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CORPORATE OVERVIEW November 2025
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2 © 2025 Spyre Therapeutics, Inc. All rights reserved. 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 at the date hereof, is subject to change without notice, and is based on publicly available information, internally developed data as well as third party information from other sources; (b) does not purport to contain all the information that may be necessary or desirable to fully and accurately evaluate an investment in the Company; (c) is not to be considered as a recommendation by the Company that any person make an investment in the Company; (d) is for information purposes only and shall not constitute an offer to buy, sell, issue or subscribe for, or the solicitation of an offer to buy, sell or issue, or subscribe for any securities of the Company in any jurisdiction in which such offer, solicitation or sale would be unlawful. Where any opinion or belief is expressed in this presentation, it is based on certain assumptions and limitations and is an expression of present opinion or belief only. This presentation should not be construed as legal, financial or tax advice to any individual, as each individual’s circumstances are different. This document is for informational purposes only and should not be considered a solicitation or recommendation to purchase, sell or hold a security. Forward-Looking Information Certain information set forth in this presentation contains “forward-looking statements” within the meaning of applicable United States securities legislation. Except for statements of historical fact, certain information contained herein constitutes forward- looking statements which include but are not limited to statements regarding: our business strategy, including our ability to develop best-in-class and first-in-class therapeutics for inflammatory bowel disease (IBD), rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpA) and other immune-mediated diseases that meaningfully improve both efficacy and convenience compared to today’s standard of care; the potential consistency of the SPY001, SPY002, SPY072 and SPY003 Phase 1 trial final data readouts with previously disclosed data for our programs; the efficacy, safety profile, dosing regime, convenience, commercial viability and tolerability of SPY001, SPY002, SPY072 and SPY003, including combinations; Spyre’s ongoing and future clinical development activities, including the expected timing of the ongoing platform SKYWAY Phase 2 basket trial, including timing of data readouts, plans for and timing of cohort initiation and data readouts for the ongoing SKYLINE Phase 2 platform trial, enrollment of clinical trials and number of data readouts expected to be delivered in 2026 and 2027 and the advancement of SPY003 to the SKYLINE Phase 2 platform trial; our ability to provide anticipated readouts ahead of any disclosed bispecific approaches against our targets; the planned induction and maintenance dosing regimen for SPY001 and our other product candidates, including the potential for a Q3M-Q6M dosing profile; the potential therapeutic benefits of our product candidates as monotherapies or in combinations and their extended half-life, including the expected duration of half-life in comparison to competitor products; potential cost savings from the trial designs of our Phase 2 platform trial and Phase 2 basket trial; potential alignment with regulatory authorities and anticipated regulatory submissions; expected timing for regulatory feedback; estimated market sizes, potential growth opportunities, potential value creation and sample transactions; the length of time that the Company believes its existing cash resources will fund its operations, including expectations of cash runway extending into the second half of 2028; expectations regarding our potential therapeutic combinations, including dosing regime, and the potential benefits thereof; and management’s assessment of future plans and operations which are based on current internal expectations, estimates, projections, assumptions and beliefs, which may prove to be incorrect. Forward-looking statements can often be identified by the use of words such as “may”, “will”, “could”, “would”, “anticipate”, ‘believe”, expect”, “intend”, “potential”, “estimate”, “scheduled”, “plans”, “planned”, “forecasts”, “goals” and similar expressions or the negatives thereof. Forward- looking statements are neither historical facts nor assurances of future performance. Forward-looking statements are based on a number of factors and assumptions made by management and considered reasonable at the time such information is provided, and forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause the actual results, performance or achievements to be materially different from those expressed or implied by the forward-looking statements, including uncertainties and risks arising from regulatory feedback, including potential disagreement by regulatory authorities with our clinical trial design, interpretation of data and our ongoing or planned clinical trials for our product candidates, including our plans for and timing of cohort initiation for combination therapy arms for the ongoing SKYLINE Phase 2 platform trial across different jurisdictions; the potential for final clinical data not being consistent with or different than the previously disclosed data for our programs; the expected or potential impact of macroeconomic conditions, including inflationary pressures, rising interest rates, general economic slowdown or a recession, changes in tariff/trade and monetary policy, volatile market conditions, financial institution instability, as well as geopolitical instability, including the ongoing military conflicts between Ukraine and Russia, conflicts in the Middle East, and geopolitical tensions between the United States and other countries, including China, on our operations; the implementation of changes in law, tariffs, sanctions, export or import controls, and other government measures that could impact our business operations, including restricting international trade by the United States, China or other countries and the BIOSECURE Act or similar act if passed into law; the impacts of adverse events or disappointing results in clinical trials of third parties, including our competitors developing product candidates that target similar mechanisms of action and/or indications as our product candidates; and those uncertainties and factors described under the heading “Risk Factors,” “Risk Factor Summary” and “Note about Forward-Looking Statements” in the Company’s most recent Annual Report on Form 10-K, as supplemented and updated by subsequent Quarterly Reports on Form 10-Q and Current Reports on Form 8-K that the Company has filed or will file with the SEC, as well as discussions of potential risks, uncertainties, and other filings by the Company from time to time, as well as risk factors associated with companies that operate in the biopharma industry, including those associated with the uncertainties of drug development. All of the forward-looking statements made in this presentation are qualified by these cautionary statements and other cautionary statements or other factors contained herein. Although management believes that the expectations conveyed by forward-looking statements herein are reasonable based on information available on the date such forward-looking statements are made, there can be no assurance that forward looking statements will prove to be accurate, as actual results and future events could differ materially from those anticipated in such statements. T he Company undertakes no obligation to update forward-looking statements if circumstances or management’s estimates or opinions should change except as required by applicable securities laws. The forward-looking statements contained herein are presented for the purposes of assisting readers in understanding the Company’s plan, objectives and goals and may not be appropriate for other purposes. The reader is cautioned not to place undue reliance on forward-looking statements Industry Information This presentation also contains or references certain industry data that is based upon information from independent industry publications, market research, and surveys and other publicly available sources. Although the Company believes these sources to be generally reliable, such information is subject to interpretation and cannot be verified with complete certainty due to limits on the availability and reliability of data, the voluntary nature of the data gathering process and other inherent limitations and uncertainties. The Company has not independently verified any of the data from third party sources referred to in this presentation and accordingly, the Company makes no representation or warranty as to the origin, validity, accuracy, completeness, currency or reliability of the information in this presentation.
