Spyre Therapeutics, Inc. (NASDAQ: SYRE) has announced the acceleration of clinical timelines for SPY003, a novel half-life extended IL-23p19 monoclonal antibody (mAb), with first-in-human dosing now expected in the first quarter of 2025. This update coincides with scientific presentations at the United European Gastroenterology Week (UEGW) Congress, showcasing promising preclinical data for SPY003 and its potential in combination therapies for inflammatory bowel disease (IBD).
SPY003: Extended Half-Life IL-23 Inhibitor
SPY003 targets IL-23p19, a key cytokine involved in the pathogenesis of IBD. Approved IL-23 inhibitors have demonstrated efficacy and tolerability in treating moderate-to-severe IBD, but current therapies require dosing six times per year. SPY003 is engineered for extended half-life, potentially allowing for quarterly or twice-yearly dosing as a monotherapy in maintenance. Interim data from the first-in-human trial is anticipated in the second half of 2025.
Preclinical Data Highlights
At UEGW, Spyre presented preclinical data demonstrating SPY003's comparable in vitro potency to risankizumab, a commercially available IL-23 inhibitor. Pharmacokinetic studies in non-human primates (NHPs) revealed a half-life of approximately 30 days for SPY003, representing a greater than three-fold increase compared to risankizumab. These findings suggest that SPY003 exhibits high selectivity and affinity for IL-23, effectively inhibiting downstream cellular signaling. The extended half-life observed in NHPs supports the therapeutic potential of SPY003 for treating Crohn's disease (CD) and Ulcerative Colitis (UC) with less frequent dosing.
Combination Therapy Potential
Spyre also presented preclinical data on combining SPY003 with either SPY001 (anti-α4β7) or SPY002 (anti-TL1A). In vitro studies and in vivo murine colitis models indicated that IL-23 and TL1A synergistically promote IL-17 secretion from human and mouse immune cells. The combination of anti-IL-23 and anti-TL1A more effectively suppressed IL-17 secretion than either agent alone. Furthermore, in a T-cell transfer model of IBD, combination therapy with anti-IL-23 and anti-β7 improved body weight and reduced colonic CD4+ infiltration and IL-17 levels compared to monotherapy.
Advancing a Portfolio of Extended Half-Life Antibodies
Spyre's portfolio includes extended half-life antibodies targeting α4β7, TL1A, and IL-23. Additional preclinical data for SPY001 and SPY002, also presented at UEGW, included in vitro potency compared to benchmark antibodies, nonclinical safety data, and pharmacokinetics demonstrating extended half-life in NHPs. Human pharmacokinetic simulations for SPY001 and both SPY002 candidates support potential Q8-12W dosing regimens in IBD.
"The Spyre team has made significant progress in advancing its potentially best-in-class molecules into first-in-human studies within an expected nine-month window," said Cameron Turtle, DPhil, chief executive officer of Spyre. "With these promising molecules against the top three validated targets in IBD, we believe that Spyre is uniquely positioned to develop monotherapy and combination products with the potential to meaningfully improve both efficacy and convenience compared to today's standard of care."
