Spyre Therapeutics, Inc. · NASDAQ:SYRE

Spyre Therapeutics — Investor Presentation (October 2026)

36 slides from Spyre Therapeutics's investor presentation, October 2026

  1. Slide 1: Corporate Overview

    CORPORATE OVERVIEW October 2026

  2. Slide 2: Disclosures

    Disclosures The information contained in this presentation has been prepared by Spyre Therapeutics, Inc. and its affiliates (“Spyre” or the “Company”) and contains information pertaining to the business and operations of the Company. The information contained in this presentation: (a) is provided as

  3. Slide 3: Building a diversified I&I portfolio across three large markets with high unmet need

    Building a diversified I&I portfolio across three large markets with high unmet need Gastroenterology Rheumatology Dermatology $40B+ 2030 Global market for UC and CD $10B+ 2030 Global market for PsA & axSpA $5B+ 2030 Global market for HS Three potential Potential Potential first- and best-in-class f

  4. Slide 4: Advancing a robust pipeline with exceptional financial strength

    Advancing a robust pipeline with exceptional financial strength Trial Indication Program Target Phase 1 Phase 2 Phase 3 Anticipated Milestones Gastro UC SPY120 α4β7 + TL1A SPY130 α4β7 + IL-23 2027: Ph2 POC SPY230 TL1A + IL-23 SPY001 α4β7 SPY002 TL1A 2027: Ph2 POC SPY003 IL-23 Rheum PsA 4Q 2026: Ph2

  5. Slide 5: Spyre programs aim to elevate the standard on efficacy, safety, and dosing across I&I

    Spyre programs aim to elevate the standard on efficacy, safety, and dosing across I&I Gastroenterology Rheumatology Dermatology Bubble size = $0.5B (2025 Sales) 60 50 40 Pbo-adjusted clinical remission (UC) 50 35 Pbo-adjusted HiSCR75 (HS) 40 Pbo-adjusted ACR50 (PsA) SPY230 | SPY772 40 Potential futu

  6. Slide 6: Multiple Phase 2 POC readouts expected across GI, rheum, and derm over the next ~18 months

    Multiple Phase 2 POC readouts expected across GI, rheum, and derm over the next ~18 months Gastroenterology Rheumatology Dermatology Ph2 platform trial evaluating SPY001, SPY002, Ph2 basket trial evaluating SPY072 in RA, Ph2 surrogate POC trial evaluating SPY072 + SPY003 and all pairwise combination

  7. Slide 7: Gastroenterology

    Gastroenterology UC CD SPY120 SPY130 SPY230 Target markets Key programs Trials

  8. Slide 8: Substantial unmet need remains for the millions of individuals living with IBD

    Substantial unmet need remains for the millions of individuals living with IBD • ~2.4M individuals in the U.S. are diagnosed with IBD (~1.3M UC and ~1.0M CD)1 • Substantial unmet need remains due to: – Minority remission rates and lack of durability with existing therapies – Side effects and safety

  9. Slide 9: JNJ's VEGA and DUET studies demonstrated the ability for combinations to break the monotherapy efficacy ceiling

    JNJ’s VEGA and DUET studies demonstrated the ability for combinations to break the monotherapy efficacy ceiling Naïve (1L) UC patients (VEGA) Refractory (3L+) UC patients (DUET-UC) ~Additive absolute W12 mMS clinical remission rate Synergistic absolute W48 mMS clinical remission rate  74% of patien

  10. Slide 10: Spyre is unique in developing uncompromising combinations from first principles

    Spyre is unique in developing uncompromising combinations from first principles Orthogonal MOAs rationally chosen Next-generation molecules engineered Developing coformulations optimized based on attractive risk-benefit profiles for best-in-class potential for infrequent, SC delivery α4β7 Optimized

  11. Slide 11: SKYLINE is a two-part study, with Part B combination evaluation now enrolling

    SKYLINE is a two-part study, with Part B combination evaluation now enrolling Part A: Open-label monotherapy evaluation (N=~130) Enrollment complete UC mMS 5-9 INDUCTION MAINTENANCE OBJECTIVES KEY ENDPOINTS SPY001 (α4β7) Monotherapy POC P Change in RHI at W12 Sequential activation SPY002 (TL1A) S Cl

  12. Slide 12: Monotherapies met all objectives in SKYLINE Part A, progressing Spyre's differentiated combination approach

    Monotherapies met all objectives in SKYLINE Part A, progressing Spyre’s differentiated combination approach SPY001 SPY002 SPY003 Combinations PART A PRIMARY ΔRHI from baseline -9.2 -10.7 -10.0 PART A SECONDARY % Clinical remission 40% 33% 20% 2027 Objective: % Endoscopic improvement 51% 42% 30% Deep

