Slide 1: Anti-TL1A Phase 1 Results and Phase 2 Development Updates
Exhibit 99.2 Anti-TL1A Phase 1 Results and Phase 2 Development Updates June 2025
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
Slide 3: Agenda
Agenda Cameron Turtle, DPhil Introduction and Executive Summary Chief Executive Officer Joshua Friedman, MD, PhD SPY002 & SPY072 Phase 1 Interim Results SVP, Clinical Development Deanna Nguyen, MD SKYLINE-UC Phase 2 Study SVP, Clinical Development Joshua Friedman, MD PhD SKYWAY-RD Phase 2 Study SVP,
Slide 4: Introduction: Today's Objectives
Introduction Today’s 1 2 3 Objectives Report Launch Unveil Anti-TL1A data SKYLINE-UC SKYWAY-RD Phase 1 results for two A Phase 2 platform study A Phase 2 basket study potential best-in-class in ulcerative colitis evaluating anti-TL1A in molecules evaluating three three rheumatologic monotherapies &
Slide 5: Engineering for new heights in the treatment of IBD & beyond
Engineering for new heights in the treatment of IBD & beyond Validated targets Half-life extension Fixed-dose combinations Engineered for prolonged activity to enable Rationale combinations to address distinct MOAs rationally chosen based on attractive infrequent administration disease drivers risk-
Slide 6: Two anti-TL1A antibodies advanced into Ph1 with best-in-class preclinical properties
Recall: We advanced two anti-TL1A antibodies into Ph1 with best-in-class preclinical properties SPY002 (formerly SPY002-091) SPY072 (formerly SPY002-072) In vitro potency (TF-1 apoptosis) In vitro potency (TF-1 apoptosis) 100 100 80 80 60 60 40 40 20 20 SPY002 SPY072 Tulisokibart 0 Tulisokibart 0 0.
Slide 7: SPY002 and SPY072 met Phase 1 objectives, advancing into Phase 2
SPY002 and SPY072 met Phase 1 objectives, and Spyre plans to advance both into Phase 2 SPY002 SPY072 Simulated mean PK profiles Median PD profiles Simulated mean PK profiles Median PD profiles SPY002 SPY072 Placebo Placebo st st 1 gen 1 gen SPY002 SPY072 anti-TL1As anti-TL1As Well tolerated PK suppo
Slide 8: Transitioning to a mid-stage development company
Transitioning to a mid-stage development company… PHASE 1 PHASE 2 PHASE 3 P PH HA AS SE E 2 2 S SP PY Y0 00 01 1 S SP PY Y0 00 02 2 S SP PY Y0 00 01 1 S Su uc cc ce es ss sffu ull iin nv ve es sttiig ga attiio on na all a ag ge en ntts s 2H S SP PY Y0 00 03 3 P Ph h2 2 p plla attffo or rm m ttr riia
Slide 9: Two innovative and capital-efficient Phase 2 trials
…with two innovative and capital-efficient Phase 2 trials Ph2 platform trial evaluating SPY001, SPY002, SPY003 Ph2 basket trial evaluating SPY072 in rheumatoid and pairwise combinations in ulcerative colitis arthritis, psoriatic arthritis, and axial spondyloarthritis SPY072 Dose A SPY001 RA UC SPY07
Slide 10: Anticipated proof-of-concept readouts in 2026-27
Anticipated 9 proof-of-concept readouts in 2026-27 for the treatment of IBD & beyond Trial Indication Program Target Phase 1 Phase 2 Phase 3 Anticipated Milestones α4β7 UC SPY001 2026: Ph2 open-label POC TL1A SPY002 2027: Ph2 pbo-controlled data IL-23 SPY003 SPY120 α4β7 + TL1A 2027: Ph2 POC SPY130 α
Slide 11: Potential additive paths to significant value creation in 2026-27
Potential additive paths to significant value creation in 2026-27 mid- 2026 2027 2025 Trial Phase 1s 2H 2025 Programs SPY001 SPY002 SPY072 SPY003 SPY001 SPY002 SPY003 SPY072 SPY120 SPY130 SPY230 Interim safety, PK, PD Monotherapy OL POC Anti-TL1A POC Combination POC Readout HVs UC RA, PsA, axSpA UC
Slide 12: SPY002 and SPY072 Phase 1 interim results
SPY002 and SPY072 Phase 1 interim results Today’s 1 2 3 Objectives Report Launch Unveil Anti-TL1A data SKYLINE-UC SKYWAY-RD Phase 1 results for two A Phase 2 basket study A Phase 2 platform study potential best-in-class evaluating anti-TL1A in in ulcerative colitis molecules three rheumatologic eval
Slide 13: Ph1 SAD studies with interim data up to 20 weeks
