Slides
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Corporate overview February 2025
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2 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 accuratelyevaluate 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 therapeutics for inflammatory bowel disease (IBD) or rheumatoid arthritis (RA) that meaningfully improve both efficacy and convenience compared to today’s standard of care; our ability to develop first-in-class therapeutics for RA; our plans to expand the development of our product candidates, including SPY002, to indications beyond IBD and RA; the expected timing of Phase 1 trial for SPY003, including timing of trial initiation and data readouts; the SPY001 phase 1 trial final data readouts not being consistent with or being different than the interim Phase 1 results; the efficacy, safety, tolerability, convenience and commercial viability of SPY001 and our other product candidates; the planned induction and maintenance dosing regimen for SPY001 and our other product candidates; the potential for increased or accelerated efficacy; the therapeutic benefits of our product candidates as monotherapies or in combinations and their extended half-life; the expected design, patient population and timing of the platform Phase 2 trial, including timing of each cohort and data readouts; our plans to provide Phase 2 platform study proof-of-concept readouts in 2027, including quantity of such readouts and our ability to provide such readouts ahead of any disclosed bispecific approaches against our targets; potential cost savings from the Phase 2 trial design; potential alignment with regulatory authorities and anticipated regulatory submissions; expected timing for regulatory feedback; estimated market sizes and potential market opportunities; expectations regarding patient, investigator and physician preferences; the potential for a Q3M-Q6M dosing profile for each of our product candidates, including combinations thereof; expectations regarding our potential therapeutic combinations and the potential benefits thereof; estimated cash runway lasting into second half of 2028 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 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. The 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 Engineering for new heights in the treatment of IBD & beyond 1Spyre holds exclusive worldwide licensed rights for SPY001, SPY002, and SPY003 from Paragon Therapeutics, Inc. SPY003 license is restricted to IBD, all other program licenses are unrestricted as to indication. *SC=subcutaneous, Q3M-Q6M dosing profiles are expected maintenance profiles based on human PK simulations. All of the milestones for data including timing are as anticipated or expected as of the date of this presentation and subject to regulatory feedback. POTENTIAL SC Q3M-Q6M DOSING* INDICATION TARGET PROGRAM1 PRECLIN. PHASE 1 PHASE 2 PHASE 3 Next-generation monotherapies Ulcerative Colitis α4β7 SPY001 TL1A SPY002 IL-23 SPY003 Paradigm-changing combinations α4β7 + TL1A SPY120 α4β7 + IL-23 SPY130 TL1A + IL-23 SPY230 Indication expansion Rheumatoid Arthritis TL1A SPY002 2Q25: SPY002 Ph1 data 2H25: SPY003 Ph1 data Mid-2025: Ph2 initiation 2026: Ph2 open-label data 2027: Ph2 pbo-controlled data Our strategy Our pipeline Mid-2025: Ph2 initiation 2026: Ph2 data 2027: Ph2 pbo-controlled data
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4 Spyre’s portfolio uniquely enables product profiles with potential superior efficacy and convenience Note: 1VEGA trial was not pbo-controlled. 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 exposures Standard of care IBD biologics JNJ’4804 TNF+IL-23 combo (VEGA1)