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3 © 2025 Spyre Therapeutics, Inc. All rights reserved. Nine proof-of-concept readouts expected in 2026-27 Milestones expected as of the date of this presentation. 1Reflects cash includes cash, cash equivalents, & marketable securities as of 9/30/25 of $486.2 million plus $296.5 million in net proceeds from the recently closed October 2025 underwritten public offering of common stock; UC=ulcerative colitis; RD=rheumatic disease; RA=rheumatoid arthritis; PsA=psoriatic arthritis; axSpA=axial spondyloarthritis; POC=proof of concept $783 million pro forma cash as of September 30, 20251, with expected runway into 2H 2028 Trial Indication Program Target Phase 1 Phase 2 Phase 3 Anticipated Milestones UC SPY001 2026: Ph2 open-label POC 2027: Ph2 pbo-controlled dataSPY002 SPY003 SPY120 2027: Ph2 POCSPY130 SPY230 RA SPY072 2026: Ph2 POCPsA axSpA α4β7 TL1A IL-23 α4β7 + TL1A α4β7 + IL-23 TL1A + IL-23 TL1A
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4 © 2025 Spyre Therapeutics, Inc. All rights reserved. Engineering for new heights in the treatment of IBD & beyond Validated targets Half-life extension Fixed-dose combinations Concept image of drug delivery device shown for illustrative purposes only. Coformulations TL1A IL-23 α4β7 MOAs rationally chosen based on attractive risk-benefit profiles Engineered for prolonged activity to enable infrequent administration Rational combinations to address distinct disease drivers Potential best-in-class monotherapies & combinations in IBD Potential first-in-class anti-TL1A in rheumatic diseases YTE
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5 © 2025 Spyre Therapeutics, Inc. All rights reserved. Our next-generation antibodies are engineered to match or exceed the potency of first-generation molecules SPY001 (α4β7) potency SPY002 (TL1A) potency SPY003 (IL-23) potency Data on file. Potency refers to in vitro potency: SPY001 assay reports inhibition of cells expressing a4b7 binding to MAdCAM-1. SPY002 assay reports inhibition of TL1A-induced apoptosis in TF-1 cells. SPY003 assay reports inhibition of cellular STAT3 signaling. Vedolizumab, tulisokibart, and risankizumab are synthesized comparator antibodies. 0.01 0.1 1 10 0 10 20 30 40 50 60 mAb Concentration (nM) %Inhibition 0.001 0.01 0.1 1 10 100 0 50 100 mAb Concentration (nM) % Inhibition 0.001 0.01 0.1 1 10 100 0 20 40 60 80 100 mAb Concentration (nM) Inhibition % Potential for comparable efficacy at similar or lower doses Potential upside: Improved efficacy with higher exposures Vedolizumab SPY001 Tulisokibart Risankizumab SPY002 SPY003 α4β7 TL1A IL-23
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6 © 2025 Spyre Therapeutics, Inc. All rights reserved. Each of our programs harness the body’s natural recycling mechanism for antibodies to prolong activity YTE modification YTE-modified mAbs are returned to circulation for continued activity mAb=monoclonal antibody; FcRn=neonatal Fc receptor Antibodies are subject to degradation when internalized YTE modification increases internal binding to FcRn FcRn binding promotes recycling of mAbs to circulation YTE FcRn YTE
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7 © 2025 Spyre Therapeutics, Inc. All rights reserved. YTE modification significantly extends half-life, supporting potential for quarterly or twice annual dosing SPY001 human PK simulation SPY002 human PK simulation SPY003 human PK simulation SPY001 PK simulation based on PK data as of 03/19/2025 cutoff; SPY002 PK simulation based on PK data from 5/31/2025 cutoff; SPY003 PK simulation based on PK data from 9/15/2025 cutoff. Vedolizumab, Afimkibart, and Risankizumab simulations based on published data (Rosario, M, et. al. (2015); Danese, Silvio, et al. (2024) Thakre, Neha et. al. (2024); no head-to-head clinical trials have been conducted. Concept image of drug delivery device shown for illustrative purposes only. Vedolizumab SPY001 Afimkibart Risankizumab SPY002 SPY003 2-4 Maintenance doses per year 2-4 Maintenance doses per year 2-4 Maintenance doses per year Target Profiles
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8 © 2025 Spyre Therapeutics, Inc. All rights reserved. Developing potential paradigm-changing combination therapies in IBD Inflammatory bowel disease Rational combinations targeting diverse disease drivers Potential Q3M-Q6M chronic dosing interval based on PK modeling. Concept image of drug delivery device shown for illustrative purposes only. Target Q3M-Q6M maintenance dosing SPY120 SPY130 SPY230 α4β7 TL1A IL-23 α4β7 TL1A IL-23 IBD
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9 © 2025 Spyre Therapeutics, Inc. All rights reserved. Expanding into rheumatic diseases with a distinct anti-TL1A Rheumatic diseases Potential first-in-class anti-TL1A Potential Q3M-Q6M chronic dosing interval based on PK modeling. SPY072 Rheumatoid arthritis Psoriatic arthritis Axial spondyloarthritis Target Q3M-Q6M chronic dosing RA axSpA PsA
