8-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

WASHINGTON, D.C. 20549

FORM 8-K

CURRENT REPORT

Pursuant to Section 13 or 15(d)

of the Securities Exchange Act of 1934

Date of Report (Date of earliest event reported): January 13, 2025

SPYRE THERAPEUTICS, INC.

(Exact name of Registrant as Specified in Its Charter)

Delaware	001-37722	46-4312787
(State or Other Jurisdiction of Incorporation)	(Commission File Number)	(IRS Employer Identification No.)
221 Crescent Street Building 23 Suite 105
Waltham, MA		02453
(Address of Principal Executive Offices)		(Zip Code)

Registrant’s Telephone Number, Including Area Code: 617 651-5940

Not Applicable

(Former Name or Former Address, if Changed Since Last Report)

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:

☐ Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

☐ Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

☐ Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

☐ Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Securities registered pursuant to Section 12(b) of the Act:

Title of each class	Trading Symbol(s)	Name of each exchange on which registered
Common Stock, $0.0001 Par Value Per Share	SYRE	The Nasdaq Stock Market LLC (Nasdaq Global Select Market)

Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§ 230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§ 240.12b-2 of this chapter).

Emerging growth company ☐

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Item 2.02 Results of Operations and Financial Condition

The information set forth below under “Preliminary Financial Information for the Year Ended December 31, 2024” in Item 8.01 is incorporated by reference herein.

Item 8.01 Other Events.

On January 13, 2025, Spyre Therapeutics, Inc. (the “Company”) issued a press release (the “Press Release”) and posted an updated corporate presentation (the “Corporate Presentation”) on its website. The Press Release and the Corporate Presentation include, without limitation, updates on the Company’s ongoing and anticipated clinical trials and details regarding an indication expansion into rheumatoid arthritis (“RA”) within its SPY002 program. Copies of the Press Release and Corporate Presentation are attached as Exhibit 99.1 and Exhibit 99.2, respectively, to this Current Report on Form 8-K and are incorporated herein by reference.

Preliminary Financial Information for the Year Ended December 31, 2024

In the Press Release and the Corporate Presentation, the Company disclosed its preliminary cash, cash equivalents and marketable securities as of December 31, 2024. While the Company has not finalized its full financial results for the year ended December 31, 2024, the Company expects to report that it had approximately $603 million of cash, cash equivalents and marketable securities as of December 31, 2024. This amount is preliminary, has not been audited and is subject to adjustment pending completion of the Company’s audited financial statements for the year ended December 31, 2024. The Company’s independent registered public accounting firm has not audited, reviewed or performed any procedures with respect to this preliminary information and, accordingly, does not express an opinion or any other form of assurance with respect thereto.

Item 9.01 Financial Statements and Exhibits.

(d) Exhibits

Exhibit Number	Description
99.1	Press Release of the Company, dated January 13, 2025
99.2	Corporate Presentation (January 2025)
104	Cover Page Interactive Data File (embedded within the Inline XBRL document)

SIGNATURES

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

		SPYRE THERAPEUTICS, INC.
Date: January 13, 2025	By:	/s/ Cameron Turtle
		Cameron Turtle Chief Executive Officer

EX-99.1

Exhibit 99.1

Spyre Therapeutics Highlights 2025 Priorities and Robust Pipeline of Upcoming Clinical Readouts

Phase 1 interim results expected for SPY002, two distinct extended half-life TL1A antibodies, in 2Q2025

Phase 1 interim results expected for SPY003, an extended half-life IL-23 antibody, in 2H2025

Phase 2 platform trial in ulcerative colitis (UC) remains on track for initiation in mid-2025

with SPY001 (α4ß7), followed by SPY002 (TL1A), SPY003 (IL-23), and combinations

thereof, with initial results expected in 2026

Announces indication expansion into rheumatoid arthritis (RA) with SPY002;

Phase 2 RA trial initiation anticipated in mid-2025 with topline results in 2026

Strong balance sheet with preliminary cash, cash equivalents, and marketable

securities balance of over $600M as of December 31, 2024*, anticipated to provide

cash runway into the second half of 2028

WALTHAM, Mass., January 13, 2025 (PR NEWSWIRE) – Spyre Therapeutics, Inc. (NASDAQ: SYRE) (the “Company” or “Spyre”), a clinical-stage biotechnology company utilizing best-in-class antibody engineering, rational therapeutic combinations, and precision medicine approaches to target improved efficacy and convenience in the treatment of IBD and other immune-mediated diseases, today highlighted its 2025 priorities, including: upcoming first-in-human clinical data for SPY002 and SPY003, an indication expansion of its SPY002 program into RA, and a plan to deliver four clinical proof-of-concept readouts in 2026.

“Spyre made substantial progress in 2024 including entering first-in-human studies with SPY001 and SPY002. We reported outstanding interim Phase 1 results for SPY001 suggesting the potential for quarterly or twice-annual dosing with a molecule that has the potential to match or exceed the efficacy of the current best-selling product in IBD and look forward to reporting interim Phase 1 results for SPY002 and SPY003 in 2025. This year, we expect to advance all three programs into a groundbreaking Phase 2 platform study in ulcerative colitis patients testing monotherapies and combination therapies under a single master protocol,” said Cameron Turtle, DPhil, CEO of Spyre. “We are also announcing the planned expansion of our SPY002 program into RA, a debilitating condition affecting millions of patients worldwide with continued unmet need

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for effective agents and improved convenience. The potential benefit of anti-TL1A in RA is supported by multiple lines of evidence including human genetics, blood and tissue samples from RA patients, and animal models of disease. With SPY002’s class-leading potency and half-life established in pre-clinical studies, it has the potential to become the first-in-class and best-in-class anti-TL1A treatment for RA. Between these planned Phase 2 studies in UC and RA, we expect to deliver four proof-of-concept readouts in 2026.”

