Spyre Therapeutics, Inc.

Item 7.01 Regulation FD Disclosure. SPY003 SKYLINE Part A Induction Topline Results On September 8, 2026, Spyre Therapeutics, Inc. (“Spyre” or the “Company”) issued a press release announcing positive 12-week induction topline data from Part A of the Phase 2 SKYLINE trial of SPY003, an anti-IL-23 being investigated for the treatment of moderately-to-severely active ulcerative colitis (“UC”). A copy of the press release is attached hereto as Exhibit 99.1. The information in this Item 7.01 of this Current Report on Form 8-K, including Exhibit 99.1 attached hereto, is intended to be furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or under the Exchange Act, except as expressly set forth by specific reference in such filing.

Item 8.01 Other Events. On September 8, 2026, the Company announced positive 12-week induction topline data from Part A of the Phase 2 SKYLINE trial of SPY003, an anti-IL-23 being investigated for the treatment of moderately-to-severely active UC. SPY003 SKYLINE Part A Induction Topline Results Efficacy: POC Established Across All Three Combination Components Initial 12-week findings from SKYLINE Part A demonstrated that SPY003 met all key objectives. The study population consisted of 41% advanced therapy-exposed participants with a mean disease duration of 7.1 years, a mean baseline Robarts Histopathology Index (“RHI”) score of 17.2 ± 8.3 (SD), a mean modified Mayo Score (“mMS”) of 6.9 ± 1.2 (SD), and 59% of whom had a baseline endoscopy score of 3. SPY003 achieved the primary endpoint, demonstrating a statistically significant 10.0-point reduction in RHI score (p<0.0001), robust rates of clinical remission and endoscopic improvement, and a meaningful change in mMS. The 10.0-point reduction in RHI observed in participants receiving SPY003 is in line with the 9.2- and 10.7-point reductions observed in participants receiving SPY001 and SPY002, respectively, and all are among the largest improvements observed in UC trials to date. Endpoint (Week 12) SPY003 Change in RHI from baseline -10.0 Primary endpoint (p<0.0001) Clinical remission rate 20% Endoscopic improvement rate 30% Change in modified Mayo Score -3.5 Safety: Well-Tolerated Profiles Across All Three Monotherapies Support Combination Development As previously reported, SPY001 and SPY002 were each well tolerated in Part A, with safety profiles consistent with their respective classes, and no drug-related serious adverse events. SPY003 was well tolerated with a safety profile consistent with the IL-23 class. There were 19 subjects with treatment-emergent adverse events (“TEAEs”) during the induction treatment period. Three serious adverse events (“SAEs”) were reported, deemed not drug-related. The most common adverse events (“AEs”) (occurring in ≥ 2 patients) were arthralgia (n=2), nasopharyngitis (n=2), and urinary tract infection (n=2). SPY003 Subjects with any AE (n, %) 19 (43%) Severe (Grade ≥ 3) AE 5 (11%)1 Drug-related AE 1 (2%)2 AE leading to drug discontinuation 0 SAE 3 (7%)3 Drug-related SAE 0 AEs of special interest 0 Death 0 1Ulcerative colitis flare, intervertebral disc protrusion, anaemia, urinary tract infection, and acute cholecystitis, each in one subject; all deemed not drug-related. 2Pruritus (Grade 1) that resolved without intervention or treatment interruption. 3Hospitalization for ulcerative colitis flare, hemorrhoid thrombosis, and acute cholecystitis, each in one subject; all deemed not drug-related. Data pertain to SPY003 (N=44) through Week 12 and data cut-off of July 27, 2026. Next Steps Clinical proof-of-concept across all three inflammatory bowel disease (“IBD”) programs strengthens the biological rationale for Spyre’s combination strategy and sets the stage for Part B of the SKYLINE trial, which is actively enrolling. Part B includes two dose levels of each monotherapy as well as three high-dose combination arms (SPY120, SPY130, and SPY230). Topline induction data from Part B are expected in 2027. The Company remains at the forefront of evaluating potential first- and best-in-class monotherapies and combinations in immunology and inflammation (“I&I”), with multiple expected topline readouts over the next 12-18 months: Trial Indication Asset(s) Expected timing SKYWAY Psoriatic Arthritis (“PsA”), Axial Spondyloarthritis (“axSpA”) SPY072 4Q 2026 SKYLINE Part B UC SPY001, SPY002, SPY003, SPY120, SPY130, SPY230 2027 SKYLIGHT Hidradenitis Suppurativa (“HS”) SPY072 + IL-17A/F Late 2027 or early 2028 ───────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────