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5 Our MOAs were rationally chosen based on attractive risk-benefit profiles Source: Studies include Entyvio UC (VARSITY, assumes a 10% historical pbo control), CD (GEMINI II); tulisokibart UC (ATREMIS-UC), CD (APOLLO-CD, study was open label and adjusted using a historical pbo rate of 16%); Skyrizi UC (INSPIRE), CD (ADVANCE); Humira UC (ULTRA-II), Humira CD (CLASSIC-1, Bio-naïve patients); Zeposia UC (TRUE NORTH), CD (YELLOWSTONE), Rinvoq UC (U-ACCOMPLISH and U-ACHIEVE), CD (U-EXCEL); 1EvaluatePharma 2030 Consensus Sales; 2Merck press release; 3Ferrante M, et. al. J Crohns Colitis. 2021 Dec 18;15(12):2001-2010. MOA=mechanism of action. ~17% ~25% ~16% ~7% ~12% ~25% ~8% ~33% ~20% ~24% ~23% 0 20 40 60 80 100 Induction clinical remission rates (pbo-adjusted) by MOA Stronger efficacy in UC Gut-selective MOA Encouraging efficacy and safety profile in UC and CD Stronger efficacy in CD Well tolerated MOA3 Ulcerative colitis Crohn’s disease Week W14 | W6 W12 | W12 W12 | W12 W8 | W4 W10 | W12 W8 | W12 Safety No black box warning Not approved No black box warning Black box warning Cardiac monitoring Black box warning MOA α4β7 TL1A IL-23 TNF S1P JAK Example Efficacy ceiling TULISOKIBART Primary endpoint not met 2030 IBD SALES1: ~$8B Acquired for2: ~$12B 2030 IBD SALES1: ~$7B
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6 Our next-generation antibodies are engineered to match or exceed the potency of first-generation molecules … Note: Data on file. Details on number of replicates per study are included in later sections. SPY001 assay reports inhibition of cells expressing 47 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. SPY001 (α4β7) in vitro potency SPY002 (TL1A) in vitro potency SPY003 (IL-23) in vitro potency Potential for comparable efficacy at similar or lower doses Potential upside: Improved efficacy with higher exposures 0.01 0.1 1 10 100 0 20 40 60 80 100 mAb Concentration (nM) %Inhibition SPY002 Tulisokibart SPY001 Vedolizumab SPY003 Risankizumab 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
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7 … and share a YTE backbone that significantly extends half-life … Note: Human PK data in this presentation are derived from different clinical trials at different points in time, with differences in trial design and patient populations. No head-to-head clinical trials have been conducted. Vedolizumab PopPK simulation based on published PK parameters of vedolizumab, Rosario, M, et. al. (2015). Data on file. Pharmacokinetic data shown for SPY002, SPY003, tulisokibart, and risankizumab are from NHP studies, details on number of animals per study are included in later sections. Tulisokibart, and risankizumab are synthesized comparator antibodies. SPY001 (α4β7) Human PK SPY002 (TL1A) NHP PK SPY003 (IL-23) NHP PK SPY002 t1/2 = ~24 days Tulisokibart t1/2 = ~12 days SPY001 t1/2 = >90 days Vedolizumab t1/2 = ~25 days SPY003 t1/2 = ~30 days Risankizumab t1/2 = ~9 days 0 14 28 42 56 70 84 98 1 10 100 1000 Days Serum Conc. (μg/mL) 0 14 28 42 56 70 84 98 1 10 100 1000 Days Serum Conc. (μg/mL) Serum Conc. (µg/mL) Greater than 2-3x half-life extension vs. competitor molecules across our portfolio
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8 Serum Conc. (µg/mL) SPY001 Q3M SC SPY001 Q6M SC Vedolizumab Q2W SC Population PK modeling for SPY001 supports potential for both Q3M and Q6M maintenance dosing regimens Data on file, simulations represent median +/- interquartile range. Maintenance human PK simulations MaintenanceInduction 2-4x SC maintenance injections per year
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9 SPY001 Phase 1 interim results summary (10/30/24 cutoff) Potential for increased or accelerated induction efficacy by targeting all patients in the 4th quartile of vedo’s reported E-R relationship Ph2 induction dosing to test higher exposures Potential for as little as twice-yearly maintenance dosing in a single SC injection compared to 26 yearly SC injections for vedo Half-life of >90 days, far exceeding expectations Favorable safety profile across all dose levelsSPY001 was well tolerated Single dose of SPY001 saturated α4β7 receptors through available 12 weeks of follow-up (inhibition still ongoing) PD markers demonstrated target engagement