Anticipated 2025 milestones for Spyre’s next-generation monotherapies

• SPY001 – a highly potent and selective, half-life extended, investigational anti-α4ß7 monoclonal antibody

• Initiation of Phase 2 proof-of-concept study in UC patients in mid-2025 with target exposures that have the potential to increase or accelerate efficacy

• Longer-term Phase 1 data expected to be presented at a medical meeting in 2025, following interim data presented in November 2024 demonstrating SPY001 was well tolerated with a half-life of >90 days, supporting Q3M-Q6M dosing

• SPY002 – a program with two highly potent and selective, half-life extended, investigational anti-TL1A monoclonal antibodies

• Phase 1 studies initiated in 4Q2024 for both anti-TL1A molecules

• Phase 1 interim data for both molecules on track for 2Q2025

• SPY003 – a highly potent and selective, half-life extended investigational monoclonal antibody targeting the p19 subunit of IL-23

• Phase 1 initiation on track for 1Q2025

• Phase 1 interim data expected in 2H2025

Platform Phase 2 trial in ulcerative colitis evaluating next-generation monotherapies and paradigm-changing combinations

• Spyre plans to advance SPY001, SPY002, SPY003, and combinations thereof into a double-blind, randomized, placebo-controlled, Phase 2 platform trial with a master protocol in patients with moderately-to-severely active ulcerative colitis

• Platform trial is designed to efficiently evaluate each of Spyre’s monotherapy and combination therapies against a common placebo control and to evaluate the contribution of each monotherapy component to the safety and efficacy of Spyre’s combination therapies

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• Trial is anticipated to initiate in mid-2025 with SPY001, followed by SPY002, SPY003, and combinations thereof. All investigational products in the study are expected to be dosed as subcutaneous quarterly injections in the maintenance setting with pharmacokinetic exposures targeting maximal efficacy based on published exposure- or dose- responses for each mechanism of action

• Initial open label monotherapy data from this study are expected beginning in mid-2026, with full placebo-controlled data expected in 2027

Rheumatoid arthritis indication expansion

• SPY002 (anti-TL1A) has first-in-class and best-in-class potential in RA, a chronic autoimmune inflammatory condition that affects millions of individuals worldwide

• Lack of response, insufficient response, or waning of response to existing mechanisms highlights the need for new treatment options

• TL1A levels are elevated in the blood and synovial fluid of RA patients and higher TL1A levels are correlated with disease severity

• TL1A blockade has been shown to be efficacious in murine models of inflammatory arthritis. Blockade using Spyre’s anti-TL1A antibodies matched or exceeded the efficacy of anti-TNF treatment in collagen-induced rat models of RA

• SPY002’s projected quarterly to twice-annual subcutaneous dosing in a single autoinjector has the potential to be the most convenient product available for RA

• Phase 2 clinical trial initiation expected in mid-2025 with topline results in 2026

Strong financial position

The Company had a preliminary cash, cash equivalents, and marketable securities balance of approximately $603 million as of December 31, 2024*. The Company anticipates that this cash balance provides operational runway into the second half of 2028.

* These preliminary selected financial results are unaudited and subject to adjustment. The Company expects to report its final and complete fourth quarter and full-year 2024 financial results in late February 2025.

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About Spyre Therapeutics

Spyre Therapeutics is a biotechnology company that aims to create next-generation inflammatory bowel disease (IBD) and other immune-mediated disease products by combining best-in-class antibody engineering, rational therapeutic combinations, and precision medicine approaches. Spyre’s pipeline includes extended half-life antibodies targeting α4ß7, TL1A, and IL-23.

Forward Looking Statements

Certain statements in this press release, other than purely historical information, may constitute “forward-looking statements” within the meaning of the federal securities laws, including for purposes of the safe harbor provisions under the United States Private Securities Litigation Reform Act of 1995, concerning Spyre and other matters. These forward-looking statements include, but are not limited to, express or implied statements relating to Spyre’s management team’s expectations, hopes, beliefs, intentions or strategies regarding the future of its pipeline and business including, without limitation, the planned dosing regimen for SPY001 and SPY002 molecules, including the potential for quarterly or twice-annual dosing; the potential for its product candidates to have efficacy improvement and convenience advantage over existing products targeting IBD and RA; the therapeutic benefits of its product candidates as monotherapies or in combinations and their picomolar potencies, extended half-lives, and high concentration formulations; the potential of a SPY002 molecule to be best-in-class half-life extended anti-TL1A antibodies and best-in-class and first-in-class anti-TL1A treatment for RA; the expected designs and timing of the platform Phase 2 trials in IBD and RA, including the selection of a SPY002 molecule for each planned Phase 2 trial and the timing of each cohort; its plans to conduct its first-in-human study of SPY003, including expected timing thereof; the expected timing for receipt of interim PK, PD and safety data for its studies in IBD; the expected initiation of proof-of-concept studies, including number of proof-of-concept studies and timing for receipt of readouts; its plans to initiate a study of SPY002 in indications outside of IBD, including timing thereof; potential market opportunities; the Company’s expected cash, cash equivalents and short-term investments of approximately $603 million as of December 31, 2024; and the sufficiency of its cash runway into the second half of 2028. In addition, any statements that refer to projections, forecasts or other characterizations of future events or circumstances, including any underlying assumptions, are forward-looking statements. The words “opportunity,” “potential,” “milestones,” “pipeline,” “can,” “aim,” “strategy,” “target,” “anticipate,” “achieve,” “believe,” “contemplate,” “continue,” “could,” “estimate,” “expect,” “intends,” “may,” “might,” “plan,” “project,” “should,” “will,” “would” and similar expressions (including the negatives of these terms or variations of them) may identify forward-looking statements, but the absence of these words does

