DAY 3: New Therapeutics Under Development for IBD, with Novel Mechanisms of Action

Vipul Jairath, MBChB, DPhil, MRCP, from Western University in Ontario Canada, reported on the 28-week safety and efficacy of icotrokinra (formerly JNJ-2113), an oral therapy that selectively blocks IL-23 receptor activation, in ulcerative colitis (UC). ANTHEM-UC was a phase 2b dose-ranging trial that compared placebo (n=63) to 100 mg (n=64), 200 mg (n=62), and 400 mg (n=63) once daily icotrokinra in patients with UC with a Mayo score of greater than 2 and inadequate response to other biologic therapies. Non-responders in the placebo group at 16 weeks could be switched to icotrokinra 400 mg for a 28-week long-term extension study. The mean patient age was 41 years, 37% were on steroids at baseline, 56.7% were naïve to biologic therapy. The efficacy at 12 weeks was maintained or improved out to 28 weeks, with clinical response seen in 25.4% of patients in the placebo group and 60.9%, 62.9%, and 66.7% of patients in the 100 mg, 200 mg, and 400 mg icotrokinra groups, respectively, reaching the primary endpoint of clinical response. Icotrokinra also showed significantly better clinical and symptomatic remission, endoscopic improvement, and histologic-endoscopic mucosal improvement (HEMI) compared to placebo. No unexpected adverse events and no deaths occurred. There was 1 serious infection in the placebo group, and no serious adverse events (e.g., TB, opportunistic infections).

Dr. Jairath also presented results from the RELIEVE UCCD phase 2 trial of duvakitug in patients with Crohn’s disease (CD). Duvakitug is a monoclonal antibody that targets TL1A, a proinflammatory cytokine upstream of TNFα that amplifies the inflammatory response. Patients with moderate to severely active with prior exposure to conventional or advanced therapies were enrolled. Concomitant medications were allowed. Patients were randomized to placebo or duvakitug 450 mg or 900 mg administered subcutaneously every 2 weeks. A total of 138 patients were enrolled, 46 in each of the 3 arms. Discontinuation was 20% in the placebo and 450 mg groups and 7% in the 900 mg group. Average age was 39 years, with a disease duration of 11 years and an SES-CD score of 12.3. One-third were on corticosteroids at baseline and 67% had prior exposure to biologics, many up to 3 different therapies. Endoscopic response was seen in 13% of patients who received placebo, 26% who received 450 mg duvakitug, and 48% who received 900 mg duvakitug. Similar improvements with duvakitug at the higher dose were seen for the endpoints of endoscopic remission, clinical remission, and clinical response. Severe adverse events were similar across groups, with no deaths and only a few adverse events leading to discontinuation. Most adverse events were non-serious and transient, and the most common were anemia, headache, and nasopharyngitis.

Bruce E. Sands, MD, MS, FACG, from the Icahn School of Medicine at Mount Sinai, presented the efficacy and safety results from 2 phase 3 trials of obefazimod in patients with moderately to severely active UC. Obefazimod enhances expression of mIR-124, which regulates the inflammatory response to restore mucosal homeostasis in UC. The two induction trials (ABTECT 1 & 2) compared placebo, 25 mg once daily obefazimod, and 50 mg once daily obefazimod, in patients with UC who failed conventional therapy or one or more advanced therapies. The maintenance trial of obefazimod is ongoing. Baseline characteristics were well balanced across the two studies and treatment groups. Patients on corticosteroids were maintained at the same dose during the 8-week induction study, then tapered during maintenance, but patients could not receive any concomitant advanced therapies. At week 8, patients were assessed for the FDA primary endpoint of clinical remission, EMA co-primary endpoints of symptomatic remission and endoscopic improvement, and the secondary endpoints of HEMI and clinical response. In ABTECT 1, 2.5% of patients on placebo, 23.8% on obefazimod 25 mg, and 21.7% on obefazimod 50 mg achieved the primary endpoint of clinical remission; the rates were 6.3%, 11%, and 20% in ABTECT 2. The same dose effect was seen for all co-primary and secondary endpoints in each study and in a pooled analysis. There were no serious infections, no malignancy, and no deaths. Headache was seen more often in patients receiving the higher dose of obefazimod; headaches were mild to moderate and resolved within 2 days, and less than 1% of patients discontinued the trial because of headache. Obefazimod is currently being studied in CD and recent results in rheumatoid arthritis were positive.

