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CORRESP

 Gibson, Dunn & Crutcher LLP

One Embarcadero Center, Suite 2600

 San Francisco, CA
94111-3715

 Tel 415.393.8200

 gibsondunn.com

 February 2, 2024

 EDGAR
CORRESPONDENCE

 U.S. Securities and Exchange Commission

Division of Corporation Finance

 Office of Life Sciences

100 F Street, N.E.

 Washington, D.C. 20549

Attn: Lauren Hamill and Jason Drory

Re:
 Spyre Therapeutics, Inc.

Registration Statement on Form S-1

Filed on December 22, 2023

File No. 333-276251

Ladies and Gentlemen:

 On behalf of Spyre
Therapeutics, Inc. (the “Company” or “Spyre”), this letter responds to the comments of the staff of the Securities and Exchange Commission Division of Corporation Finance (the “Staff”) contained in
your letter, dated January 18, 2024 (the “Comment Letter”) regarding the above-referenced Registration Statement on Form S-1 (the “Registration Statement”). The
Staff’s comments are set forth below, followed by the Company’s responses. For ease of reference, the heading and numbered paragraphs below correspond to the heading and numbered comments in the Comment Letter. The Company’s responses
are set forth in ordinary type beneath the Staff comment, which is set out in bold type. References are made to the Company’s Amendment No. 1 to the Registration Statement (the “Amendment”), filed on February 2, 2024.

 Company Overview, page 4

1.
 On page 4 and in your Business section, please revise your disclosure to:

•

 Disclose the meaning of “combinations of proprietary antibodies,” “patient enrichment
strategies,” and “companion diagnostics;”

•

 With reference to your disclosure on page F-58, explain how you plan
to develop your portfolio of individual treatments to create therapeutic combination candidates, and clarify whether you plan to develop any of your candidates for use both as monotherapies and combination therapies;

•

 Explain how you plan to develop and use each of patient enrichment strategies and companion diagnostics in
your development strategy; and

 Abu Dhabi • Beijing • Brussels • Century City • Dallas •
Denver • Dubai • Frankfurt • Hong Kong • Houston • London • Los Angeles

 Munich • New York • Orange
County • Palo Alto • Paris • Riyadh • San Francisco • Singapore • Washington, D.C.

 U.S. Securities and Exchange Commission

February 2, 2024

•

 Explain how your plan to use combination candidates and patient enrichment strategies via companion
diagnostics may “enhance efficacy” in your programs. Further, please qualify your statements on pages 4, 49, and 66 to clarify that your ability to execute your strategy to “enhance efficacy” is currently aspirational.

 In response to the Staff’s comment, the Company has further clarified its plans for the development of its product candidates.
The Company submits that in addition to its plan to develop its product candidates as potential monotherapies, the Company also plans to investigate combinations of its proprietary antibodies in preclinical and clinical studies to evaluate whether
combination therapy (co-administration or co-formulation of multiple monoclonal antibodies) can lead to greater efficacy, less frequent dosing, or the enhanced
identification of patients with responsive profiles, in each case, as compared to monotherapies in IBD. This is expected to initially include SPY120, which combines SPY001 (α4ß7) and SPY002 (TL1A), and is anticipated to be followed by
combinations that include SPY003 (IL-23), SPY130 (a combination of SPY001 and SPY003) and SPY230 (a combination of SPY002 and SPY003). The Company also submits that it has no existing plans to develop
companion diagnostics restricting usage of its products to a specific sub-population of patients; instead, it intends to examine patient selection strategies via complementary diagnostics utilized in its proof-of-concept clinical studies in order to
evaluate whether patients may be matched to the optimal therapy based on genetic background and/or other biomarker signatures. Accordingly, the Company has revised its disclosure on pages 4 and 5 of the Amendment and deleted references to
“enhance efficiency” on pages 4, 52 and 73.

2.
 With respect to your strategy to use patient enrichment strategies via companion diagnostics:

•

 Please disclose in an appropriate place in the Summary and Business sections whether you anticipate that any
or all of your programs will require you to develop and obtain FDA approval of a companion diagnostic.

•

 Include balancing disclosure regarding any material risks or challenges that the development and/or use of
companion diagnostics might pose to your business and/or development strategy.