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not mean that a statement is not forward-looking. These forward-looking statements are based on current expectations and beliefs concerning future developments and their potential effects. There can be no assurance that future developments affecting Spyre will be those that have been anticipated. These forward-looking statements involve a number of risks, uncertainties (some of which are beyond Spyre’s control) or other assumptions that may cause actual results or performance and clinical trial designs, including the planned Phase 2 trials, to be materially different from those expressed or implied by these forward-looking statements. These risks and uncertainties include, but are not limited to regulatory feedback including potential disagreement by regulatory authorities with the Company’s interpretation of data and the Company’s planned clinical trials for its product candidates, including the Company’s planned Phase 2 platform clinical trial design, and those uncertainties and factors described under the heading “Risk Factors” and “Note about Forward-Looking Statements” in Spyre’s most recent Annual Report on Form 10-K filed with the SEC, as well as discussions of potential risks, uncertainties, and other important factors included in other filings by Spyre from time to time. Should one or more of these risks or uncertainties materialize, or should any of Spyre’s assumptions prove incorrect, actual results may vary in material respects from those projected in these forward-looking statements. Nothing in this press release should be regarded as a representation by any person that the forward-looking statements set forth therein will be achieved or that any of the contemplated results of such forward-looking statements will be achieved. You should not place undue reliance on forward-looking statements in this press release, which speak only as of the date they are made and are qualified in their entirety by reference to the cautionary statements herein. Spyre does not undertake or accept any duty to make any updates or revisions to any forward-looking statements. This press release does not purport to summarize all of the conditions, risks and other attributes of an investment in Spyre.

For Investors :

Eric McIntyre

VP of Finance and Investor Relations

Spyre Therapeutics

Eric.mcintyre@spyre.com

For Media :

Peg Rusconi

Peg.rusconi@vergescientific.com

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EX-99.2

Exhibit 99.2 Corporate overview January 2025

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 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; 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 our product candidates; expectations regarding our potential therapeutic combinations and the potential benefits thereof; the Company’s expected cash, cash equivalents and short-term investments of approximately $603 million as of December 31, 2024; 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. 2

Engineering for new heights in the treatment of IBD & beyond Our strategy Our pipeline 1 POTENTIAL SC Q3M-Q6M DOSING* INDICATION TARGET PROGRAM PRECLIN. PHASE 1 PHASE 2 PHASE 3 α4β7 SPY001 2Q25: SPY002 Ph1 data 2H25: SPY003 Ph1 data Next-generation TL1A SPY002 Mid-2025: Ph2 initiation monotherapies 2026: Ph2 open-label data IL-23 SPY003 2027: Ph2 pbo-controlled data Ulcerative Colitis α4β7 + TL1A SPY120 2027: Ph2 pbo-controlled data Paradigm-changing α4β7 + IL-23 SPY130 combinations TL1A + IL-23 SPY230 Rheumatoid Mid-2025: Ph2 initiation TL1A SPY002 Indication expansion Arthritis 2026: Ph2 data 1 Spyre 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. 3

Multiple opportunities for value creation with next-gen monotherapies and paradigm-changing combinations Next-generation monotherapies Paradigm-changing IBD combinations Monoclonal antibody candidates engineered Fixed-dose-combinations designed to enable for optimized potency, selectivity, and PK superior efficacy, safety, and convenience α4β7 TL1A IL-23 α4β7 + TL1A α4β7 + IL-23 IL-23 + TL1A + TL1A indication expansion Pipeline-in-a-product potential in diseases with FIC and BIC opportunity, starting with RA RA … … 4

Next-generation monotherapies

Our next-generation antibodies are engineered to match or exceed the potency of first-generation molecules … SPY001 (α4β7) in vitro potency SPY002 (TL1A) in vitro potency SPY003 (IL-23) in vitro potency SPY001 SPY002 SPY003 Risankizumab Vedolizumab Tulisokibart 60 100 50 100 80 40 60 30 40 50 20 20 10 0 0 0 0.01 0.1 1 10 0.001 0.01 0.1 1 10 100 0.01 0.1 1 10 100 mAb Concentration (nM) mAb Concentration (nM) mAb Concentration (nM) Potential for comparable efficacy at similar or lower doses Potential upside: Improved efficacy with higher exposures Note: Data on file. Details on number of replicates per study are included in later sections. SPY001 assay reports inhibition of cells expressing α4β7 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. 6 %Inhibition %Inhibition % Inhibition

… and share a YTE backbone that significantly extends half-life … SPY001 (α4β7) Human PK SPY002 (TL1A) NHP PK SPY003 (IL-23) NHP PK SPY001 t = >90 days SPY002 t = ~24 days SPY003 t = ~30 days 1/2 1/2 1/2 Risankizumab t = ~9 days Vedolizumab t = ~25 days Tulisokibart t = ~12 days 1/2 1/2 1/2 1000 1000 100 100 10 10 1 1 0 14 28 42 56 70 84 98 0 14 28 42 56 70 84 98 Days Days Greater than 2-3x half-life extension vs. competitor molecules across our portfolio 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. 7 Serum Conc. (µg/mL) Serum Conc. (μg/mL) Serum Conc. (μg/mL)

… supporting projected unified and less frequent dosing across our portfolio SPY001 (α4β7) Human PK Simulation SPY002 (TL1A) Human PK Simulation SPY003 (IL-23) Human PK Simulation SPY002 SPY001 SPY003 Vedolizumab Tulisokibart Risankizumab Potential unified Q3M-Q6M SC maintenance dosing Versus Q2W-Q8W dosing for competitor molecules Note: Date on file, figures show median +/- interquartile range. PK simulation for comparator molecules based on published clinical data. 8 Serum Conc. (µg/mL) Serum Conc. (µg/mL) Serum Conc. (µg/mL)

Phase 1 data from all molecules are expected by 2H 2025 2024 2025 SPY001 (α4β7) ü Interim data – Nov2024 Phase 1 üFPI – June 2024 SPY002 (TL1A) Interim data – 2Q 2025 Phase 1 ü FPI – Q4 2024 SPY003 (IL-23) Interim data – 2H 2025 Phase 1 FPI – Q1 2025 Anticipated milestones as of January 13, 2025 subject to regulatory feedback. 9