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10 © 2025 Spyre Therapeutics, Inc. All rights reserved. Transitioning to a mid-stage development company with two innovative Ph2 clinical trials 1Savings relative to separate Ph2 trials for each program (SKYLINE) or indication (SKYWAY) 6 INTERVENTIONS 1 INDICATION COST SAVINGS1 1 INTERVENTION 3 INDICATIONS COST SAVINGS1 40% 35% PsA axSpA RA SPY072 high SPY072 low Placebo SPY072 Placebo SPY072 Placebo UC Placebo SPY001 SPY002 SPY003 SPY120 SPY130 SPY230 MonosCombos Ph2 platform trial evaluating SPY001, SPY002, SPY003 and pairwise combinations in ulcerative colitis Ph2 basket trial evaluating SPY072 in rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis Initiated 2Q 2025 Initiated 3Q 2025
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11 © 2025 Spyre Therapeutics, Inc. All rights reserved. Potential additive paths to significant value creation in 2026-27 Milestones expected as of the date of this presentation. 1Precedent valuations provided for illustrative purposes only and may not be indicative of potential Spyre valuation; 2Vertex valuation following proof-of-concept for first Phase 2 combination study of VX-770 and VX-809. OL=open label; Check marks refer to interim Ph1 results. 2026 2027 Trial Phase 1s Programs SPY001 SPY002 SPY072 SPY003 SPY001 SPY002 SPY003 SPY072 SPY120 SPY130 SPY230 Readout Interim safety, PK, PD HVs Monotherapy OL POC UC Anti-TL1A POC RA, PsA, axSpA Combination POC UC Analog type Validated MOA, improved convenience First-in-class MOA in $30B+ market Paradigm-changing combinations Precedent1 $3B+ acquisition $10B+ acquisition $10B+ post-POC2 Q4 2025
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Inflammatory bowel disease Potential best-in-class monotherapies and combinations
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13 © 2025 Spyre Therapeutics, Inc. All rights reserved. Substantial unmet need remains for the millions of individuals living with IBD 1Lewis, James D., et al. Gastroenterology (2023). Estimate includes patients identified with indeterminate IBD. Clinical remission rates from product labels. 0 20 40 60 80 100 • ~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 concerns associated with certain treatments – Poor adherence to frequent and/or inconvenient dosing regimens Efficacy ceiling of ~25% UC placebo-adjusted clinical remission rates by MOA (Induction) Anti-TNF JAK inhibitorS1P inhibitorAnti-integrin Anti-IL-12/23 / Anti-IL-23
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14 © 2025 Spyre Therapeutics, Inc. All rights reserved. JNJ’s VEGA study demonstrated the power of combination therapy to break the efficacy ceiling in IBD VEGA combination study • Ulcerative colitis Feagan, B. G. et al. Lancet Gastroenterol. Hepatol. 8, 307–320 (2023). 25% 24% 25% 22% Anti-TNF (Golimumab) Anti-IL-23 (Guselkumab) Combination 47% Δ+22% ~Additive absolute W12 mMS clinical remission rates
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15 © 2025 Spyre Therapeutics, Inc. All rights reserved. Replacing TNF with α4β7 or TL1A may yield combinations with improved safety and efficacy α4β7 was superior to TNF in H2H UC study TL1A exceeds TNF on cross-trial comparison Product labels, Sands BE. et al. N Engl J Med. 2019; Roivant corporate presentation January 2023; Sands, Bruce E., et al. New England Journal of Medicine 391.12 (2024); Teva corporate presentation February 2025. Established α4β7 long-term safety profile and gut-restrictive MOA TL1A safety is encouraging to date 23 31 0 10 20 30 40 Clinical remission – week 52 (VARSITY) adalimumab vedolizumab Δ +8% 11 20 25 27 0 10 20 30 40 Pbo-adjusted clinical remission - induction Golimumab Afimkibart Tulisokibart Duvakitug Δ +14% TNF TL1A TNF α4β7
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16 © 2025 Spyre Therapeutics, Inc. All rights reserved. Spyre MOAs address the diverse pathophysiology of IBD by targeting distinct pathways Blockade of α4β7 prevents circulating immune cells from entering inflamed gut tissues Neutralization of TL1A suppresses inflammation and reduces fibrosis by inhibiting fibroblast activation Neutralization of IL-23 inhibits cascade of various proinflammatory cytokines Created with BioRender.com; Neurath, Markus F. Nature Reviews Gastroenterology & Hepatology 14.5 (2017): 269-278; Solitano, Virginia, et al. Med (2024). anti-α4β7 anti-TL1A anti-IL-23
