Spyre Therapeutics, Inc.

Development Pipeline Overview and Update

The Company is committed to developing next-generation therapies that elevate the standard in immunology by delivering more complete disease control, greater durability, and a simpler treatment experience for patients. The Company’s pipeline includes extended half-life antibodies targeting α4β7, TL1A, IL-23 and IL-17A/F (each as defined below), as well as rational combination programs, in large therapeutic areas of focus, each with high unmet need.

•In Gastroenterology, the Company is advancing three potential first- and best-in-class combination programs in inflammatory bowel disease (“IBD”). IBD is a chronic condition characterized by inflammation within the gastrointestinal tract, including two main disorders: ulcerative colitis (“UC”) and Crohn's disease (“CD”). In the United States, it is estimated that approximately 2.4 million individuals are diagnosed with IBD and the global market is forecasted to exceed $40 billion by 2030.

•In Dermatology, the Company is advancing a potential first- and best-in-class anti-TL1A + IL-17A/F combination program in hidradenitis suppurativa (“HS”). Additionally, the Company plans to advance a potential best-in-class anti-TL1A monotherapy agent into pivotal studies for HS in 2027. HS is a chronic inflammatory skin condition characterized by recurrent, painful nodules and abscesses, primarily in areas such as the underarms and groin. The disease can progress to draining tunnels and permanent scarring, substantially impacting patients’ quality of life. It is estimated that the disease affects approximately 3.0 million patients in the United States, with the global market forecasted to exceed $10 billion by 2035.

The Company has three ongoing Phase 2 clinical trials with meaningful proof-of-concept data readouts in 2026 and 2027:

SKYLINE Phase 2 Platform Trial in IBD -in May 2025, the Company initiated a Phase 2 induction and maintenance platform trial of SPY001 (long-acting anti-α4β7), SPY002 (long-acting anti-TL1A) and SPY003 (long-acting anti-IL-23), as well as pairwise combinations thereof (six investigational agents in total), in patients with moderately to severely active UC. The trial consists of two parts:

•Part A: Open-label assessment of the safety and preliminary efficacy of a single dose level of each investigational monotherapy. Enrollment for Part A has completed, with initial SPY001, SPY002 and SPY003 Part A topline induction data announced in April 2026, June 2026, and September 2026, respectively.

◦SPY001, SPY002, and SPY003 were well-tolerated with a safety profile consistent with in-class comparators. SPY001, SPY002, and SPY003 all achieved their respective primary endpoints, demonstrating a statistically significant reduction in the Robart’s Histopathology Index (“RHI”) score of 9.2 points, 10.7 points, and 10.0 points, respectively. Rates of key secondary endpoints of clinical remission and endoscopic improvement were clinically meaningful at 40% and 51%, respectively, for SPY001, 33% and 42%, respectively, for SPY002, and 20% and 30%, respectively, for SPY003. The change in the modified Mayo Score from baseline at Week 12 for both SPY001 and SPY002 was -3.7, and for SPY003 was -3.5, reflecting consistency across secondary endpoints.

•Part B: Randomized and placebo-controlled assessment of the safety and efficacy of monotherapies and combinations, designed to provide dose-ranging data on monotherapies, proof-of-concept, and contribution of components for combinations, with induction data expected in the third quarter of 2027. Study is enrolling ahead of schedule enabling an increased enrollment target.

SKYLIGHT Phase 2 Trial in HS -in September 2026, the Company initiated its SKYLIGHT Phase 2 trial of SPY072 in subjects with moderately to severely active HS who are initiating bimekizumab. The trial serves as a surrogate proof-of-concept study for the Company’s internal SPY772 combination program combining SPY072 (long-acting anti-TL1A) and SPY007 (long-acting anti-IL-17A/F). Topline Week 16 results are planned in late 2027 or early 2028.

SKYWAY Phase 2 Basket Trial in Rheumatic Diseases -in September 2025, the Company initiated a Phase 2 randomized and placebo-controlled basket trial of SPY072 in patients with moderately to severely active RA, PsA, or axSpA. The trial consists of three sub-studies:

•RA sub-study: Double-blind, placebo-controlled safety and efficacy study of two dose levels of SPY072 at Week 12 with open-label follow-up through Week 36. Topline proof-of-concept data were released in August 2026. Both doses of SPY072 demonstrated statistically significant benefits compared to placebo on one or more of the primary (change from baseline in DAS28-CRP), key secondary (ACR20), and exploratory endpoints (ACR50). SPY072 was well tolerated, with a safety profile consistent with the TL1A class. While SPY072 demonstrated clinical activity in RA, the results did not meet the Company’s internal bar to prioritize advancement of SPY072 in RA.

•PsA and axSpA sub-studies: Double-blind, placebo-controlled safety and efficacy studies of a single dose level of SPY072 at Week 16 with open-label follow-up through Week 40. The Company announced that SPY072 was well-tolerated, but neither sub-study met its primary endpoint of ACR20 response in PsA or change from baseline in ASDAS in axSpA.

The Company does not plan to advance SPY072 in rheumatic diseases.

The investigational therapies being studied in the Company’s clinical trials include:

SPY001 – a highly potent and selective investigational monoclonal antibody targeting the α4β7 integrin (“α4β7”), engineered with half-life extension technology and formulated at high concentration with the goal of maximizing efficacy and enabling infrequent, subcutaneous maintenance dosing. SPY001 is being evaluated for the treatment of IBD in the SKYLINE study.

SPY002 and SPY072 – two highly potent and selective, investigational anti-tumor necrosis factor-like ligand 1A (“TL1A”) monoclonal antibodies, engineered with half-life extension technology and formulated at high concentration with the goal of maximizing efficacy and enabling infrequent, subcutaneous maintenance dosing. The Company believes TL1A has emerged as one of the most promising targets in IBD and broader immunology indications. SPY002 is being evaluated for the treatment of IBD in the SKYLINE study and SPY072 is being developed for the treatment of HS, both as a monotherapy and as part of a combination.

SPY003 – a highly potent and selective investigational monoclonal antibody targeting the p19 subunit of interleukin 23 (“IL-23”), engineered with half-life extension technology and formulated at high concentration with the goal of maximizing efficacy and enabling infrequent, subcutaneous maintenance dosing. SPY003 is being evaluated for the treatment of IBD in the SKYLINE study.

SPY007 – a preclinical-stage program designed to bind to interleukin 17A (“IL-17A”) and interleukin 17F (“IL-17F”), while incorporating half-life extending modifications. SPY007 is being developed for the treatment of HS in combination with SPY072.

Rational Combinations (SPY120, SPY130, SPY230, and SPY772) – the Company is investigating combinations of its proprietary antibodies in clinical trials in order to evaluate whether combinations can potentially lead to best-in-class efficacy in several inflammatory diseases, with less frequent dosing.

•The Company is currently enrolling its SPY120, SPY130, and SPY230 combinations in Part B of the SKYLINE trial, with an expected induction read-out in 2027.

•The Company’s SPY772 combination program aims to target multiple inflammatory pathways involved in HS, pairing its novel anti-TL1A (SPY072) with SPY007, its anti-IL-17A/F. The goal is to use this long- acting, co-formulated combination in future advanced clinical development, pending the results from the Company’s SKYLIGHT proof-of-concept trial.