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10 JNJ’s VEGA study demonstrated the power of combination therapy in IBD Sources: Feagan, B. G. et al. Lancet Gastroenterol. Hepatol. 8, 307–320 (2023). 25% 24% 25% 22% Anti-TNF (Golimumab) Anti-IL23 (Guselkumab) Combination 47% Δ+22% BLACK BOX WARNING PROBABLE BLACK BOX VEGA combination study (N=71/arm) – Ulcerative colitis ~Additive absolute W12 MMS clinical remission rates
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11 Spyre combinations are rational alternatives to combos with clinical precedent Note: 1EXPLORER meta-analysis assumes a 27% remission rate for vedolizumab and 30% remission rate for adalimumab; EXPLORER included methotrexate treatment Source: 1Colombel, Jean-Frederic, et al. Clinical Gastroenterology and Hepatology 22.7 (2024): 1487-1496. 2Feagan, Brian G., et al. The Lancet Gastroenterology & Hepatology 8.4 (2023): 307-320; Clinical trial Precedent combination Spyre combinations & rationale EXPLORER1 Crohn’s – Endoscopic remission % • Exchange TNF for another TNF superfamily targeting agent • TL1A efficacy and safety appears superior on a cross-trial basis VEGA2 UC – MMS remission % • Exchange TNF for a safer and more effective class • Entyvio was superior to Humira in H2H clinical studies (VARSITY) VEGA2 UC – MMS remission % • Exchange TNF for another TNF superfamily targeting agent • TL1A efficacy and safety appears superior on a cross-trial basis 24% 25% 47% Anti-IL23 Anti-TNF Combination 24% 25% 47% Anti-IL23 Anti-TNF Combination 27% 30% 35% Anti-α4β7 Anti-TNF Combination α4β7 TNF TNF TNFIL-23 IL-23 TL1A α4β7 TL1A Spyre component exchange SPY120 SPY130 SPY230
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12 Spyre’s planned platform trial enables multiple placebo- controlled readouts of monotherapies and combinations Notes: 1Randomization among active arms; all arms may not start and finish simultaneously Design elements Illustrative schematic Design • Master protocol platform trial • Double blind, placebo-controlled Population • Moderately-to-severely active ulcerative colitis • N = ~600 Key endpoints • Primary: Clinical remission (W12) • Secondary: Endoscopic improvement (W12), Clinical response (W12), Histological improvement (W12), Histologic-endoscopic improvement (W12) R1 Placebo SPY001 (α4β7) SPY002 (TL1A) SPY003 (IL-23) SPY120 (α4β7 + TL1A) SPY130 (α4β7 + IL-23) SPY230 (TL1A + IL-23) Pending regulatory feedback Platform design allows cohorts to be added over time. Anticipate initiating trial with monotherapies beginning in mid-2025 with open-label mono readouts beginning in mid-2026.
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13 Comparison to other trials highlights potential advantage of designing a portfolio from the ground up w/ unified dosing Trial arm Induction (12W) Maintenance (through 26W) Placebo Q3M SPY001 Q3M SPY002 Q3M SPY003 Q3M SPY120 Q3M SPY130 Q3M SPY230 Q3M ✓ Unified dosing intervals and formats enables blinded trial ✓ Two IV induction doses, Q3M-Q6M SC chronic dosing ✓ Clear approach to advance coformulation for Ph3; >180mg/mL citrate-free formulations in development for all SPY product candidates Trial arm Induction (12W) Maintenance (through 24W) Mono 1 Q4W Mono 2 Q2W Mono 3 Q8W Combo 1 Q2W Combo 2 Q4W × Unblinded, open-label trial × Mix of IV, SC, and OBI routes of administration × Combos default to highest dosing frequency (Q2W or Q4W) × Unclear strategy to single product combination for Ph3 Example 3rd party platform trial2Planned platform trial1 Note: 1Pending regulator feedback; 2Inferred 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