  13. Slide 13: SPY001, SPY002, and SPY003 demonstrated robust rates of clinical remission

    SPY001, SPY002, and SPY003 demonstrated robust rates of clinical remission Clinical remission Percentage of subjects α4β7 TL1A IL-23 S1P JAK mIR-124 50 42%1 40% 40 33% 32%1 30%1 30 27% 26% 26% 25%1 26%1 23% 24% 24% 20% 20%1 20 18% 18%1 10 0 SPY001 SPY001 Vedolizumab MORF057 SPY002 SPY002 Tulisokibar

  14. Slide 14: SPY001, SPY002, and SPY003 endoscopic improvement rates are among the highest reported

    SPY001, SPY002, and SPY003 endoscopic improvement rates are among the highest reported Endoscopic improvement Percentage of subjects α4β7 TL1A IL-23 S1P JAK mIR-124 60 51% 50 47%1 41% 42% 40%1 40%1 40 37% 36% 37% 32%1 33%1 33%1 30% 30%1 30 26% 27% 27% 20 10 0 SPY001 SPY001 Vedolizumab MORF057 SPY002

  15. Slide 15: SPY001, SPY002, and SPY003 performed similarly on change in partial Mayo score and fecal calprotectin over time

    SPY001, SPY002, and SPY003 performed similarly on change in partial Mayo score and fecal calprotectin over time Partial Mayo score (Δ ± 95% CI) Fecal calprotectin (fold Δ ± 95% CI) 0 1.00 SPY001 SPY002 SPY003 -1 0.75 -2 0.50 -3 0.25 -4 -5 W0 W2 W4 W6 W8 W12 W0 W6 W12 © 2026 Spyre Therapeutics, Inc.

  16. Slide 16: Monotherapy results establish a strong foundation for best-in-disease combination potential

    Monotherapy results establish a strong foundation for best-in- disease combination potential JNJ VEGA study 80 80 Clinical remission, Week 12 Clinical remission, Week 12 60 60 47% 40% 40 40 33% ’27 ’27 25% ’27 24% 20% 20 20 0 0 Anti-α4β7 Anti-TL1A Anti-IL-23 α4β7 + TL1A α4β7 + IL-23 TL1A + IL-23 Ant

  17. Slide 17: IBD treatment is moving to combination therapy and Spyre is positioned to lead with three differentiated combos

    IBD treatment is moving to combination therapy and Spyre is positioned to lead with three differentiated combos Target Sponsor Program MOAs Profile 1-m 2 3 4 5 6 7 8 9 10 11 12 Q3M-Q6M SPY120 α4β7+TL1A AI Q3M-Q6M SPY130 α4β7+IL-23 AI Q3M-Q6M SPY230 TL1A+IL-23 AI Q4W JNJ-4804 TNF+IL-23 AI Skyrizi + Q

  18. Slide 18: Best-in-class monotherapies provide foundation for paradigm-changing combinations for IBD

    Best-in-class monotherapies provide foundation for paradigm-changing combinations for IBD Potential for best-in-indication positioning (UC example) Target product profiles 60 Monos: Comparable-to-better efficacy vs. standard of care Pbo-adjusted clinical remission (UC) $1B 2025 Sales 50 Combos: Mean

  19. Slide 19: Rheumatology

    Rheumatology PsA axSpA SPY072 SPY772 SPY230 Target markets Key programs Trials

  20. Slide 20: Substantial unmet need remains for the millions of individuals living with PsA and axSpA

    Substantial unmet need remains for the millions of individuals living with PsA and axSpA • ~2M individuals in the U.S. diagnosed with PsA (~1M1), and axSpA (~1M2) • Substantial unmet need remains due to: – Minority remission rates, inability to control multiple aspects of disease, and lack of durabi

  21. Slide 21: Spyre anti-TL1A antibody meets or exceeds the efficacy of etanercept in rat models of arthritis

    Spyre anti-TL1A antibody meets or exceeds the efficacy of etanercept (anti-TNF) in rat models of arthritis Superior efficacy in semi-preventative model Comparable efficacy in therapeutic model Collagen Treatment period Collagen Treatment period 8 8 Healthy Healthy Vehicle Vehicle Isotype control Iso

  22. Slide 22: Anti-TL1A treatment led to comparable improvements in psoriatic skin lesions in mouse IMQ model

    Additionally, anti-TL1A treatment led to comparable improvements in psoriatic skin lesions in mouse IMQ model Anti-TL1A reduces skin lesions Comparable efficacy to anti-IL-23 and anti-TNF 6 Histopathology Score 4 10 Healthy control Disease control 2 8 anti-TL1A **** **** **** PASI Scores (0-12) anti

  23. Slide 23: SKYWAY Phase 2 basket study evaluating SPY072 (anti-TL1A) in RA, PsA, and axSpA

    SKYWAY Phase 2 basket study evaluating SPY072 (anti-TL1A) in RA, PsA, and axSpA Sub-study A: SPY072 in moderate-to-severely active rheumatoid arthritis (RA) DOUBLE-BLIND OPEN-LABEL FOLLOW UP KEY INCLUSION KEY ENDPOINTS SPY072 Dose A Swollen joint count ≥ 4 Change in DAS28-CRP at W12 RA 1:1:1 P N=143