 In response to the Staff’s comment, the Company
submits that it currently intends to examine patient selection strategies via complementary diagnostics utilized in its proof-of-concept clinical studies rather than pursuing companion diagnostics. Accordingly, the Company has added disclosure on
the regulatory pathway of approval for complementary diagnostics and has balanced such disclosure with a discussion of material risks or challenges inherent in the development of complementary diagnostics on pages 4, 52 and 73 of the Amendment,
respectively.

3.
 Please revise to qualify the following statement that appears on pages 4 and 66: “We have purposely
engineered our product candidates to bind potently and selectively to target epitopes with extended half-lives.” In this regard, we note your disclosure on page 48 indicating that potent binding and selectivity are “the aim” of your
product engineering.

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 U.S. Securities and Exchange Commission

February 2, 2024

 In response to the Staff’s comment, the Company has revised its disclosure on pages 4 and 73 of the
Amendment to remove “purposely” from the referenced statement and added additional clarifying language.

4.
 We note that your statement on page 17 that your success is “dependent on observing a longer half-life
of your programs in humans than other mAbs currently marketed and in development” lacks sufficient context in the Summary and Business sections.

•

 Please revise pages 4 and 66 to clearly describe your strategy to engineer “long-acting” product
candidates that will exhibit extended pharmacokinetic half-lives.

•

 In your revisions, please also specifically explain the meaning of the term “extended half-life” and
how your focus on half-life extension relates to potential dosing convenience or otherwise advise.

 In response to the Staff’s
comment, the Company has revised its disclosure on pages 4, 52 and 74 of the Amendment by providing additional detail regarding its strategy of engineering its product candidates. In doing so, the Company has explained that “extended
half-life” means extended pharmacokinetic half-lives that are achieved through modifications in the Fc domain that increase affinity to human FcRn and increase antibody recycling. Furthermore, the Company has explained that it anticipates that
half-life extension will enable less frequent administration compared to marketed or development-stage monoclonal antibodies that do not incorporate half-life extension modifications.

5.
 We note your stated intention to deliver your product candidates through self-administered, subcutaneous
injection via a pre-filled pen. Please revise your Summary and Business sections to disclose whether you anticipate that your product candidates may be regulated by the FDA as drug/device combination products.
Explain the implications of drug/device combination product classification with respect to the regulatory approval process, including how this process differs from the process of obtaining FDA approval for drugs.

In response to the Staff’s comment, the Company submits that while a pre-filled pen is an industry-standard
approach for subcutaneously-delivered monoclonal antibodies that is not typically regulated as a drug/device combination and is frequently utilized by other drug developers, the specific delivery mechanism or technology that the Company intends to
use to deliver its product candidates is currently under review and has not yet been selected. Accordingly, the Company has revised its disclosure on pages 5 and 52 of the Amendment. Furthermore, the Company has added disclosure under the Summary
and Business on pages 4, 5 and 74 of the Amendment regarding the regulation of combination products on page 88 of the Amendment.

 3

 U.S. Securities and Exchange Commission

February 2, 2024

6.
 Please balance the discussion of your Company’s development strategy and candidate programs by
prominently highlighting in the Summary that:

•

 the drug and/or device development process is inherently uncertain, your development approach is unproven,
preclinical evidence to support your approach is preliminary and limited, and you have yet to test any product candidate in humans; and

•

 there can be no guarantee that you will be able to develop product candidates that will be found to be safe
and effective so as to obtain necessary regulatory approvals.

 In response to the Staff’s comment, the Company has revised its
disclosure on page 76 of the Amendment to balance the discussion of its development strategy and candidate programs with additional bold-faced disclaimer language.

Risk Factor Summary, page 9

7.
 We note your stated plan to use patient enrichment strategies via companion diagnostics in your product
development. If material, please add summary risk and corresponding risk factor disclosure addressing the risks and challenges related to your proposed use of companion diagnostic tools needed to leverage your strategy.

In response to the Staff’s comment, the Company submits that development of companion diagnostics is not currently core to its plans; instead, it intends
to focus on examining patient selection strategies via complementary diagnostics in its clinical studies to evaluate whether patients can be matched to the optimal therapy based on genetic background and/or other biomarker signatures. Accordingly,
the Company has revised its disclosures on pages 10, 20, 23 and 24 of the Amendment.

8.
 Given your stated intention to deliver your product candidates through injection via a prefilled pen, please
add summary risk and corresponding risk factor disclosure discussing any risks or challenges related to the development and/or regulatory approval of your product candidates if the FDA may consider your product candidates to be drug/device
combination products.