Paradigm-changing combinations

Our MOAs were rationally chosen based on attractive risk-benefit profiles Induction clinical remission rates (pbo-adjusted) by MOA 100 1 1 2 2030 IBD SALES : 2030 IBD SALES : Acquired for : Ulcerative colitis Crohn’s disease ~$8B ~$7B 80 ~$12B Stronger efficacy in Stronger efficacy in Encouraging efficacy UC CD 60 and safety profile in UC and CD 3 Gut-selective MOA Well tolerated MOA 40 ~33% Efficacy ceiling ~25% ~25% ~24% ~23% ~20% ~17% ~16% 20 ~12% Primary ~8% ~7% endpoint not met 0 W14 | W6 W12 | W12 W12 | W12 W8 | W4 W10 | W12 W8 | W12 Week No black box warning Not approved No black box warning Black box warning Cardiac monitoring Black box warning Safety α4β7 TL1A IL-23 TNF S1P JAK MOA Example TULISOKIBART 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); 1 2 3 EvaluatePharma 2030 Consensus Sales; Merck press release; Ferrante M, et. al. J Crohns Colitis. 2021 Dec 18;15(12):2001-2010. MOA=mechanism of action. 11

Spyre MOAs address the diverse pathophysiology of IBD by targeting distinct pathways Blockade of α4β7 prevents circulating immune cells Neutralization of TL1A suppresses inflammation and Neutralization of IL-23 inhibits cascade of from entering inflamed gut tissues reduces fibrosis by inhibiting fibroblast activation various proinflammatory cytokines anti-IL-23 anti-α4β7 anti-TL1A Created with BioRender.com; Neurath, Markus F. Nature Reviews Gastroenterology & Hepatology 14.5 (2017): 269-278; Solitano, Virginia, et al. Med (2024). 12

JNJ’s VEGA study demonstrated the power of combination therapy in IBD VEGA combination study (N=71/arm) – Ulcerative colitis ~Additive absolute W12 MMS clinical remission rates Δ+22% 47% 22% 25% 24% 25% Anti-TNF Anti-IL23 Combination (Golimumab) (Guselkumab) BLACK BOX WARNING PROBABLE BLACK BOX Sources: Feagan, B. G. et al. Lancet Gastroenterol. Hepatol. 8, 307–320 (2023). 13

Spyre combinations are rational alternatives to combos with clinical precedent Clinical trial Precedent combination Spyre combinations & rationale 1 Spyre component exchange EXPLORER Crohn’s – Endoscopic remission % • Exchange TNF for another TNF 35% superfamily targeting agent 30% 27% • TL1A efficacy and safety appears superior on a cross-trial basis SPY120 α4β7 TNF TL1A Anti-α4β7 Anti-TNF Combination 2 VEGA UC – MMS remission % • Exchange TNF for a safer and 47% more effective class 25% 24% • Entyvio was superior to Humira in H2H clinical studies (VARSITY) SPY130 IL-23 TNFα4β7 Anti-IL23 Anti-TNF Combination 2 VEGA UC – MMS remission % • Exchange TNF for another TNF 47% superfamily targeting agent 25% 24% • TL1A efficacy and safety appears superior on a cross-trial basis SPY230 IL-23 TNF TL1A Anti-IL23 Anti-TNF Combination 1 Note: EXPLORER meta-analysis assumes a 27% remission rate for vedolizumab and 30% remission rate for adalimumab; EXPLORER included methotrexate treatment 1 2 Source: Colombel, Jean-Frederic, et al. Clinical Gastroenterology and Hepatology 22.7 (2024): 1487-1496. Feagan, Brian G., et al. The Lancet Gastroenterology & Hepatology 8.4 (2023): 307-320; 14

Spyre monotherapies and combinations have potential best-in-indication Q3M & Q6M dosing profile for IBD 1 Expected Annual Maintenance Dosing Category Benchmark Annual injections SPY001 2 - 4x SC Q3M-Q6M SPY002 2 - 4x SC Q3M-Q6M SPY003 2 - 4x SC Q3M-Q6M Portfolio SPY120/130/230 2 - 4x SC Q3M-Q6M α4β7 Mono Entyvio 26x SC Q2W 2 TL1A Mono Tulisokibart 13 - 26x SC Q2-Q4W IL-23 Mono Skyrizi 6x OBI Q8W Simponi TNF Mono 12x SC Q4W Black box 3 JNJ’4804 Combos 12x SC Q4W Probable black box 1 2 3 Source: Product labels and disclosed clinical trials. Annual injections after induction doses; Based on NCT06430801 Version 1 JNJ’4804 is Johnson and Johnson’s combination of Simponi (anti-TNF) and Tremfya (anti-IL-23); OBI=on body injector 15

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- 1 (VEGA ) class efficacy with SPY001 SPY002 SPY003 higher exposures 20 Standard of care IBD biologics Potential for Q3M & Q6M dosing profiles 0 1 2 3 4 5 6 Maintenance dosing interval (months) 1 Note: VEGA trial was not pbo-controlled. 16 Pbo-adjusted clinical remission (%)

Spyre’s planned platform trial enables multiple placebo- controlled readouts of monotherapies and combinations Pending regulatory feedback Design elements Illustrative schematic Design SPY001 (α4β7) • Master protocol platform trial SPY002 (TL1A) • Double blind, placebo-controlled SPY003 (IL-23) Population 1 • Moderately-to-severely active ulcerative R SPY120 (α4β7 + TL1A) colitis SPY130 (α4β7 + IL-23) • N = ~600 SPY230 (TL1A + IL-23) Key endpoints • Primary: Clinical remission (W12) Placebo • Secondary: Endoscopic improvement (W12), Clinical response (W12), Platform design allows cohorts to be added over time. Anticipate initiating trial with Histological improvement (W12), monotherapies beginning in mid-2025 with open-label mono readouts beginning in mid-2026. Histologic-endoscopic improvement (W12) 1 Notes: Randomization among active arms; all arms may not start and finish simultaneously 17

Comparison to other trials highlights potential advantage of designing a portfolio from the ground up w/ unified dosing 1 rd 2 Planned platform trial Example 3 party platform trial Induction (12W) Maintenance (through 24W) Trial arm Induction (12W) Maintenance (through 26W) Trial arm Placebo Q3M Q4W Mono 1 SPY001 Q3M Q2W Mono 2 Q3M SPY002 Q3M SPY003 Q8W Mono 3 Q3M SPY120 Q2W Combo 1 SPY130 Q3M Q4W Combo 2 SPY230 Q3M ü Unified dosing intervals and formats enables blinded trial × Unblinded, open-label trial ü Two IV induction doses, Q3M-Q6M SC chronic dosing × Mix of IV, SC, and OBI routes of administration ü Clear approach to advance coformulation for Ph3; >180mg/mL × Combos default to highest dosing frequency (Q2W or Q4W) citrate-free formulations in development for all SPY product × Unclear strategy to single product combination for Ph3 candidates 1 2 Note: Pending regulator feedback; Inferred 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 18

