P0023 Anti-TL1A and anti-IL-23 combination therapy is superior to its constituent monotherapies in mouse anti-CD40 colitis

Abstract Background Targeted biologic treatments for IBD have substantially improved patient care by offering alternatives to broad immunosuppression while providing favorable safety profiles. However, less than half of patients typically respond to a given biologic treatment, and many of those will lose response over time. Combination therapy offers the potential to increase response rates and durability due to simultaneous inhibition of multiple disease-relevant pathways. Spyre Therapeutics is developing targeted, biologic combination therapies for IBD including SPY230, a combination of fully human, half-life extended antibodies targeting TL1A and IL-23. In this study, mouse surrogate antibodies targeting mouse TL1A and IL-23 were dosed alone or in combination in the anti-CD40 mouse model of colitis to compare the efficacy of monotherapy to combination therapy. Methods Female, immune compromised mice (CB17-SCID) were injected intraperitoneally with 5 mg/kg of an anti-CD40 agonist antibody (BioXCell) on study Day 0 to induce colitis. Anti-mouse TL1A (25 mg/kg) and anti-mouse IL-23 (25 mg/kg or 5 mg/kg) were injected intravenously on study Day -1 and Day 2. Body weight and disease activity score were measured daily until the end of the study on Day 5. Colon weight and length were measured on Day 5. Distal colon histopathology was scored by a blinded pathologist. Results Treatment with anti-TL1A resulted in a reduction in body weight loss and improved disease activity score compared to the vehicle control group. Treatment with anti-IL-23 at 25 mg/kg and 5 mg/kg showed a dose-dependent reduction in body weight loss and improvement in disease activity score. Treatment with the combination of anti-TL1A and anti-IL-23 resulted in significantly reduced body weight loss and improved disease activity score at both anti-IL-23 dose levels compared to either individual monotherapy. Colon weight-to-length ratio and distal colon histopathology scores were superior for the combination treatment compared to either monotherapy treatment. Conclusion The combination of anti-TL1A and anti-IL-23 was more efficacious in mouse anti-CD40 colitis than anti-TL1A and anti-IL-23 monotherapies. These preclinical results support advancement of SPY230 in the ongoing SKYLINE-UC Phase 2 platform study in UC. Conflict of interest: Dr. Siegel, Matt: Employee and shareholder of Spyre Therapeutics Giles, David: Employee and shareholder of Spyre Therapeutics Lewis, Emily: Employee and shareholder of Spyre Therapeutics Friedman, Joshua: Employee and shareholder of Spyre Therapeutics Rose, Mark: Employee and shareholder of Spyre Therapeutics Spencer, Andy: Employee and shareholder at Spyre Therapeutics