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17 © 2025 Spyre Therapeutics, Inc. All rights reserved. Spyre’s combinations demonstrate additive-to-superior efficacy in mouse TNBS colitis model α4β7 + TL1A α4β7 + IL-23 TL1A + IL-23 Data on file. Preclinical models utilized surrogate antibodies. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. vehicle (2-way ANOVA with Dunnett’s correction). N=8 per group. TNBS=trinitrobenzene sulfonic acid. -1 0 1 2 3 4 5 6 0 2 4 6 8 10 12 Days DAI score ******** Healthy Vehicle Control anti-β7 (25 mg/kg) anti-TL1A (25 mg/kg) anti-β7 + anti-TL1A (25 mg/kg, 25 mg/kg) ******** ***** Disease improvement -1 0 1 2 3 4 5 6 0 2 4 6 8 10 12 Days ** *** ***** **** **** *** **** Healthy Vehicle control anti-β7 (25 mg/kg) anti-IL-23 (1 mg/kg) anti-β7 + anti-IL-23 (25 mg/kg, 1 mg/kg) -1 0 1 2 3 4 5 6 0 2 4 6 8 10 12 Days **** **** **** **** **** ** * Healthy Vehicle anti-TL1A (25 mg/kg) anti-IL-23 (25 mg/kg) anti-TL1A + anti-IL-23 (25 mg/kg, 25 mg/kg)
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18 © 2025 Spyre Therapeutics, Inc. All rights reserved. Spyre’s portfolio uniquely enables product profiles with potential superior efficacy and convenience Positioning of Spyre programs is illustrative and based on Phase 1 results for SPY001 and SPY002 only and illustrates what we believe we can potentially achieve. Placebo-adjusted clinical remission data are derived from different clinical trials conducted at different times, with differences in trial design and patient populations. As a result, cross-trial comparisons cannot be made, and no head-to-head clinical trials have been conducted. 0 1 2 3 4 5 6 20 40 60 80 Maintenance dosing interval (months) Pbo-adjusted clinical remission (%) Potential for Q3M & Q6M dosing profiles ILLUSTRATIVE SPY001 SPY002 SPY003 Potential to break the efficacy ceiling with combinationsSPY120 SPY130 SPY230 Potential for best-in-class efficacy with higher exposuresStandard of care IBD biologics
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19 © 2025 Spyre Therapeutics, Inc. All rights reserved. Coformulations are more likely to achieve the optimal target profile compared to bispecifics Sources: Zheng, Songmao, et al. Mabs. (2020); Kroenke, Mark A., et al. Frontiers in Immunology 12 (2021); clinicaltrials.gov; bsAb=bispecific antibody 1:1 Fixed antibody ratios limits dose flexibility/optimization Reduced avidity reduces target engagement Immune complex formation & immunogenicity to unique constructs increases clearance & reduces target engagement Potential challenges unique to bispecifics Potential impact on product profile Examples Increased total dosage to saturate the more abundant target Increased total dosage to achieve full target engagement Increased and/or more frequent dosing Decreased durability Lack of drug-like properties JNJ-8104 (TNF/IL-17) ABT-122 (TNF/IL-17) AMG-966 (TL1A/TNF) PF-07261271 (TL1A/p40) JNJ-8104 (TNF/IL-17) MEDI-7352 (TNF/NGF) >20-fold decrease in potency observed with JNJ-8104 bsAb vs. parental mAb co-administration 1:1 2:2
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20 © 2025 Spyre Therapeutics, Inc. All rights reserved. Co-administration of mAbs can reduce immunogenicity whereas bispecific formats can increase immunogenicity ADA rates for bsAbs vs. coformulations Case studies Clin Pharmacol Ther. 2017;101(S1):S81; J. of Clin Pharmacol. 2019; 59(7): 968-978; J. of Clin Pharmacol. 2018; 58(6): 803-813; Front Immunol. 2021 Dec 14:12:782788; Shao et al. Clin Pharmacol Ther. 2024 Jun;115(6):1418-1427. doi: 10.1002/cpt.3235. OA=osteoarthritis; UC=ulcerative colitis; HV=healthy volunteers. Asset Target Immunogenicity Population Structure golimumab + guselkumab (JNJ-4804) TNFα + IL-23 UC Separate human IgG1 mAbs JNJ-3539 TNFα / IL-17 HVs IgG-fynomer (2x2) JNJ-8104 TNFα / IL-17 HVs Duobody (1x1) ABT-122 TNFα / IL-17 HVs Dual variable domain (2x2) AMG-966 TNFα / TL1A HVs Four unique heavy and light chain pairs (1x1) MEDI-7352 TNFα / NGF OA IgG-scFv (2x2) RO7837195 (PF-07261271) TL1A / p40 HVs CrossmAb (1x1) 6% 93% 100% 99% 98% 72% 100% CombobsAbs DISCONTINUED DISCONTINUED DISCONTINUED DISCONTINUED DISCONTINUED PHASE 2 … We demonstrate here that AMG966 forms large immune complexes ... which drive an antibody response and resulted in loss of exposures … … Combination therapy appeared to decrease the incidence of antibodies to golimumab … PHASE 2 TL1A trimer TNF trimer AMG-966 IL-23 dimer TNF trimer guselkumab golimumab AMG-966 ADAs Time Time Exposure Exposure Golimumab Guselkumab No impact on drug exposure Loss of drug exposure AMG-966 bispecific JNJ-4804 coformulation
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21 © 2025 Spyre Therapeutics, Inc. All rights reserved. SKYLINE: Phase 2 platform study evaluating three monotherapies and three combinations in UC mMS=modified mayo score; RHI=Robarts Histopathology Index; HEMI=Histo-Endoscopic Mucosal Improvement; P=primary endpoint; S=secondary endpoint Initiation of each cohort subject to regulatory clearance. Part A: Open-label monotherapy evaluation (N=~100) SPY001 (α4β7) SPY002 (TL1A) SPY003 (IL-23) SPY120 (α4β7+TL1A) SPY130 (α4β7+IL-23) SPY230 (TL1A+IL-23) Placebo OBJECTIVES KEY ENDPOINTS W12 W48 Seamless enrollment after Part A Monotherapy POC Change in RHI at W12 Clinical remission at W12 Endoscopic improvement at W12 Change in mMS at W12 P S Monotherapy dose optimization Combination POC Contribution of components S Clinical remission at W12 Endoscopic improvement at W12 Clinical response at W12 Histological improvement at W12 HEMI at W12 Clinical remission at W48 P S S S S S S SPY001 (α4β7) SPY002 (TL1A) SPY003 (IL-23) INDUCTION MAINTENANCE W12 W48 Sequential activation after Ph1 P Part B: PBO-controlled factorial combination evaluation (N=~550) UC mMS 5-9 UC mMS 5-9 P INDUCTION MAINTENANCE