David A. Schwartz, MD, FACG, from Vanderbilt University Medical Center, shared results from STOMP-2, a multicenter randomized trial of AVB-114, a plug tissue composite designed to reduce inflammation and induce healing in patients with anal fistula. Current standard of care involves surgery and combination therapy to control infection and promote healing. Initial studies in 20 refractory patients found that AVB-114 resulted in 76% drainage cessation at 1 year, with MRI results that were consistent with clinical remission and no relapse at 1 year when drainage stopped at 6 months. The STOMP-2 trial was conducted at 14 sites in 48 subjects and included an 8-week run in period for collection of adipose tissue for embedding into the plug. Patients were randomized 1:1 to standard of care (n=24) or AVB-114 (n=24). More females were randomized to standard of care and more patients in the AVB-114 arm had a longer fistula duration, but both groups had similar previous exposure to advanced therapy. Improvement in the primary combined endpoint of radiologic response, drainage cessation, and visual closure of opening was seen with ABV-114, with quick separation from the standard of care group. By 9 months, improvement in the primary endpoint was 38% higher with ABV-114 than standard of care. Complete radiologic response at 9 months was 20.8% in the AVB-114 arm and 8.3% in the standard of care arm. All patient-reported components of the perianal disease activity index contributed to the observed improvement with AVB-114. A similar number of adverse events occurred in each group, with proctalgia reported in the AVB-114 arm related to the physical presence of the plug and suturing. No serious treatment-emergent adverse events were reported.

Darell Pardi, MD, MS, FACG, from the Mayo Clinic, presented results from the first Phase 1 trial of the safety, tolerability, and pharmacodynamics of R-3750, an engineered Lactococcus lactis strain that expresses the immunoregulatory surface layer protein (SlpA). SlpA signaling in the mucosa reduces pro-inflammatory cytokines and restores the gut epithelial barrier. The study included 12 patients with mild to moderate UC who received escalating doses of oral R-3750 for 35 days and then were followed out to 125 days. R-3750 was safe and well tolerated at all three dose levels. Significant reductions in SCCAI, partial Mayo score, and IBD-related quality of life were seen by day 125. Stool frequency declined during the dosing phase of the trial and was maintained through day 125. Expansion of regulatory T cells was seen during treatment and returned to baseline levels by day 125. A shift in the microbiome away from pro-inflammatory taxa, with enrichment of metabolic pathways known to be involved in gut health, was seen at the end of the treatment phase.

Dana J Luken, MD, PhD, FACG, from the Jill Roberts Center for Inflammatory Bowel Disease as Weill Cornell, presented the results of a phase 2a study of the safety, tolerability, and efficacy of PL8177 in adults with active UC. PL8177 is a synthetic selective melanocortin receptor 1 agonist that reduces stress-related signaling in tissues and drives non-inflammatory immune responses. The oral formulation inhibits degradation to optimize release in the lower GI tract. The study enrolled 12 participants who received PL8177 (n=9) or placebo (n=3) prior to early termination of the study. Mean age was 47.1 years and 50% were female, 42% had mild disease and 58% had moderate disease. Compared to placebo, a greater percentage of patients who received PL8177 achieved the primary endpoint of endoscopic improvement, and secondary endpoints of symptomatic remission, clinical response and remission, and HEMI. Twelve adverse events were reported in 4 participants who received PL8177 and 6 adverse events were reported in 1 participant who received placebo. All adverse events were unlikely to be treatment-related.