  24. Slide 24: SPY072 is a potential first-in-class & best-in-class therapy for rheumatic diseases

    SPY072 is a potential first-in-class & best-in-class therapy for rheumatic diseases Potential for best-in-indication positioning SPY072 target product profile 50 $0.5B 2025 Sales First-in-class anti-TL1A Pbo-adjusted ACR50 (PsA) Comparable-to-better efficacy 40 SPY230 | SPY772 Potential future expan

  25. Slide 25: Dermatology

    Dermatology HS SPY772 Target markets Key programs Trials

  26. Slide 26: Hidradenitis suppurativa remains underdiagnosed and inadequately controlled, creating substantial lifelong burden

    Hidradenitis suppurativa remains underdiagnosed and inadequately controlled, creating substantial lifelong burden • HS is a chronic, recurrent inflammatory skin disease estimated to affect ~3M U.S. patients, though estimates vary widely and diagnosis is often delayed by 7-10 years • Substantial unme

  27. Slide 27: Dual targeting of clinically validated TL1A & IL-17A/F pathways to address complementary drivers of HS

    Our approach: Dual targeting of clinically validated TL1A & IL-17A/F pathways to address complementary drivers of HS TL1A and IL-17A/F are clinically validated targets in HS Biological & translational rationale for TL1A + IL-17A/F in HS HS disease pathogenesis IL-17A/F-driven Overlapping TL1A-driven

  28. Slide 28: SKYLIGHT is a Phase 2 study evaluating dual inhibition of TL1A and IL-17A/F

    SKYLIGHT is a Phase 2 study evaluating dual inhibition of TL1A and IL-17A/F STUDY OBJECTIVE Participants with moderate to severe HS Combination efficacy and safety versus  18-75 years of age bimekizumab monotherapy  HS lesions in ≥2 anatomical areas, with ≥1 area meeting SPY072 (TL1A) + bimekizuma

  29. Slide 29: SPY772 combines our novel anti-TL1A and anti-IL-17A/F antibodies

    SPY772 combines our novel anti-TL1A and anti-IL-17A/F antibodies SPY772 design principles SPY772 development strategy SPY072 SPY772 + Surrogate POC SPY072 SPY007 SKYLIGHT POC & SPY007 timelines aligned TL1A IL-17A/F for future development SPY007 Phase 1/1b High target potency Long-acting SPY772 Adva

  30. Slide 30: SPY772 has the potential to become a best-in-indication therapy for HS

    SPY772 has the potential to become a best-in-indication therapy for HS Potential for best-in-indication positioning SPY772 target product profile 50 45 0.5B 2025 Sales Meaningfully improved efficacy 40 vs. standard of care Pbo-adjusted HiSCR75 35 30 SPY772 Target Profile Favorable safety profile 25

  31. Slide 31: Catalysts & capitalization

    Catalysts & capitalization SPYRE

  32. Slide 32: Capitalized to deliver one of the industry's most compelling catalyst maps

    Capitalized to deliver one of the industry's most compelling catalyst maps Trial 2026 2027  SPY001 α4β7 Ph2 UC induction POC   SPY001 α4β7 Ph2 UC maintenance data  SPY002 TL1A Ph2 UC induction POC   SPY002 TL1A Ph2 UC maintenance data  SPY003 IL-23 Ph2 UC induction POC (Sept. 2026)   SPY003

  33. Slide 33: Cash and shares outstanding

    Cash and shares outstanding $1.1B cash as of June 30, 2026 1 Expected runway into 2H 2029 Number of shares (M) Common stock2 Shares outstanding 88.1 Common stock Series A preferred stock 13.8 equivalents3 Common stock and common stock Total outstanding 101.9 equivalents2,3 1Reflects cash, cash equiv

  34. Slide 34: Elevate the Standard in Immunology

    ELEVATE THE STANDARD IN IMMUNOLOGY

  35. Slide 35: 2026 PsA readout: Aiming for ACRs and PASI comparable-to-better than SOC analogs

    2026 PsA readout: Aiming for ACRs and PASI comparable-to- better than SOC analogs Appendix Primary endpoint Secondary & exploratory endpoints Placebo-adjusted % (W12-24) Placebo-adjusted % (W12-24) 100 80 Upside 60 Min. ~30% ~20% 40 ~15% IL-23 IL-17 TNF IL-17 20 TNF IL-17 TNF IL-23 JAK JAK IL-17 JAK

  36. Slide 36: 2026 axSpA readout: Aiming for ΔASDAS and ASAS comparable-to-better than SOC analogs

    2026 axSpA readout: Aiming for ΔASDAS and ASAS comparable-to-better than SOC analogs Appendix Primary endpoint Secondary & exploratory endpoints Placebo-adjusted ΔASDAS (W12-16)1 Placebo-adjusted % (W12-16)2 Cosentyx Bimzelx Xeljanz Rinvoq 0.0 100 80 IL-17 JAK -0.4 60 JAK IL-17 ~25% 40 ~25% -0.8 20

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