Both molecules studied in similar Ph1 SAD studies, with interim data up to 20-weeks of follow up Trial design elements SPY002 and SPY072 SAD PK and safety follow up Design 20 weeks 100 mg SC • Double-blind, pbo-controlled, first-in-human trial 16 weeks • Escalating SAD cohorts 16 weeks 300 mg SC 12
Slide 14: SPY002 and SPY072 well tolerated with favorable safety profile
SPY002 and SPY072 were well tolerated with a favorable safety profile (pooled, blinded data) SPY002 safety profile SPY072 safety profile SAD SAD N (%) 100 mg 300 mg 300 mg 1000 mg 1500 mg Pooled 100 mg 300 mg 300 mg 1000 mg 1500 mg Pooled N= 8 8 8 8 8 40 8 8 8 8 8 40 At least one 3 (38%) 2 (25%) 3 (
Slide 15: Prolonged and dose proportional PK
SPY002 and SPY072 demonstrated prolonged and dose proportional PK SPY002 mean PK profiles SPY072 mean PK profiles ~75-day t Pending t 1/2 1/2 Waiting for comparable follow-up to accurately estimate half-life © 2025 Spyre Therapeutics, Inc. Interim analysis as of May 30, 2025 data cutoff. 15 All righ
Slide 16: SPY072 showed comparable PK to SPY002
SPY072 showed comparable PK to SPY002 at clinically relevant doses through available follow up SPY002 & SPY072 mean PK profiles (IV) SPY002 & SPY072 mean PK profiles (SC) 1000 mg IV (N=6) 300 mg SC (N=6) Remove 1500 SPY072 Pending t Pending t SPY072 300 mg IV (N=6) 1/2 100 mg SC (N=6) 1/2 1000 mg IV
Slide 17: Suppressed free TL1A through 20 weeks of follow-up
SPY002 and SPY072 suppressed free TL1A through 20- weeks of follow-up at the lowest dose tested SPY002 median free sTL1A PD profiles SPY072 median free sTL1A PD profiles © 2025 Spyre Therapeutics, Inc. Interim analysis as of May 30, 2025 data cutoff. Median values below LLOQ of 8pg/mL plotted as one
Slide 18: Increased total TL1A in a durable, dose-dependent manner
SPY002 and SPY072 increased total TL1A in a durable and dose-dependent manner SPY002 mean total sTL1A PD profiles SPY072 mean total sTL1A PD profiles © 2025 Spyre Therapeutics, Inc. Interim analysis as of May 30, 2025 data cutoff. 18 All rights reserved.
Slide 19: Interim PK supports quarterly or twice annual dosing
Interim PK supports quarterly or twice annual dosing Afimkibart Ph2 UC results SPY002 simulated concentration-time profile SPY002 Q3M 50 mg Q4W Induction Maintenance Clinical remission by mMS SPY002 Q6M 150 mg Q4W % 2-4x SC maintenance injections per year 450 mg Q4W 50 39% 40 38% 36% Afimkibart simu
Slide 20: SPY002 and SPY072 Phase 1 interim results summary
SPY002 and SPY072 Phase 1 interim results summary xx Favorable safety profile across all dose levels Well-tolerated Extended half-lives support potential for quarterly or twice annual xx Prolonged PK exposure dosing Rapid & sustained target xx PD was durable through 20-weeks at the lowest dose teste
Slide 21: SKYLINE-UC Phase 2 study
SKYLINE-UC Phase 2 study Today’s 1 2 3 Objectives Report Launch Unveil Anti-TL1A data SKYLINE-UC SKYWAY-RD Phase 1 results for two A Phase 2 platform study A Phase 2 basket study potential best-in-class in ulcerative colitis evaluating anti-TL1A in molecules evaluating three three rheumatologic mono
Slide 22: SKYLINE-UC: Phase 2 platform study in UC
SKYLINE-UC: Phase 2 platform study evaluating three monotherapies and three combinations in UC Part A: Open-label monotherapy evaluation (N=~100) KEY ENDPOINTS OBJECTIVES UC mMS 5-9 INDUCTION MAINTENANCE P Monotherapy POC Change in RHI at W12 SPY001 (α4β7) Sequential S activation SPY002 (TL1A) Clini
Slide 23: Capital-efficient trial designed to be attractive to patients and investigators
Capital-efficient trial that is designed to be attractive to patients and investigators CAPTIAL EFFICIENT PATIENT CENTRIC STREAMLINED UNIFIED DOSING PART A PART B INDUCTION MAINTENANCE 6 actives 40% vs. Open-label 1 placebo Cost savings and reduced sample size compared to individual Ph2 studies for
Slide 24: Portfolio enables product profiles with potential superior efficacy and convenience
Spyre’s portfolio uniquely enables product profiles with potential superior efficacy and convenience ILLUSTRATIVE 80 60 Potential to break the efficacy ceiling with 40 SPY120 SPY130 SPY230 combinations JNJ’4804 TNF+IL-23 combo Potential for best-in-class 1 (VEGA ) efficacy with higher exposures SPY0