Platform design is attractive to patients and investigators with 6 ways to win at up to 40% lower cost 6 High enthusiasm 6 ways to win Operational efficiency With 3 combination arms and Including 3 optimized monotherapies & Up to 40% lower cost vs. low placebo randomization rate 3 paradigm-changing combinations individual Ph2 trials Startup activities underway with FPI anticipated in mid-2025, pending regulatory feedback 19

Optimized coformulations are the preferred approach for inhibiting multiple targets in IBD Allows for dose optimization Coformulations allow opportunity for adjustment of antibody ratios to achieve of each component desired concentration of each mAb Coformulations retain extension of monoclonal half-lives and support extended Extended dosing intervals dosing intervals Potentially improved Coformulations have the potential to retain or improve immunogenicity profile of immunogenicity profile monotherapy antibody components Appropriate for targets in α4β7 exists on circulating immune cells whereas IL-23 and TL1A are cytokines different compartments located in inflamed tissue 20

>100 surveyed gastros showed a strong preference for long- acting, safe combinations with efficacy +10pp over monos Relative preference share of hypothetical IBD market entrants ~7x Hypothetical Q3M Spyre combo ~3x Hypothetical monthly TNF Hypothetical combo TNF-like agent Efficacy ~25% ~35% ~35% MMS clinical remission Safety Black box Black box No black box Dosing Q1M Q1M Q3M Source: Spyre conjoint survey of >100 U.S. gastroenterologists 21 Profile tested

TL1A indication expansion

TL1A has scientific rationale across multiple diseases 1 TL1A exacerbates inflammation TL1A has been implicated in a wide range of human diseases and fibrosis based on genetic, proteomic, and/or preclinical data Not exhaustive • Ulcerative colitis (UC) Gastroenterology • Crohn’s disease (CD) • Rheumatoid arthritis (RA) • Systemic lupus erythematosus (SLE) Rheumatology • Axial spondyloarthritis (axSpA) • Psoriatic arthritis (PsA) • Systemic sclerosis-interstitial lung disease (SSc-ILD) • Asthma Pulmonology • Pulmonary sarcoidosis • Psoriasis (PsO) • Hidradenitis suppurativa (HS) Dermatology • Atopic dermatitis (AD) 1 Note: Figure created with BioRender.com; Non-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). 23

Rheumatoid arthritis (RA) is a foothold to the >$30B rheumatology market WW Sales by indication (2028E) No novel MOAs have been introduced in RA since U.S. Dollars 2012 despite the potential for multi-$B peak sales MOA entry year and global peak sales IBD 1998 2005 2006 2011 2012 2025 Rheumatology >100% TNF CD20 JAK ~$18B ~$1B ~$5B ~$18B RA CD80/86 IL-6 ~$4B ~$4B ~$18B ~$18B CD ~$12B ~$12B UC Source: Barclays UCB Immunology Deep Dive (2023); Evaluate Pharma (2024); company websites. 24

Significant unmet need remains in RA despite multiple approved MOAs 60 Support for SPY002 TPP TNF CD80/86 CD20 IL-6 50 § Novel MOAs are still needed to treat RA, particularly for refractory patients who cycle through all MOAs 40 “ … We need more new medicines with new mechanisms of action, as we know some patients won’t respond …” - Rheumatologist, Academic Medical Center 30 Potential for novel MOA with comparable- to-better efficacy and improved SC dosing frequency (Q3M-Q6M)§ Many patients will prefer less frequently dosed 20 therapies, assuming similar (or better) efficacy “… The idea that you could take a medicine twice a year 10 and get similar efficacy would be very attractive ...” - Rheumatologist, Private Practice 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Dosing interval (weeks) 1 Note: Data at 12W or 16W if 24W unavailable; data from studies with all MTX- and bDMARD-naïve patients were excluded; For Rituxan, each dose requires 2 infusions separated by 2 weeks; Anakinra not shown (~9% pbo-adjusted ACR40 and QD (once-daily) SC dosing). TPP=target product profile. 25 1 Efficacy (pbo-adjusted ACR50 at 6 months , %)

Multiple published studies support anti-TL1A as a potential treatment option in RA TL1A is elevated in RA patients relative to healthy TL1A administration exacerbates arthritis in murine models 1, 2, 3 2,4 controls & increases with disease severity and administration of anti-TL1A reduces arthritis TL1A serum concentration TL1A serum concentration Murine arthritis score Anti-TL1A dramatically reduces erosions in hind paws of CIA mice p < 0.001 p = 0.009 p < 0.05 Ig Healthy RA patients Moderate RA Severe RA 0 1 10 100 No CIA anti-TL1A control TL1A concentration (ng) 1 2 3 4 Source: Sun, X. et al. Scand. J. Rheumatol. 42(2), 97-101 (2013); Song, Y. et al. Arthritis Res. Ther., 22(1), 106 (2020); Bamias, G., Clin. Immunol., 129(2), 249-255 (2008); Bull, M., et al. J. Exp. Med. 205(11); Charts are illustrative representations of figures within data sources. CIA=collagen-induced arthritis 26

Spyre anti-TL1A antibody meets or exceeds the efficacy of etanercept (anti-TNF) in rat models of RA Superior efficacy vs. anti-TNF in semi-preventative model Comparable efficacy vs. anti-TNF in therapeutic model Healthy Healthy 8 8 Vehicle Vehicle Isotype control Isotype control 6 6 Etanercept Etanercept anti-TL1A 4 anti-TL1A 4 * * 2 2 * * * 0 0 0 10 20 30 0 10 20 30 Day Day Collagen Collagen immunization immunization etanercept (anti-TNF) etanercept (anti-TNF) anti-TL1A anti-TL1A Start of Start of treatment treatment Note: * P< 0.0001 vs. isotype control; 2-way ANOVA using Dunnett's correction for multiple comparisons. 27 Arthritis score Arthritis score

