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United States securities and exchange commission logo
January 18, 2024
Cameron Turtle
Chief Executive Officer
Spyre Therapeutics, Inc.
221 Crescent Street
Building 23, Suite 105
Waltham, MA 02453
Re:Spyre Therapeutics, Inc.
Registration Statement on Form S-1
Filed December 22, 2023
File No. 333-276251
Dear Cameron Turtle:
            We have reviewed your registration statement and have the following comments.
            Please respond to this letter by amending your registration statement and providing the
requested information. If you do not believe a comment applies to your facts and circumstances
or do not believe an amendment is appropriate, please tell us why in your response.
            After reviewing any amendment to your registration statement and the information you
provide in response to this letter, we may have additional comments.
Registration Statement on Form S-1 filed December 22, 2023
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
•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

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ability to execute your strategy to "enhance efficacy" is currently aspirational.
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.
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.
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.
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.
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.

Risk Factor Summary, page 9
7.We note your stated plan to use patient enrichment strategies via companion diagnostics in

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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.
8.Given your stated intention to deliver your product candidates through injection via a pre-
filled 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.
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 advise.
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.
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.
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.
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

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to clarify the term of the Paragon Agreement.
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
.
Management's Discussion and Analysis of Financial Condition and Results of Operations
Future Funding Requirements and Operational Plan, page 59
15.Please update the final paragraph in this section consistent with your disclosure in the
"Recent Developments" section and elsewhere regarding shareholder approval of the
conversion of your Series A Preferred Stock.  In addition, please update your "Recent
Developments" section to discuss the December 2023 SPA for Series B Preferred Stock.
Contractual Obligations and Other Commitments, page 63
16.You state here and on page 66 that as of the date of this prospectus, the Option remains
unexercised with respect to three research programs under the Paragon Agreement.
•Such disclosures are inconsistent with statements on pages 17, 49, and 116
indicating that you exercised your Option for the PSY001 and SPY002 programs in
July 2023 and December 2023, respectively, and the remaining two options for the
SPY003 and SPY004 programs remain outstanding.  Please reconcile or advise.
•Also, please update this section as appropriate to clarify the current status of your
expected obligations under the Paragon Agreement based on your exercise of the
Option to date.
Management's Discussion and Analysis of Financial Condition and Results of Operations
Contractual Obligations and Other Commitments, page 63
17.You disclose that as of the date of the filing of this prospectus, the Option remains
unexercised with respect to the three remaining research programs under the Paragon
Agreement. However, on pages 48 and 49 you disclose that in December 2023 you
exercised the Option for the SPY002 program. Please clarify.
Business
Company Overview, page 66
18.We note your disclosure "[f]or more information on the Paragon Agreement, see
discussion under the heading “Paragon Agreement” below." However, we are unable to
locate the heading. Please revise your disclosure to describe all the material terms of the
Paragon Agreement as amended.
Our Strategy, page 66

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19.We note your statements on pages 66 and 67 that your antibodies have "best-in-class"
potential.  Given the development stage of your programs and length of the drug approval
process, it is premature and inappropriate to speculate or imply that any Spyre product
candidates will ultimately be approved or become best-in-class.  Please remove these
statements and any similar statements throughout.
20.Please revise in an appropriate place to explain what a genetic- or biomarker-based
companion diagnostic is, and how you plan to develop and use such companion
diagnostics to match treatment targets to IBD sub-populations.
21.With respect to the half-life extension pillar of your development strategy, please revise
your Business section in the appropriate place(s) to:
•explain the basic operation of half-life extension technologies including YTE and LS
amino acid substitutions, and describe your efforts to develop programs using such
technologies, as mentioned on page 18;
•explain how your focus on half-life extension/optimization has the potential to confer
a more favorable dosing schedule for your programs, assuming they successfully
complete clinical development; and
•if material, describe the non-human primate study referenced on page 18, including
quantitative information regarding the range of results observed regarding the
increased half-life properties of your programs or otherwise.
Our Portfolio, page 67
22.Please remove or revise your statement that you are advancing a "broad pipeline" of
antibodies for the treatment of IBD, or advise.  In this regard, we note your disclosure that
you are initially focused and substantially dependent on the success of the SPY001 and
SPY002 programs that each address IBD.  We also refer to disclosure on page F-36
stating that the Company determined that the pipeline candidates within its portfolio are
"similar in nature."
23.We note the inclusion of SPY003, SPY004 and combination programs SPY120, SPY130
and SPY230 in your pipeline table. In this regard:
•It is seemingly premature to highlight the SPY003 and SPY004 programs in
the pipeline table given your disclosure that you are investing a majority of your
efforts and financial resources into optioned co-lead programs SPY001 and SPY002,
disclosure that you have not exercised the Option with respect to SPY003 and
SPY004, and your limited disclosures regarding SPY003 and SPY004 in the
registration statement.  Please remove SPY003 and SPY004 from the table, or
explain why these programs are currently material to your business so as to warrant
inclusion therein.
•It is also seemingly premature to highlight your combination programs in the pipeline
table given that your individual programs appear to be in early preclinical stages,
certain of your combination programs purport to involve combination

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with SPY003 (IL-23) which you have not yet exercised the Option on, and you have
provided only limited disclosures regarding your combination programs in the
registration statement.  Please remove your combination programs from the pipeline
table or advise as to the materiality of each such program.

Please note that we do not object to your narrative discussion of SPY003, SPY004, and
your combination programs in the Business section.
24.Please also revise the pipeline table on page 67 as follows:
•Disclose the indication for which you are currently developing each program.
•Disclose whether you have nominated a development candidate for each program.
•Revise the columns so they are clearly delineated from each other.  Include columns
of equal width for each of Phase 1, Phase 2 and Phase 3 of clinical testing.
•The table should not be used to prematurely project or imply successful completion
of the stages required prior to regulatory approval.  To the extent that you disclose
the next anticipated milestone for a candidate in the table, only provide the next
material step in the regulatory review process (e.g., development candidate
nomination, intended timing of IND submissions, etc.).  The narrative discussion
following the pipeline table is more appropriate for discussing aspirational plans for
your product candidates beyond the immediate next step, such as expected interim
data from any future Phase 1 trials.
•Ensure the font and type used is clearly legible.  For example only, we note that the
information currently presented under the column titled "Clinical" is not clearly
readable even with enhanced pixelation.
•With respect to footnote 1 to the table, revise to explain that the SPY001 and SPY002
License Agreements are still being finalized and clarify the expected timing for
entering into these agreements.
25.In the narrative discussion following the pipeline table, you discuss the potential timing of
Phase 1 clinical trials of SPY001 and SPY002 without addressing the necessary
submission of INDs to the FDA.  For each of SPY001 and SPY002, clarify when you plan
to submit an IND and specify the indication(s) to be covered.
26.Please expand your narrative disclosure following the pipeline table to provide a more
fulsome discussion of each of your individual and combination programs and clarify the
status of development activities to date. In your revisions, please:
•Clarify your role and involvement in completed or ongoing development efforts