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14 Optimized coformulations are the preferred approach for inhibiting multiple targets in IBD Coformulations retain extension of monoclonal half-lives and support synchronized extended dosing intervalsExtended dosing intervals Coformulations allow opportunity for adjustment of antibody ratios to achieve desired concentration of each mAb, including for targets in distinct compartments (e.g., circulating α4β7 vs. cytokines in inflamed tissue) Allows for dose optimization of each component Coformulations have the potential to retain or improve immunogenicity profile of monotherapy antibody components Potentially improved immunogenicity profile Spyre’s planned Phase 2 platform study in UC is expected to provide three combination proof-of-concept readouts in 2027, ahead of any disclosed bispecific approaches against our targets
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15 Note: Figure created with BioRender.com; 1Non-exhaustive. Source: 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). TL1A has scientific rationale across multiple diseases Rheumatology • Rheumatoid arthritis (RA) • Systemic lupus erythematosus (SLE) • Axial spondyloarthritis (axSpA) • Psoriatic arthritis (PsA) Pulmonology • Systemic sclerosis-interstitial lung disease (SSc-ILD) • Asthma • Pulmonary sarcoidosis Dermatology • Psoriasis (PsO) • Hidradenitis suppurativa (HS) • Atopic dermatitis (AD) Gastroenterology • Ulcerative colitis (UC) • Crohn’s disease (CD) TL1A exacerbates inflammation and fibrosis TL1A has been implicated in a wide range of human diseases1 based on genetic, proteomic, and/or preclinical data Not exhaustive
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16 Multiple published studies support anti-TL1A as a potential treatment option in RA Source: 1Sun, X. et al. Scand. J. Rheumatol. 42(2), 97-101 (2013); 2Song, Y. et al. Arthritis Res. Ther., 22(1), 106 (2020); 3Bamias, G., Clin. Immunol., 129(2), 249-255 (2008); 4Bull, M., et al. J. Exp. Med. 205(11); Charts are illustrative representations of figures within data sources. CIA=collagen-induced arthritis Healthy RA patients 0 1 10 100 No CIA anti-TL1AIg control TL1A is elevated in RA patients relative to healthy controls & increases with disease severity1, 2, 3 TL1A administration exacerbates arthritis in murine models and administration of anti-TL1A reduces arthritis2,4 TL1A serum concentration Murine arthritis score TL1A concentration (ng) Anti-TL1A dramatically reduces erosions in hind paws of CIA mice Moderate RA Severe RA TL1A serum concentration p < 0.001 p = 0.009 p < 0.05
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17 Spyre anti-TL1A antibody meets or exceeds the efficacy of etanercept (anti-TNF) in rat models of RA 0 10 20 30 0 2 4 6 8 Day Arthritis score Healthy Vehicle anti-TL1A Etanercept Isotype control 0 10 20 30 0 2 4 6 8 Day Arthritis score Healthy Vehicle Isotype control Etanercept anti-TL1A Start of treatment Collagen immunization Collagen immunizationetanercept (anti-TNF) anti-TL1A Start of treatment etanercept (anti-TNF) anti-TL1A Note: * P< 0.0001 vs. isotype control; 2-way ANOVA using Dunnett's correction for multiple comparisons. Superior efficacy vs. anti-TNF in semi-preventative model Comparable efficacy vs. anti-TNF in therapeutic model * * * * *
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18 Catalyst rich 2025 planned with expected Ph1 readouts on TL1A and IL-23 programs and multiple Ph2 initiations 20262025 SPY001 (α4β7) ❑ UC Platform Ph2 Initiation ❑ UC Ph2 data SPY002 (TL1A) ❑ Ph1 data (2Q) ❑ RA Ph2 Initiation ❑ UC Ph2 data ❑ RA Ph2 data SPY003 (IL-23) ❑ Ph1 Initiation (1Q) ❑ Ph1 data ❑ UC Ph2 data External events ❑ DUET-UC/CD Ph2b JNJ TNF + IL-23 combo All of the milestones for data including timing are as anticipated or expected as of the date of this presentation and subject to regulatory feedback.
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Thank you – Q&A