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22 © 2025 Spyre Therapeutics, Inc. All rights reserved. Capital-efficient trial that is designed to be attractive to patients and investigators 40% PATIENT CENTRIC STREAMLINED UNIFIED DOSING INDUCTION MAINTENANCE (W48)PART A PART B 6 actives vs. 1 placebo MonosCombosPlacebo Open-label Cost savings and reduced sample size compared to individual Ph2 studies for each program CAPTIAL EFFICIENT
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23 © 2025 Spyre Therapeutics, Inc. All rights reserved. Comparison to other trials highlights advantage of designing a portfolio from the ground up w/ unified dosing Pending regulator feedback; 1Inferred dosing regimen based on Clinicaltrials.gov posting and dosing regimens of individual agents in commercial or prior monotherapy clinical trial settings. OBI=on body injector TARGET-CD1 INDUCTION MAINTENANCE (THROUGH W24) INDUCTION MAINTENANCE (THROUGH W24) Unified dosing intervals and formats enables blinded trial Two IV induction doses, Q3M-Q6M SC chronic dosing Clear approach to advance coformulation for Ph3 × Mix of IV, SC, and OBI routes of administration; open label trial × Combos default to highest dosing frequency (Q2W or Q4W) × Unclear strategy to single product combination for Ph3 ARM SPY001 SPY002 SPY003 SPY120 SPY130 SPY230 PBO ARM Mono 1 Mono 2 Mono 3 Combo 1 Combo 2
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24 © 2025 Spyre Therapeutics, Inc. All rights reserved. SKYLINE: On-track for expected 6 POC readouts through 2027 Milestones expected as of the date of this presentation. Phase 1 SPY003 Ph1 (4Q) Phase 2 platform study Ph2 Initiation Part A monotherapy results SPY001 (α4β7) open-label POC SPY002 (TL1A) open-label POC SPY003 (IL-23) open-label POC Part B monotherapy results SPY001 (α4β7) pbo-controlled data SPY002 (TL1A) pbo-controlled data SPY003 (IL-23) pbo-controlled data Part B combination results SPY120 (α4β7+TL1A) POC SPY130 (α4β7+IL-23) POC SPY230 (TL1A+IL-23) POC Phase 2 basket study Ph2 Initiation Ph2 results SPY072 (TL1A) RA POC SPY072 (TL1A) PsA POC SPY072 (TL1A) axSpA POC 2026 20272H 2025 6 POC readouts 3 POC readouts
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Rheumatic diseases Potential first-in-class anti-TL1A in RA, PsA, and axSpA
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26 © 2025 Spyre Therapeutics, Inc. All rights reserved. Substantial unmet need remains for the millions of individuals living with RA, PsA, and axSpA 1Hunter, Theresa M., et al. Rheumatol Int (2017); 2Ogdie, Alexis, et al. Rheumatol Ther (2021); Danve, Abhijeet, and Atul Deodhar. Clinical rheumatology 38.3 (2019). Efficacy rates by MOA from product labels. Note: 3Week 24 data when available, otherwise data is Week 12 or 16; 4Includes IL-12/23 and IL-23 0 20 40 60 80 100 TNF JAK IL-6 CD20 CD80/86 • >3M individuals in the U.S. diagnosed with RA (>1.5M1), PsA (~1M2), and axSpA (~1M2) • Substantial unmet need remains due to: – Minority remission rates, inability to control multiple aspects of disease, and lack of durability with existing therapies – Limited MOAs to cycle through following incomplete responses – Poor adherence to frequent and/or inconvenient dosing regimens Placebo-adjusted efficacy rates by MOA (W243) TNF JAK IL-17 TNF JAK IL-17 IL-234 RA (ACR50) axSpA (ASAS40)PsA (ACR50)
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27 © 2025 Spyre Therapeutics, Inc. All rights reserved. TL1A has been implicated in several inflammatory and fibrotic diseases, with strong rationale in rheumatic diseases TL1A exacerbates inflammation and fibrosis Target rheumatic diseases share mechanistic pathways with IBD, where POC is established Figure created with BioRender.com. 1 Logos indicate planned or active clinical POC studies. Hisamoto, T. et al. Int. J. Mol. Sci. 24, 1813 (2023); Herro, R. et al. J. Immunol. 205(9), 2414-2422 (2020); Ma, C. et al. Int. Immunopharm. 137, 112360 (2024); Richard, A. et al. JLB 3(98), 333-345 (2015); Song, Y. et al. Arthritis Research & Therapy 22, 106 (2020); Xu, W. et al. Frontiers in Immunology 13, 891328 (2022). Increasing overlap with clinically validated biology POC studies1 TH1 | TH17 | TH9 Fibroblasts FLS | osteoclasts NK | TH2 | ILCs Ulcerative colitis (UC) • Crohn’s disease (CD) • • Rheumatoid arthritis (RA) • • Psoriatic arthritis (PsA) • Axial spondyloarthritis (axSpA) • Psoriasis (PsO) • Hidradenitis suppurativa (HS) • • Primary biliary cholangitis (PBC) • • Pulmonary sarcoidosis • Interstitial lung disease (SSc-ILD) • Metabolic steatohepatitis (MASH) • Atopic dermatitis (AD) • Asthma •
