sinai in Los Angeles, CA, shared efficacy and safety data from the long-term extension of the phase 2 ANTHEM-UC dose-ranging trial of icotrokinra in moderately to severely active ulcerative colitis (UC). Icotrokinra is a first-in-class oral peptide that blocks the IL-23 receptor and prevents IL-23 binding. Icotrokinra 100 mg, 200 mg, and 400 mg met all endpoints at week 12, with durable responses through week 28. Patients who responded at week 28 entered an open-label extension through week 76, and patients in the placebo arm switched to icotrokinra 400 mg. The study population had extensive disease, and 25% of patients had failed two classes of advanced therapy. Icotrokinra was well tolerated, and 85% of patients remained in the study through week 76 (n=48 for 100 mg, n=44 for 200 mg and n=44 for 400 mg). At week 76, clinical response rates ranged from 72.7% to 81.3%, clinical remission rates from 56.3% to 59.1%, and endoscopic improvement rates from 63.6% to 68.2% across doses. Symptomatic remission was seen as early as week 4 and was maintained in approximately 70% of patients through week 76.

Dr. Bruce E. Sands of the Icahn School of Medicine at Mount Sinai in New York, NY, shared efficacy data for obefazimod in ulcerative colitis (UC) from the ABTECT induction program. Obefazimod acts on Th17 cells and macrophages to help restore immune balance in UC. The international ABTECT program included two induction trials and one maintenance trial. It enrolled patients with moderately to severely active UC who had failed conventional or biologic therapies. The pooled induction analysis included 317 patients who received placebo, 316 who received obefazimod 25 mg, and 636 who received obefazimod 50 mg. The population was highly refractory and extremely sick. Approximately 60% had a Mayo endoscopic subscore of 3, half had received prior advanced therapies, and 25% had failed a JAK inhibitor. For the primary endpoint at week 8, 18% of patients in the obefazimod 25 mg group and 21% in the 50 mg group achieved clinical remission. Secondary endpoints showed the same pattern, including clinical response, symptomatic remission, endoscopic improvement, and histo-endoscopic mucosal improvement (HEMI). Symptomatic response was seen as early as week 1 and symptomatic remission by week 2. When the investigators compared patients with an inadequate response to prior therapies against those with an adequate response, both groups showed consistent improvement in symptomatic response and remission over time.

In the final presentation, Dr. Rubin returned to present findings from the long-term extension of QUASAR, the phase 3 registration trial of guselkumab, in patients with moderately to severely active ulcerative colitis (UC). This post hoc analysis examined long-term changes over 3 years. In QUASAR, patients received guselkumab induction for 12 weeks. They were then randomized to guselkumab 100 mg, guselkumab 200 mg, or placebo (withdrawal) through week 44. The long-term extension continues patients on guselkumab 100 mg (n=155) or 200 mg (n=148) and is ongoing; this analysis was limited to the first 3 years. At induction, a little more than half of patients were naive to advanced therapy, a third were taking corticosteroids and 25% were taking an immunomodulator. Dr. Rubin presented the results as Sankey diagrams that tracked Geboes histologic score categories over time. The Geboes score characterizes the histologic extent of inflammation, with grades that progress from structural changes through inflammatory infiltrates to crypt destruction and erosions. Most patients who achieved histologic remission at week 12 or week 44 were highly likely to maintain it at later time points, and continued therapy increased the likelihood of maintaining remission. When Geboes categories were overlaid with Mayo endoscopic subscores, histologic remission occurred slightly earlier than endoscopic improvement, and both were sustained over 3 years. When the histologic data were overlaid with symptomatic remission, they showed the same pattern of improvement, also sustained through 3 years.