Spyre anticipates RA Ph2 initiation in mid-2025 with topline data expected 2H26 2024 2025 2026 SPY002-072 (TL1A) Phase 1 (Healthy volunteers) FPI 4Q24 SPY002-091 (TL1A) Phase 1 (Healthy volunteers) FPI Interim data & molecule selection 4Q24 2Q25 SPY002 (TL1A) FPI Topline results Phase 2 (RA patients) Mid-2025 2H26 Anticipated milestones as of January 13, 2025, subject to regulatory feedback. 28

Corporate Team and cash runway

Leadership Scott Burrows Brian Connolly Melissa Cooper Paul Fehlner Joshua Friedman Janet Gunzner-Toste Chief Financial Officer Chief Technical Officer SVP, People SVP, Chief Intellectual SVP, Clinical Development SVP, Operations Property Counsel MiRa Huyghe Heidy King-Jones Justin LaFountaine Deanna Nguyen Sheldon Sloan Andrew Spencer Cameron Turtle SVP, Development Chief Legal Officer and SVP, Corporate SVP, Clinical Chief Medical Officer SVP, Preclinical Research Chief Executive Officer Operations Corporate Secretary Development Development and Development 30

Board of Directors Peter Harwin Michael Henderson Tomas Kiselak Jeffrey Albers Mark McKenna Sandra Milligan Laurie Stelzer Cameron Turtle 31

Catalyst rich 2025 planned with expected Ph1 readouts on TL1A and IL-23 programs and multiple Ph2 initiations 2025 2026 q UC Platform Ph2 Initiationq UC Ph2 data SPY001 (α4β7) q UC Ph2 data q Ph1 data (2Q)q RA Ph2 Initiation SPY002 (TL1A) q RA Ph2 data q Ph1 Initiation (1Q)q Ph1 dataq UC Ph2 data SPY003 (IL-23) q DUET-UC/CD Ph2b External events JNJ TNF + IL-23 combo Anticipated milestones as of January 13, 2025 subject to regulatory feedback. 32

Cash and shares outstanding 1 $603M preliminary cash as of December 31, 2024 Number of shares (M) Expected runway into 2H 2028 Common stock • Shares outstanding 60.3 • Series A preferred stock 13.8 Common stock equivalents • Series B preferred stock 0.7 Common stock and common • Total outstanding 74.8 2 stock equivalents 1 Notes: Cash includes cash, cash equivalents, & marketable securities as of 12/31/24 on a preliminary and unaudited basis, subject to adjustment. The Company expects to report its final and complete fourth 2 quarter and full-year 2024 financial results in late February 2025; Shares outstanding on a pro forma and as-converted basis as of 12/31/24, 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. 33

Thank you

SPY001 Appendix Next-generation anti-α4β7 antibody

SPY001 is engineered to have next-generation antibody properties Identical epitope target as vedolizumab with comparable potency and selectivity in vitro >90-day human half-life supports both Q3M and Q6M SC maintenance dosing regimens IND-enabling tox studies completed with NOAEL at the highest dose tested High concentration (180 mg/mL) citrate-free SC formulations developed for clinical studies SPY001 Phase 1 study ongoing with interim data announced Nov. 2024 36

SPY001 potency & selectivity match vedolizumab in vitro SPY001 & vedolizumab epitope Potent and selective inhibition of cellular adhesion SPY001 and SPY001 and vedolizumab potently inhibit No inhibition of unwanted VCAM-1- vedolizumab MAdCAM-1-mediated (gut) cellular adhesion mediated (CNS) cellular adhesion bind the same α4 Subunit epitope 70 SPY001 (IC = 86 pM) 50 70 SPY001 Vedolizumab (IC = 83 pM) 50 Vedolizumab 60 60 (α4β1) Natalizumab β7 Subunit 50 50 40 40 30 30 20 20 Potent and selective binding to α4β7 10 10 1 0 Antibodyα4β7α4β1αEβ7 0 -10 2 2 SPY001 K <1 nM NB NB 0.01 0.1 1 10 D 0.001 0.01 0.1 1 10 100 mAb Concentration (nM) mAb Concentration (nM) 2 2 Vedolizumab K <1 nM NB NB D 1 Dissociation constant (K ) measured by surface plasmon resonance (SPR) D 2 NB = no binding by a particular antibody to a test molecule Source: Data on file. Vedolizumab is a synthesized comparator antibody. 37 %Inhibition of Total Adhesion (Integrin-mediated Adhesion by MAdCAM-1) %Inhibition of Total Adhesion (Integrin-mediated Adhesion by VCAM-1)

SPY001 Phase 1 trial is ongoing - interim data includes up to 4 months of follow up (10/30/24 data cutoff) Multiple ascending dose follow up Trial design elements Single ascending dose follow up Design ~4 months ~2 months 300 mg SC 300 mg SC • Double-blind, pbo-controlled, first-in-human trial • Nested SAD and MAD cohorts ~3 months ~1 month 600 mg SC 600 mg IV Population • Healthy adult volunteers ~2 months 1000 mg SC • N=8/cohort (3:1 randomization) Endpoints ~1 month 1000 mg IV • Primary: Safety • Secondary: Pharmacokinetics, anti-drug antibodies (ADAs) ~1 month 100 mg SC • Exploratory: Pharmacodynamic markers 38

Interim data show SPY001 was well tolerated with a favorable safety profile SAD MAD 100 mg 300 mg 600 mg 1000 mg 1000 mg Pooled 300 mg 600 mg Pooled N (%) N= 8 8 8 8 8 40 8 8 16 At least one 1 (13%) 3 (38%) 2 (25%) 3 (38%) 0 9 (23%) 2 (25%) 3 (38%) 5 (31%) TEAE At least one 0 0 0 0 0 0 0 0 0 TESAE At least one Drug-related 0 0 0 1 (13%) 0 1 (3%) 0 0 0 1 AE At least one 0 0 0 0 0 0 0 0 0 ≥Grade 2 TEAE 1 TEAE=treatment-emergent adverse events. TESAE=treatment-emergent serious adverse events. Injection site discomfort starting 6 hours after 4 SC injections and resolved 2 hours later without intervention. 39