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28 © 2025 Spyre Therapeutics, Inc. All rights reserved. TL1A is upregulated in RA, PsA, and axSpA relative to healthy controls Rheumatoid arthritis Psoriatic arthritis Axial spondyloarthritis Spyre analysis of RA-MAP, Li, Sifang, et al. BMC Musculoskeletal Disorders 25.1 (2024), and Johnsson, Hanna, et al. Arthritis Research & Therapy. ** P≤0.01, *** P ≤0.001, **** P ≤0.0001. Unpaired tailed t-test used for RA and axSpA analysis, One-way ANOVA used in PsA. RA=rheumatoid arthritis; PsA=psoriatic arthritis; axSpA=axial spondyloarthritis; HC=healthy controls. Source Whole blood Sequencing Microarray Sample size N=192 RA, 30 HC Skin biopsy Bulk RNA seq N=9 per cohort Whole blood Microarray N=52 axSpA, 20 HC Healthy Control PsA Uninvolved PsA Lesion -50 0 50 100 150 200TNFSF15 Counts ✱✱ ✱✱ Healthy Control axSpA 0 200 400 600 800TNFSF15 Counts ✱✱✱ Healthy Control Rheumatoid arthritis -2000 0 2000 4000 6000 8000 TNFSF15 Counts ✱✱✱✱
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29 © 2025 Spyre Therapeutics, Inc. All rights reserved. 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 * P< 0.0001 vs. isotype control; 2-way ANOVA using Dunnett's correction for multiple comparisons. Data on file. 5 10 15 20 25 0 2 4 6 8 Day Arthritis score Healthy Vehicle Isotype control anti-TNF anti-TL1A 5 10 15 20 25 0 2 4 6 8 Day Arthritis score Healthy Vehicle anti-TL1A anti-TNF Isotype control * * * * * Treatment periodTreatment periodCollagen Collagen Disease improvement Disease improvement
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30 © 2025 Spyre Therapeutics, Inc. All rights reserved. SPY072 is a potential first-in-class therapy for rheumatic diseases with quarterly or twice-annual dosing Positioning of Spyre programs is illustrative and based on Phase 1 interim results. Placebo-adjusted clinical data are derived from different clinical trials conducted at different times, with differences in trial design and patient populations. As a result, cross-trial comparisons cannot be made, and no head-to-head clinical trials have been conducted. 0 1 2 3 4 5 6 10 20 30 40 50 60 Dosing interval (months) Pbo-adjusted ACR20 / ASAS20 (%) Potential for novel MOA with comparable-to-better efficacy and improved SC dosing frequency (Q3M-Q6M)PsA RA axSpA Today’s SOC ILLUSTRATIVE
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31 © 2025 Spyre Therapeutics, Inc. All rights reserved. SKYWAY: Phase 2 basket study evaluating SPY072 (anti- TL1A) in RA, PsA, and axSpA RF=rheumatoid factor; ACPA= Anti-citrullinated protein antibodies; cs/b/tsDMARD=conventional synthetic, biologic, or targeted synthetic disease modifying antirheumatic drugs; BASDAI=Bath Ankylosing Spondylitis Disease Activity Index; P=primary endpoint; S=secondary endpoint; E=exploratory endpoint. Sub-study A: SPY072 in moderate-to-severely active rheumatoid arthritis (RA) SPY072 Dose A SPY072 Dose B Placebo DOUBLE-BLIND OPEN-LABEL FOLLOW UP RA N=120 KEY INCLUSION KEY ENDPOINTS W12 W36 1:1:1 Swollen joint count ≥ 4 Tender joint count ≥ 4 RF+, ACPA+, or bony erosions IR to cs/b/tsDMARDs Change in DAS28-CRP at W12 Proportion ACR20 at W12 ACR50/70 at W12 P S Sub-study B: SPY072 in moderate-to-severely active psoriatic arthritis (PsA) SPY072 Dose A Placebo PsA N=90 W16 W40 2:1 Tender joint count ≥ 3/68 Swollen joint count ≥ 3/66 Active PsO lesion or history IR to NSAIDs or cs/b/tsDMARDs Proportion ACR20 at W16 Change in DAPSA at W16 ACR50/70 at W16 P S Sub-study C: SPY072 in moderate-to-severely active axial spondyloarthritis (axSpA) SPY072 Dose A Placebo axSpA N=75 W16 W40 2:1 Radiographic / non-radiographic BASDAI ≥ 4 & back pain ≥ 4 IR to NSAIDs or b/tsDMARDs Change in ASDAS at W16 Proportion ASAS40 at W16 P S E E P P P
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32 © 2025 Spyre Therapeutics, Inc. All rights reserved. Operationally-efficient design with shared sites and specialty 1Based on comparative CRO quotes. 35% SHARED SITES SHARED SPECIALTY Cost savings compared to individual Ph2 studies for each indication1 CAPITAL EFFICIENT Rheumatologist PsA patients axSpA patients RA patients Increased investigator productivity 50 5030 20 Separate studies SKYWAY-RD PsA RA axSpA 100 50% Reduced total site requirement
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33 © 2025 Spyre Therapeutics, Inc. All rights reserved. SKYWAY: 3 POC readouts expected through 2026 Milestones expected as of the date of this presentation and pending regulatory feedback. Phase 1 SPY003 Ph1 (4Q) Phase 2 platform study Ph2 Initiation Part A monotherapy results SPY001 (α4β7) open-label POC SPY002 (TL1A) open-label POC SPY003 (IL-23) open-label POC Part B monotherapy results SPY001 (α4β7) pbo-controlled data SPY002 (TL1A) pbo-controlled data SPY003 (IL-23) pbo-controlled data Part B combination results SPY120 (α4β7+TL1A) POC SPY130 (α4β7+IL-23) POC SPY230 (TL1A+IL-23) POC Phase 2 basket study Ph2 Initiation Ph2 results SPY072 (TL1A) RA POC SPY072 (TL1A) PsA POC SPY072 (TL1A) axSpA POC 2026 20272H 2025 6 POC readouts 3 POC readouts
