Spyre Therapeutics (SYRE) Status Update summary

Interim Phase 1 Results and Clinical Development Plans

• SPY002 and SPY072 demonstrated favorable safety, tolerability, and pharmacokinetics, with no grade 3/4 adverse events, supporting quarterly or twice-annual dosing and a half-life of approximately 75 days, over three times longer than first-generation molecules.

• Both antibodies achieved full suppression of TL1A for up to 20 weeks at the lowest dose tested, with no significant impact of anti-drug antibodies on pharmacokinetics or pharmacodynamics.

• Most adverse events were mild, with COVID-19 and nausea being the most frequent; no events exceeded Grade 2 severity.

• Both molecules showed low immunogenicity and prolonged half-lives, with ongoing monitoring for anti-drug antibodies.

• SPY002 is advancing to the SKYLINE-UC Phase 2 study in ulcerative colitis, while SPY072 will move to the SKYWAY-RD Phase 2 basket study in rheumatologic diseases.

Phase 2 Trial Designs and Timelines

• SKYLINE-UC is a platform Phase 2 trial in ulcerative colitis, evaluating three monotherapies and three combinations, with induction data expected in 2026 and 2027.

• SKYWAY-RD is a Phase 2 basket study of SPY072 in rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis, starting in Q3 2025, with proof-of-concept data expected in 2026.

• Both trials are designed for capital efficiency, with SKYLINE-UC and SKYWAY-RD expected to deliver 40% and 35% cost savings, respectively, compared to separate studies.

• Nine proof-of-concept readouts are anticipated across both programs in 2026-2027, supported by a cash runway into the second half of 2028.

• SKYWAY-RD will include double-blind, placebo-controlled sub-studies for each rheumatologic condition, with open-label follow-up.

Competitive Positioning and Strategic Rationale

• Anti-TL1A antibodies target validated pathways in IBD and rheumatologic diseases, with preclinical data showing superior or comparable efficacy to anti-TNF agents.

• Combination and co-formulation strategies are designed to maximize efficacy and minimize immunogenicity, with potential to break the efficacy ceiling in IBD.

• The portfolio avoids targets with black box warnings, aiming for superior safety and efficacy compared to TNF-based combinations.

• Market opportunities for targeted indications exceed $60B in annual revenue.

• The platform and basket trial designs enable rapid, cost-effective identification of optimal product candidates for pivotal studies.