Slide 25: Co-administration of mAbs can reduce immunogenicity versus bispecifics
Co-administration of mAbs can reduce immunogenicity whereas bispecific formats can increase immunogenicity ADA rates for TNF or TL1A bsAbs vs. coformulations Case studies Asset Target Immunogenicity Population Structure IL-23 dimer JNJ-4804 coformulation TNF trimer guselkumab Gol golimumab + Separat
Slide 26: SKYLINE-UC: on-track for expected 6 POC readouts through 2027
SKYLINE-UC: First patients in screening and on-track for expected 6 POC readouts through 2027 2H 2025 2026 2027 6 POC readouts 3 POC readouts Phase 1 q SPY003 Ph1 ü q Ph2 Initiation Part A monotherapy results Part B monotherapy results q SPY001 (α4β7) open-label POCq SPY001 (α4β7) pbo-controlled dat
Slide 27: SKYWAY-RD Phase 2 study
SKYWAY-RD Phase 2 study Today’s 1 2 3 Objectives Report Launch Unveil Anti-TL1A data SKYLINE-UC SKYWAY-RD Phase 1 results for two A Phase 2 platform study A Phase 2 basket study potential best-in-class in ulcerative colitis evaluating anti-TL1A in molecules evaluating three three rheumatologic monot
Slide 28: SKYWAY-RD: Phase 2 basket study of SPY072 in RA, PsA, axSpA
SKYWAY-RD: 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 ENDPOINTS KEY INCLUSION SPY072 Dose A P Swollen joint count ≥ 4 Change in DAS28-CRP at W12 RA 1:1:1 S
Slide 29: Operationally-efficient design with shared sites and specialty
Operationally-efficient design with shared sites and specialty CAPITAL EFFICIENT SHARED SITES SHARED SPECIALTY Reduced total site requirement Increased investigator productivity 50% 100 RA patients PsA 20 PsA patients RA 30 35% 50 axSpA patients axSpA 50 Separate studies SKYWAY-RD Cost savings compa
Slide 30: TL1A is upregulated in RA, PsA, and axSpA
TL1A is upregulated in RA, PsA, and axSpA relative to healthy controls Axial spondyloarthritis Rheumatoid arthritis Psoriatic arthritis 800 ✱✱✱✱ ✱✱ ✱✱✱ ✱✱ 600 400 200 0 Healthy axSpA Control Source Whole blood Skin biopsy Whole blood Sequencing Microarray Bulk RNA seq Microarray Sample size N=192 RA
Slide 31: Anti-TL1A antibody versus etanercept in rat arthritis models
Spyre anti-TL1A antibody met or exceeded the efficacy of etanercept (anti-TNF) in rat models of arthritis Superior efficacy vs. anti-TNF in semi-preventative model Comparable efficacy vs. anti-TNF in therapeutic model Collagen Treatment period Collagen Treatment period * * * * * © 2025 Spyre Therape
Slide 32: SPY072 potential first-in-class therapy for rheumatologic conditions
SPY072 is a potential first-in-class therapy for rheumatologic conditions with anticipated Q3M-Q6M dosing ILLUSTRATIVE 60 50 40 axSpA Potential for novel MOA with comparable-to-better PsA efficacy and improved SC dosing frequency (Q3M-Q6M) 30 RA 20 Today’s SOC 10 0 1 2 3 4 5 6 Dosing interval (month
Slide 33: SKYWAY-RD: POC readouts expected through 2026
SKYWAY-RD: 3 POC readouts expected through 2026 2H 2025 2026 2027 6 POC readouts 3 POC readouts Phase 1 q SPY003 Ph1 ü q Ph2 Initiation Part A monotherapy results Part B monotherapy results q SPY001 (α4β7) open-label POCq SPY001 (α4β7) pbo-controlled data Phase 2 platform study q SPY002 (TL1A) open-
Slide 34: Closing and Q&A
Closing and Q&A Today’s Spokespeople Cameron Turtle Josh Friedman Deanna Nguyen Sheldon Sloan Scott Burrows Chief Executive Officer Chief Financial Officer SVP, Clinical SVP, Clinical Chief Medical Officer Development Development © 2025 Spyre Therapeutics, Inc. 34 All rights reserved.
Slide 35: Anticipated proof-of-concept readouts and cash runway
Anticipated 9 proof-of-concept readouts in 2026-27 for the treatment of IBD & beyond 1 $565M cash 2H 2025 2026 2027 Runway into 2H 2028 6 POC readouts 3 POC readouts Phase 1 q SPY003 Ph1 ü q Ph2 Initiation Part A monotherapy results Part B monotherapy results q SPY001 (α4β7) open-label POCq SPY001 (
Slide 36: Thank you
Thank you Engineering for new heights in the treatment of IBD and beyond