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Corporate Leadership and cash runway
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35 © 2025 Spyre Therapeutics, Inc. All rights reserved. Leadership Scott Burrows Chief Financial Officer Brian Connolly Chief Technical Officer Joshua Friedman SVP, Clinical Development Janet Gunzner-Toste SVP, Operations MiRa Huyghe SVP, Development Operations Heidy King-Jones Chief Legal Officer and Corporate Secretary Justin LaFountaine SVP, Corporate Development Deanna Nguyen SVP, Clinical Development Andrew Spencer SVP, Preclinical Research and Development Cameron Turtle Chief Executive Officer Paul Fehlner SVP, Chief Intellectual Property Counsel Melissa Cooper SVP, People Sheldon Sloan Chief Medical Officer Cristina Damatarca SVP, Drug Safety & Pharmacovigilance
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36 © 2025 Spyre Therapeutics, Inc. All rights reserved. Board of Directors Mark McKenna Peter Harwin Michael Henderson Tomas Kiselak Laurie Stelzer Cameron Turtle Jeffrey Albers Sandra Milligan
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37 © 2025 Spyre Therapeutics, Inc. All rights reserved. Nine proof-of-concept readouts expected in 2026-27 for the treatment of IBD & beyond Milestones expected as of the date of this presentation and pending regulatory feedback. Phase 1 SPY003 Ph1 Phase 2 platform study Ph2 Initiation Part A monotherapy results SPY001 (α4β7) open-label POC SPY002 (TL1A) open-label POC SPY003 (IL-23) open-label POC Part B monotherapy results SPY001 (α4β7) pbo-controlled data SPY002 (TL1A) pbo-controlled data SPY003 (IL-23) pbo-controlled data Part B combination results SPY120 (α4β7+TL1A) POC SPY130 (α4β7+IL-23) POC SPY230 (TL1A+IL-23) POC Phase 2 basket study Ph2 Initiation Ph2 results SPY072 (TL1A) RA POC SPY072 (TL1A) PsA POC SPY072 (TL1A) axSpA POC 6 POC readouts 3 POC readouts 2026 20272H 2025
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38 © 2025 Spyre Therapeutics, Inc. All rights reserved. Cash and shares outstanding 1Reflects cash includes cash, cash equivalents, & marketable securities as of 9/30/25 of $486.2 million plus $296.5 million in net proceeds from the recently closed October 2025 underwritten public offering of common stock; 2Shares outstanding on a pro forma and as-converted basis as of 9/30/25, inclusive of the October 2025 financing, which (i) gives effect to the full conversion of the Company’s preferred stock, and (ii) disregards beneficial ownership limitations that may limit the ability of certain holders of preferred stock to convert into common stock. Common stock Common stock equivalents $783M pro forma cash as of September 30, 20251 Expected runway into 2H 2028 Number of shares (M) Shares outstanding • Series A preferred stock • Series B preferred stock Total outstanding 77.6 13.8 0.7 92.1Common stock and common stock equivalents2
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Engineering for new heights in the treatment of IBD and beyond THANK YOU
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40 © 2025 Spyre Therapeutics, Inc. All rights reserved. SPY001 (α4β7) Ph1 Data See Ph1 interim data disclosures from November 2024 (Company Webcast) and May 2025 (DDW poster) available on our corporate website. PK results from 3/19/2025 data cutoff informed selected Ph2 dosing regimens in ongoing SKYLINE study, see catalyst tracker in this presentation for latest Ph2 data disclosure guidance. SPY001 Well tolerated with a favorable safety profile PK supports quarterly or twice annual maintenance dosing Rapid & sustained target engagement Advanced to SKYLINE Ph2 study
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41 © 2025 Spyre Therapeutics, Inc. All rights reserved. SPY001 potency & selectivity match vedolizumab in vitro SPY001 & vedolizumab epitope Potent and selective inhibition of cellular adhesion Data on file. α4 Subunit β7 Subunit SPY001 and vedolizumab bind the same epitopeAntibody α4β71 α4β1 αEβ7 SPY001 KD <1 nM NB2 NB2 Vedolizumab KD <1 nM NB2 NB2 1Dissociation constant (KD) measured by surface plasmon resonance (SPR); 2NB = no binding by a particular antibody to a test molecule 0.001 0.01 0.1 1 10 100 -10 0 10 20 30 40 50 60 70 mAb Concentration (nM) %Inhibition of Total Adhesion (Integrin-mediated Adhesion by VCAM-1) Vedolizumab SPY001 Natalizumab 0.01 0.1 1 10 0 10 20 30 40 50 60 70 mAb Concentration (nM) %Inhibition of Total Adhesion (Integrin-mediated Adhesion by MAdCAM-1) Vedolizumab (IC50 = 83 pM) SPY001 (IC50 = 86 pM) SPY001 and vedolizumab potently inhibit MAdCAM-1-mediated (gut) cellular adhesion No inhibition of unwanted VCAM-1- mediated (CNS) cellular adhesion