Interim data demonstrated >90-day half-life, which exceeded 1 expectations (~4-fold vs. published vedo half-life ) SPY001 simulated concentration-time profile Human half-life SPY001 300mg SC Vedolizumab 300mg SC Median +/- IQR SPY001 >90 days ~4-fold VEDO ~25 days 1 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). 40 Serum Conc. (µg/mL)

SPY001 exhibits dose-proportional pharmacokinetics SAD mean PK profiles MAD mean PK profiles t > 100 days 1/2 t = 91 days 1/2 1 Dose proportionality observed between 300 - 1000 mg Initial MAD PK consistent with SAD PK 1 Note: Cohorts with sufficient follow up for dose proportionality assessment. 41 Mean Serum Conc. (µg/mL) Mean Serum Conc. (µg/mL)

Modeled Phase 2 induction exposures exceeded those of vedolizumab with all patients anticipated in quartile 4 Potential upside: Greater remission w/ higher exposure Phase 2 Induction human PK simulations Targeting all patients with W6 1 Vedolizumab Week 14 Deep Remission Rates in UC (%) concentration in Quartile 4 SPY001 By Week 6 trough concentration quartile ~100% Vedolizumab 100 Median +/- IQR 50 Quartile 4 ~25% 37% (41-100 µg/mL) 0 Vedo SPY001 Quartile 3 31% (32-41 µg/mL) Quartile 2 20% Vedo W6 Quartile 4 (25-32 µg/mL) Quartile 1 12% (2-25 µg/mL) +25% FDA pharmacology review recommended testing higher vedo doses 2 post-marketing with the aim to improve induction efficacy 1 2 Source: Casteele, N. V. et al. Aliment. Pharmacol. Ther. 56, 463–476 (2022); Vedolizumab FDA Clinical Pharmacology Review; PK simulation for comparator molecules based on published clinical data. 42 Serum Conc. (µg/mL) % patients in Q4

Population PK modeling for SPY001 supports potential for both Q3M and Q6M maintenance dosing regimens Maintenance human PK simulations Maintenance Induction 2-4x SC maintenance injections per year SPY001 Q3M SC SPY001 Q6M SC Vedolizumab Q2W SC Data on file, simulations represent median +/- interquartile range. 43 Serum Conc. (µg/mL)

SPY001 saturated α4β7 receptors through ~12-weeks of follow-up after a single dose % MAdCAM-1 Bound on CD4+ Memory T cells Notes: Data shown are Mean +/- SD for each cohort at each visit; pooled placebo. (n): Placebo (2-6), SPY001 300 mg SC (5-6), SPY001 600 mg SC (6), SPY001 1000 mg SC (6). Data have been slightly offset for visualization. 44

SPY001 Phase 1 interim results summary (10/30/24 cutoff) SPY001 was well tolerated Favorable safety profile across all dose levels Half-life of >90 days, far Potential for as little as twice-yearly maintenance dosing in a single exceeding expectations SC injection compared to 26 yearly SC injections for vedo Ph2 induction dosing to test Potential for increased or accelerated induction efficacy by targeting th higher exposures all patients in the 4 quartile of vedo’s reported E-R relationship PD markers demonstrated target Single dose of SPY001 saturated α4β7 receptors through available 12 engagement weeks of follow-up (inhibition still ongoing) 45

SPY002 Appendix Next-generation anti-TL1A antibody

SPY002 candidates are engineered to achieve an optimal profile Advanced two candidates into Ph1 with novel epitopes that optimize potency and binding profiles in vitro Half-life extension through validated Fc modification to potentially enable Q3M-Q6M SC dosing IND-enabling tox studies completed with NOAEL at the highest dose tested High concentration (200 mg/mL) citrate-free SC formulations developed for clinical studies SPY002 Ph1 study initiated in Q4 2024 47

Each SPY002 development candidate targets a distinct epitope and exhibits unique binding properties Single TL1A subunit epitope Superior or comparable potency in multiple assays Each SPY002 candidate targets a distinct Superior or comparable inhibition of TF-1 Superior or comparable inhibition of IFNγ epitope on a single TL1A monomer apoptosis secretion Duvakitug (TEV-48574) SPY002 candidates RO7790121 RO7790121 (RVT-3101) Duvakitug Tulisokibart Tulisokibart (MK-7240) 100 100 80 80 60 60 40 40 20 20 0 0 • Epitope locations were resolved by CryoEM 0.01 0.1 1 10 100 0.1 1 10 100 1000 10000 100000 mAb Concentration (nM) mAb Concentration (ng/mL) • Illustrative locations are overlayed with the crystal structure of trimeric TL1A Source: Data on file. Duvakitug not benchmarked in IFN secretion assay; Duvakitug, RO7790121, and tulisokibart are synthesized comparator antibodies. γ 48 Inhibition % Inhibition%

SPY002 candidates exhibit increased half-life in NHP compared to first-generation anti-TL1As SPY002 DC1: >2-3x Increased Half-life in NHPs SPY002 DC2: >2-3x Increased Half-life in NHPs SPY002 t : ~24 days SPY002 t : ~24 days 1/2 1/2 Tulisokibart t : ~12 days Tulisokibart t : ~12 days 1/2 1/2 RO7790121 t : ~7 days RO7790121 t : ~7 days 1000 1000 1/2 1/2 100 100 10 10 1 1 0 14 28 42 56 70 84 98 0 14 28 42 56 70 84 98 Time (day) Time (day) Source: Data on file. Group size was n=5 for SPY002 mAbs and tulisokibart at final endpoints for half-life determination; No RO7790121 detected after day 28; Duvakitug not compared in these models given low human half-life (7-10 days), ECCO 2024 abstract P633; Duvakitug, RO7790121, and tulisokibart are synthesized comparator antibodies. 49 Serum Conc. (μg/mL) Serum Conc. (μg/mL)

