P0834Interim Phase 1 Results for SPY003, a Novel Half-life Extended Monoclonal Antibody Targeting IL-23, Suggest a Potential for Q3M or Q6M Maintenance Dosing for Inflammatory Bowel Disease

Abstract Background Several anti-IL-23 antibodies have been approved for the treatment of UC and Crohn’s disease. SPY003 is an investigational fully humanized IgG1 monoclonal antibody that specifically binds to IL-23(p19) at an epitope similar to risankizumab. The antibody includes a YTE modification to increase FcRn binding affinity, thereby extending its half-life. A Phase 1, first-in-human study in healthy volunteers is being conducted to characterize the safety, tolerability, PK, and PD properties of SPY003. Methods Study SPY003-207-101 is a randomized, double-blind, placebo-controlled single ascending dose (SAD) and multiple dose (MD) Phase 1 study in healthy volunteers aged 18 to 65. Study participants were randomized to either SPY003 or placebo in a 3:1 ratio in dose cohorts as follows: 200 mg IV, 600 mg SC, 600 mg IV, or 1200 mg IV as single doses, or 1200 mg IV at Weeks 0 and 4. One Chinese ethnobridging (Eb) 1200 mg IV dose cohort was also evaluated with a 4:1 active:placebo ratio. Blood was collected to evaluate safety, PK, PD, and ADA assessments at scheduled study visits. Interim safety and bioanalytical data with up to five months of follow-up from the first SAD cohort were analyzed. Results Noncompartmental PK analysis suggested dose-proportional PK with no ethnic sensitivity. Half-life extension of SPY003 was confirmed, with a cohort mean estimate of approximately 85 days (∼3-fold relative to that published for risankizumab). PD analysis demonstrated reductions in IL-23 pathway activity. Interim blinded safety data from all cohorts demonstrated SPY003 to be well tolerated with no serious adverse events and with most adverse events being mild in severity and deemed unrelated to study drug. Conclusion SPY003 was well tolerated in SAD, MD, and Eb Phase 1 cohorts. Interim PK confirmed half-life extension, supporting potential quarterly or twice annual maintenance dosing. PD analysis following single doses of SPY003 confirmed target-dependent PD effects. These results support advancement of SPY003 into clinical trials in IBD as a monotherapy and as a component of combination treatments. Conflict of interest: Vugmeyster, Yulia: Employee and shareholder of Spyre Therapeutics McLean, Rachel: Employee and shareholder of Spyre Therapeutics Patel, Preeyam: Employee and shareholder of Spyre Therapeutics Hew, Kinjal: Employee and shareholder of Spyre Therapeutics Sheldon, Curtis: Employee and shareholder of Spyre Therapeutics Svejnoha, Emily: Employee and shareholder of Spyre Therapeutics Wang, Bing: Employee of Cinlanian, LLC Lu, Jd: Employee and shareholder of Spyre Therapeutics Connolly, Brian: Employee and shareholder of Spyre Therapeutics Huyghe, Mira: Employee and shareholder of Spyre Therapeutics Friedman, Joshua: Employee and shareholder of Spyre Therapeutics Nguyen, Deanna: Employee and shareholder of Spyre Therapeutics