P0978 SKYLINE-UC: The First Platform Study in Ulcerative Colitis Assessing Efficacy and Safety of Three Long-Acting Antibodies Administered as Single Agents and in Combinations

Abstract Background SPY001, SPY002, and SPY003 are investigational monoclonal antibodies to α4β7, TL1A, and IL-23, respectively, which are validated targets in IBD. All three antibodies incorporate YTE modifications in the Fc region for half-life extension, potentially enabling quarterly or semiannual dosing either as monotherapy or combination treatments. Preclinical data suggest at least additive effectiveness for the pairwise combinations in preventing colitis development. The aim of this study is to assess the efficacy & safety of SPY001, SPY002, and SPY003 as single agents & in pairwise combinations (SPY120 [SPY001 & SPY002], SPY130 [SPY001 & SPY003], SPY230 [SPY002 & SPY003]) in UC through a patient-centric study design that enables sharing of data from placebo and monotherapy treatment arms, thereby minimizing the number of participants assigned to placebo and enrolled overall. Methods This ongoing platform study has been designed to maximize operational efficiency and to optimize scientific robustness in evaluating multiple interventions. The platform study uses a master protocol that governs shared features such as eligibility criteria, schedule of assessments, etc. Intervention-specific information such as dosing regimens are described in appendices. The study will comprise an open-label Part A and a randomized, placebo-controlled Part B (Figure 1). Part A will evaluate the preliminary efficacy and safety of SPY001, SPY002, and SPY003 as single agents. Part B will evaluate these three single agents in two dosing regimens in a placebo-controlled manner as well as SPY120, SPY130, and SPY230 combinations using a factorial design to allow comparisons between combinations, single agents, and placebo and to support Phase 3 dose regimen optimization. The study utilizes a treat-through design. A unified dosing schedule enables blinding with a minimum of sham administrations. Given the open-label nature of Part A, a histology-based outcome (change in RHI) will serve as the primary endpoint. Clinical remission will be assessed as the primary endpoint in Part B. Results Evaluating 6 interventions as a platform study is predicted to reduce sample size by 45% compared to investigating the same hypotheses in 3 separate studies, each with a factorial design. Part A data are anticipated to be available in 2026; Part B data are anticipated to be available in 2027. Conclusion SKYLINE-UC is an innovative platform study that will evaluate 6 interventions, including 3 single agents and 3 pairwise combinations. The study is designed to provide proof of concept for each investigational monotherapy and combination compared to placebo, dose-ranging data on each monotherapy, and a preliminary assessment of the additive and/or synergistic benefit of combinations. Conflict of interest: Danese, Silvio: Personal Fees: AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, Vifor Lecture fees from Abbvie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer, Takeda Jairath, Vipul: Consulting Fees: Abbvie, Alimentiv, Amgen, Anaptys Bio, Asahi Kasei, Asieris, Astra Zeneca, Attovia, Blackbird Labs, BMS, Boehringer Ingleheim, Biomebank, Caldera, Calluna, Catalytic Health, Celltrion, Ensho, Enthera, Exeliome Biosciences, Ferring, Fresenius Kabi, Gilead, Granite Bio, GSK, Janssen, Lilly, Merck, Mountainfield, MRM Health, Nxera, Organon, OSE Immunotherapeutics, Pendopharm, Pioneering Medicine, Pfizer, Prometheus, Roche/Genentech, Sanofi, SCOPE, Shattuck Labs, Sorriso, Spyre, Synedgen, Takeda, Teva, Tillotts, Union Therapeutics, Ventus, Ventyx, Vividion, Xencor, Zealand Pharma. Lu, Jd: Employee and shareholder of Spyre Therapeutics Zinder, Matthew: Employee and shareholder of Spyre Therapeutics Vugmeyster, Yulia: Employee and shareholder of Spyre Therapeutics Friedman, Joshua: Employee and shareholder of Spyre Therapeutics Huyghe, Mira: Employee and shareholder of Spyre Therapeutics Sloan, Sheldon: Employee and shareholder of Spyre Therapeutics Ms. Nguyen, Deanna: Employee and shareholder of Spyre Therapeutics