SPY002 Phase 1 initiated in 4Q 2024 Expected Ph1 study design Phase 1 milestones ü q IND clearance ü q Phase 1 initiation in 4Q 2024 SAD 5 q Interim FIH data expected 2Q 2025 SAD 4 SAD 3 q Safety and tolerability SAD 2 q Pharmacokinetics SAD 1 q Pharmacodynamics (sTL1A) q ADA Single-ascending and multiple-ascending dose cohorts • Healthy volunteers • n=8/cohort (3:1 randomization) Phase 1 results to inform which molecule advances to Phase 2 development 50

Phase 1 interim PK to confirm the potential of Q3M-Q6M maintenance dosing, as predicted by NHP data​ SPY002 human half-life targets Human PK simulations Q3M based on Q6M based on Half-life (days) PK modeling PK modeling SPY002 Tulisokibart 1 Humans ~45 ~65 24 NHPs 2 Humans 19 Q2-4W SC 3 NHPs 12 1 2 3 Source: Human YTE mAb half-life is on average 3.1x of NHP half-life; Haraya, Kenta, and Tatsuhiko Tachibana. BioDrugs (2023); Prometheus corporate presentation – Ph1 results; Spyre preclinical studies; tulisokibart is a synthesized comparator antibody 51 TULISOKIBART SPY002 Serum Conc. (µg/mL)

Tulisokibart and RO7790121 dose responses support opportunity for improved efficacy in maintenance Clinical remission (mMayo) Endoscopic improvement W50 or W56 250 mg 48% 48% Q4W TULISOKIBART 100 mg 32% 36% ARTEMIS-UC Q4W Greater maintenance efficacy with higher doses 250 mg 56% 68% TULISOKIBART Q4W APOLLO-CD 100 mg 42% 59% Q4W 450 mg 36% 50% Q4W Greater maintenance RO7790121 150 mg 39% 39% efficacy with higher Q4W TUSCANY-2 doses 50 mg 31% 38% Q4W Source: UEGW 2024 posters OP079 and OP196; Artemis and Apollo patients were re-randomized for maintenance period while Tuscany-2 was a treat-through design. 52

SPY003 Appendix Next-generation anti-IL-23 antibody

SPY003 is engineered to have next-generation antibody properties Similar epitope target as risankizumab with comparable potency and selectivity in vitro Half-life extension through validated Fc modification to potentially enable Q3M-Q6M SC maintenance dosing IND-enabling tox studies completed with NOAEL at the highest dose tested High concentration (180 mg/mL) citrate-free SC formulation developed for clinical studies SPY003 Ph1 study initiation expected in 1Q 2025 Note: SPY003 license is restricted to IBD indications. 54

SPY003 targets a similar epitope as risankizumab with comparable potency in vitro Similar epitope to risankizumab Comparable potency in multiple assays SPY003 and risankizumab bind the SPY003 and risankizumab potently SPY003 and risankizumab potently same p19 subunit of IL-23 inhibit pSTAT signaling inhibit IL-17 release SPY003 Risankizumab 100 100 50 50 0 0 0.01 0.1 1 10 100 1000 0.001 0.01 0.1 1 10 100 SPY003 epitope mAb Concentration (nM) mAb Concentration (nM) Risankizumab epitope Source: Data on file. Risankizumab is a synthesized comparator antibody. 55 % Inhibition % Inhibition

SPY003 exhibits >3x the half-life of risankizumab in NHPs NHP PK profiles of SPY003 and risankizumab Half-life 1000 ~30 days SPY003 100 ~3-fold vs. risankizumab 10 ~9 days Risankizumab 1 0 14 28 42 56 70 84 98 Days Source: Data on file. Group size was n = 4 in the NHP studies with n = 4 and n = 3 at the final timepoint for half-life determination for SPY003 and risankizumab, respectively. Risankizumab is a synthesized comparator antibody. 56 Serum Conc. (μg/mL)

SPY003 Phase 1 initiation expected in 1Q 2025 Expected Ph1 study design Phase 1 milestones q Phase 1 initiation expected 1Q 2025 q Interim FIH data expected 2H 2025 SAD 5 q Safety and tolerability SAD 4 SAD 3 q Pharmacokinetics SAD 2 q ADA SAD 1 Single-ascending and multiple-ascending dose cohorts • Healthy volunteers • n=8/cohort (3:1 randomization) 57

Phase 1 interim PK to confirm the potential of Q3M-Q6M maintenance dosing, as predicted by NHP data​ SPY003 human half-life targets Human PK simulations SPY003 Q3M based on Q6M based on Half-life (days) Risankizumab PK modeling PK modeling 1 Humans ~45 ~60 30 NHPs 2 Humans 28 Q8W OBI 3 NHPs 9 1 2 3 Source: Human YTE mAb half-life is on average 3.1x of NHP half-life; Haraya, Kenta, and Tatsuhiko Tachibana. BioDrugs (2023); Skyrizi BLA Spyre preclinical studies; risankizumab is a synthesized comparator antibody. 58 RISA SPY003 Serum Conc. (µg/mL)

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Document and Entity Information	Jan. 13, 2025
Cover [Abstract]
Amendment Flag	false
Entity Central Index Key	0001636282
Document Type	8-K
Document Period End Date	Jan. 13, 2025
Entity Registrant Name	SPYRE THERAPEUTICS, INC.
Entity Incorporation State Country Code	DE
Entity File Number	001-37722
Entity Tax Identification Number	46-4312787
Entity Address, Address Line One	221 Crescent Street
Entity Address, Address Line Two	Building 23
Entity Address, Address Line Three	Suite 105
Entity Address, City or Town	Waltham
Entity Address, State or Province	MA
Entity Address, Postal Zip Code	02453
City Area Code	617
Local Phone Number	651-5940
Written Communications	false
Soliciting Material	false
Pre Commencement Tender Offer	false
Pre Commencement Issuer Tender Offer	false
Security 12b Title	Common Stock, $0.0001 Par Value Per Share
Trading Symbol	SYRE
Security Exchange Name	NASDAQ
Entity Emerging Growth Company	false