 In response to the Staff’s comment, the Company submits that while a
pre-filled pen is an industry-standard approach for subcutaneously delivered monoclonal antibodies that is not typically regulated as a drug/device combination and is frequently utilized by other drug
developers, the specific delivery mechanism for its product candidates is currently under review and has not yet been selected. Accordingly, the Company has revised its disclosure on pages 5, 10, 23 and 52 of the Amendment to clarify that it is
evaluating delivery mechanisms and has not yet selected a final delivery mechanism and to add risk factor disclosure discussing the risks or challenges related to the development and/or regulatory approval of our product candidates in conjunction
with the development and/or regulatory approval of drug delivery device(s) through which we intend to deliver our product candidates.

 4

 U.S. Securities and Exchange Commission

February 2, 2024

 Risk Factors

We will need to raise additional capital…, page 11

9.
 On page 12, please remove the reference to being subject to the limitations set forth in Instruction I.B.6
of Form S-3, or otherwise advice.

 In response to the Staff’s comment, the Company has
revised its disclosure on page 13 of the Amendment to remove the reference.

 We have historically incurred losses, have a limited operating
history…, page 13

10.
 In the first sentence of the third paragraph, please revise to clarify whether the reference to
“conducting clinical trials” pertains only to your legacy product candidates. In this regard, it appears from your disclosure throughout that all of your current programs are in preclinical stages of development and have not yet been
tested in humans.

 In response to the Staff’s comment, the Company confirms that the reference to “conducting clinical
trials” pertains only to its legacy product candidates. Accordingly, the Company has revised its disclosure on page 15 of the Amendment to clarify the development status of its current product candidates.

11.
 We note your disclosure that the holders of your Series B Preferred Stock may be entitled to require you to
settle their shares of Series B Preferred Stock for cash at a price per share equal to the fair value of the Series B Preferred Stock, as described in your Series B Certificate of Designation. Please revise your disclosure to describe how the fair
value is determined and quantify the aggregate amount of the potential cash redemption as of a recent date or otherwise advise.

 In
response to the Staff’s comment, the Company has revised its disclosure on page 15 of the Amendment to add a discussion of how fair value is determined in connection with a hypothetical cash settlement of Series B Preferred Stock and the
aggregate amount of a potential cash settlement, for illustrative purposes, if the Company was obligated to settle the conversion of all outstanding Series B Preferred Stock as of January 2, 2024, pursuant to the terms of the Series B
Certificate of Designation.

 5

 U.S. Securities and Exchange Commission

February 2, 2024

 Our Certificate of Incorporation provides that…, page 42

12.
 We note the exclusive forum provisions in your certificate of incorporation and bylaws. Please clarify
whether these provisions apply to actions arising under the Securities Act or Exchange Act. In that regard, please note that while Section 27 of the Exchange Act creates exclusive federal jurisdiction over all suits brought to enforce any duty
or liability created by the Exchange Act, Section 22 of the Securities Act creates concurrent jurisdiction for federal and state courts over all suits brought to enforce any duty or liability created by the Securities Act or the rules and
regulations thereunder.

 In response to the Staff’s comment, the Company has revised its disclosure on page 46 of the Amendment
to affirmatively state that, “These choice of forum provisions will not apply to claims brought to enforce a duty or liability created by the Exchange Act.” Additionally, the Company has made parallel revisions to its disclosure in the
section titled “Description Of Capital Stock–Certificate of Incorporation and Bylaw Provisions” on page 138 of the Amendment.

Our relationship with Paragon and Parapyre, page 49

13.
 We note your disclosure describing the Parapyre Option Obligation, “which provided for an annual equity
grant of options to purchase 1% of the then outstanding shares of Pre-Merger Spyre’s common stock, on a fully diluted basis, on the last business day of each calendar year during the term of the Paragon
Agreement.” Please update your disclosure to clarify the term of the Paragon Agreement.

 In response to the Staff’s
comment, the Company has revised its disclosure on page 53 of the Amendment to clarify the terms of the Parapyre Option Obligation.

 Research and
Development Expenses, page 53

14.
 Please revise the disclosure to break out the dollar amount of external research and development expenses
incurred for each period presented. Alternatively, disaggregate research and development expenses by nature or type of expense for each period presented.

In response to the Staff’s comment, the Company has revised its disclosure on pages 58-60 of the Amendment to break out the respective dollar amounts of
internal and external research and development expenses incurred for each period presented.

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 U.S. Securities and Exchange Commission

F