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42 © 2025 Spyre Therapeutics, Inc. All rights reserved. SPY001 PK supports quarterly or twice annual maintenance dosing SPY001 simulated PK profile Data on file, simulations represent median +/- interquartile range; SPY001 simulation based on Ph1 PK data as of 03/19/2025 cutoff. Serum Conc. (µg/mL) SPY001 Q3M SC SPY001 Q6M SC Vedolizumab Q2W SC MaintenanceInduction 2-4x SC maintenance injections per year
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43 © 2025 Spyre Therapeutics, Inc. All rights reserved. SPY002 and SPY072 (TL1A) Ph1 Data See Ph1 interim data disclosure from June 2025 (Company Webcast) available on our corporate website. PK data results from 5/31/2025 data cutoff informed selected Ph2 dosing regimens in ongoing SKYLINE study and planned SKYWAY study, see catalyst tracker in this presentation for latest Ph2 data disclosure guidance. SPY072 SPY002 Well tolerated with a favorable safety profile PK supports quarterly or twice annual maintenance dosing Rapid & sustained target engagement SPY002 advanced to SKYLINE Ph2 study SPY072 advanced to SKYWAY Ph2 study
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44 © 2025 Spyre Therapeutics, Inc. All rights reserved. SPY002 and SPY072 each target distinct epitopes and exhibit unique binding properties Single TL1A subunit epitope Superior or comparable potency in multiple assays Data on file. Duvakitug not benchmarked in IFNγ secretion assay; Duvakitug, RO7790121, and tulisokibart are synthesized comparator antibodies. Superior or comparable inhibition of TF-1 apoptosis Superior or comparable inhibition of IFNγ secretionSPY002 and SPY072 each target a distinct epitope on a single TL1A monomer Tulisokibart (MK-7240) RO7790121 (RVT-3101) Duvakitug (TEV-48574) • Epitope locations were resolved by CryoEM • Illustrative locations are overlayed with the crystal structure of trimeric TL1A 0.01 0.1 1 10 100 0 20 40 60 80 100 mAb Concentration (nM) Inhibition % mAb Concentration (ng/mL) Inhibition% 0.1 1 10 100 1000 10000 100000 0 20 40 60 80 100 Tulisokibart Afimkibart Duvakitug SPY002 & SPY072
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45 © 2025 Spyre Therapeutics, Inc. All rights reserved. SPY002 PK supports quarterly or twice annual maintenance dosing Afimkibart Ph2 UC results SPY002 simulated PK profile SPY002 simulations based on Ph1 PK data as of May 30, 2025 cutoff. Afimkibart simulations based on Danese, Silvio, et al. Official journal of the American College of Gastroenterology | ACG 119.10S (2024). mMS = Modified Mayo Score. SPY002 Q3M SC SPY002 Q6M SC Afimkibart QM SC 30% 31% 38% 39% 29% 36% 0 10 20 30 40 50 Clinical remission by mMS % Week 14 Week 56 50 mg Q4W 150 mg Q4W 450 mg Q4W Induction Maintenance 2-4x SC maintenance injections per year SPY002 Q3M SPY002 Q6M Afimkibart simulated 450 mg Ctrough Afimkibart simulated 150 mg Ctrough Afimkibart simulated 50 mg Ctrough N=46 N=29 N=28 N=42 N=26 N=28
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46 © 2025 Spyre Therapeutics, Inc. All rights reserved. SPY003 (IL-23) summary Data on file. Risankizumab as a synthesized comparator antibody was used for preclinical potency studies; PK data results from Sept. 19, 2025 data cutoff informed selected Ph2 dosing regimens in ongoing SKYLINE study SPY003 Similar epitope and preclinical potency to risankizumab Well tolerated with a favorable safety profile PK supports quarterly or twice annual maintenance dosing Advancing to SKYLINE Ph2 study
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47 © 2025 Spyre Therapeutics, Inc. All rights reserved. SPY003 targets a similar epitope as risankizumab with comparable potency in vitro Similar epitope to risankizumab Comparable potency in multiple assays Data on file. Risankizumab is a synthesized comparator antibody. 0.01 0.1 1 10 100 1000 0 50 100 mAb Concentration (nM) % Inhibition 0.001 0.01 0.1 1 10 100 0 50 100 mAb Concentration (nM) % Inhibition SPY003 epitope Risankizumab epitope SPY003 and risankizumab potently inhibit pSTAT signaling SPY003 and risankizumab potently inhibit IL-17 release SPY003 and risankizumab bind the same p19 subunit of IL-23
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48 © 2025 Spyre Therapeutics, Inc. All rights reserved. SPY003 PK supports quarterly or twice annual maintenance dosing Skyrizi Ph3 UC results SPY003 simulated PK profile SPY003 simulations based on Ph1 PK data as of Sept. 19, 2025 cutoff. Risankizumab simulations based on Thakre, Neha, et al. C linical Pharmacology & Therapeutics 116.3 (2024). Skyrizi package insert. mMS = Modified Mayo Score. SPY003 Q3M SC SPY003 Q6M SC Skyrizi Q2M OBI Induction Maintenance 2-4x SC maintenance injections per year 26% 45% 41% 0 10 20 30 40 50 Clinical remission by mMS (W52) % Placebo 180 mg SC 360 mg SC N=182 N=179 N=186 Risankizumab simulated 360 mg Ctrough Risankizumab simulated 180 mg Ctrough SPY003 Q3M SPY003 Q6M