United States securities and exchange commission logo





                             February 16, 2024

       Cameron Turtle
       Chief Executive Officer
       Spyre Therapeutics, Inc.
       221 Crescent Street
       Building 23, Suite 105
       Waltham, MA 02453

                                                        Re: Spyre Therapeutics,
Inc.
                                                            Amendment No. 1 to
Registration Statement on Form S-1
                                                            Filed February 5,
2024
                                                            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.

       Amendment No. 1 to Registration Statement on Form S-1 filed February 5,
2024

       Prospectus Summary
       Company Overview, page 4

   1.                                                   We note your response
to prior comment 6. Please revise to address the part of that
                                                        comment requesting
certain balancing disclosures to be included in the Summary.
       Risk Factor Summary, page 10

   2.                                                   Please revise your
summary risk factors to disclose, if true, that additional time may be
                                                        required to obtain
regulatory approval for your product candidates and future product
                                                        candidates because of
their status as combination therapies. In this regard, we note your
                                                        disclosure on page 88
that the FDA indicated it intends to assess each potential
                                                        combination on a
case-by-case basis.
       Our Relationship with Paragon and Parapyre, page 53
 Cameron Turtle
FirstName LastNameCameron     Turtle
Spyre Therapeutics, Inc.
Comapany16,
February  NameSpyre
            2024       Therapeutics, Inc.
February
Page 2 16, 2024 Page 2
FirstName LastName

3.       Please revise the last paragraph of this section to clarify how the
provisions of the Papyre
         Option Obligation relate to the term of the Paragon Agreement. In this
regard, we note
         based on your disclosure on page F-40 that the Parapyre Option
Obligation provides for
         an annual equity grant of options for Parapyre to purchase 1% of the
then outstanding
         shares of 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."
Business, page 73

4.       In your Business section, please revise your disclosure where
appropriate to:
             Better explain the meaning of "complementary diagnostics" and
explain how such
             term differs from "companion diagnostics," including with respect
to the regulatory
             approval pathways.
             Discuss the advantages and disadvantages of potentially using
patient selection
             strategies based on development and use of a complementary
diagnostic. Explain
             how your plan to develop and use a complementary diagnostic may
impact your
             overall clinical development plan, including your clinical trial
design and regulatory
             strategy, as well as your commercialization strategy, if
ultimately approved.
Our Strategy, page 73

5.       With respect to the patient selection and complementary diagnostics
pillar of your
         development strategy, please revise in an appropriate place to explain
what a genetic- or
         biomarker-based complementary diagnostic is, and how you plan to
develop and use such
         complementary diagnostics to match treatment targets to IBD
sub-populations to
         implement a precision immunology approach.
Our Combination Therapy Approach, page 74

6.       You disclose that you plan to investigate combinations of your
proprietary antibody
         therapies in preclinical studies in 2024 and in clinical studies
beginning in 2025.
             Please revise to clarify that commencement of clinical trials is
subject to approval of
             an IND or equivalent foreign regulatory submission.
             Further, you state that your preclinical studies and preclinical
trials involving your
             combination therapies are expected to initially include SPY120.
Please disclose
             when you plan to submit an IND or foreign regulatory submission
for SPY120 or
             otherwise advise. Also, please make conforming revisions to the
section captioned
             "SPY120     combination anti-4  7 and anti-TL1A mAbs" on page 79.
Our Portfolio, page 75

7.       We note your response to prior comment 23. Your response letter and
other disclosures
         suggest that SPY-003 and at least some of your combination product
candidates are not
         currently material to your business given the early stage of
discovery. With respect to
         SPY003, we note:
 Cameron Turtle
FirstName LastNameCameron     Turtle
Spyre Therapeutics, Inc.
Comapany16,
February  NameSpyre
            2024       Therapeutics, Inc.
February
Page 3 16, 2024 Page 3
FirstName LastName
                Your disclosures regarding SPY003 are limited in comparison
with your discussion
              of co-lead product candidates SPY001 and SPY002.
                Your disclosure on page 19 indicates that you are investing a
majority of your efforts
              and financial resources into optioned co-lead product candidates
SPY001 and
              SPY002.
                It appears that under the terms of the Paragon Agreement, (a)
Paragon has granted
              you only a limited license to the antibody technology arising
from the non-optioned
              research programs solely to evaluate the Option and for the
purpose of allowing you
              to determine whether to exercise the Option with respect to each
such program; and
              (b) unless and until you exercise the Option with respect to
SPY003, the execution of
              a SPY003 License Agreement will not occur.
                You state in the response letter and on page 79 that (i) the
Company is still in the
              process of narrowing down potential clones to select a
development candidate for
              SPY003, which is not expected to occur until at least mid-2024,
if at all; and (ii) the
              Company will not exercise the Option to acquire IP rights for the
SPY003 program
              until after such candidate nomination occurs.

         In addition to the foregoing, we note the following with respect to
your combination
         product candidates:
             Your disclosures regarding your combination product programs
remain limited in
             comparison with your discussion of co-lead product candidates
SPY001 and SPY002.
             You disclose on page 79 that each of SPY130 and SPY230 include
combination with
             non-optioned SPY003, for which no development candidate has been
nominated.
             You disclose on page 74 that with respect to your combination
therapies, your
             preclinical studies and clinical trials planned for 2024 and 2025,
respectively, are
             expected to initially include SPY120, which combines optioned
product candidates
             SPY001 and SPY002.

         As such, please limit the product candidates and programs included in
your pipeline table
         to those that are currently material to you and your operations, and
for which you have
         exercised the Option to exclusively license all of Paragon's right,
title, and interest in,
         including all intellectual property license rights thereto. Please
remove the references to
         SPY003 and combination programs that include SPY003 from your pipeline
table. We
         will not object to your discussion of your development plans for
SPY003. SPY004, and
         your combination programs including SPY003 in the narrative discussion
in the Business
         section.
SPY001 - anti-4  7 mAb, page 76

8.       You state on page 76: "The JDC is the decision-making body for SPY001
and our other
         pipeline programs prior to the execution of the SPY-001 License
Agreement and we will
         control and lead the development process once the SPY001 License
Agreement is
         executed." For the avoidance of doubt, please clarify whether you will
control and lead
         the development process for each of SPY002, non-optioned programs
SPY003 and
 Cameron Turtle
Spyre Therapeutics, Inc.
February 16, 2024
Page 4
       SPY004, and each of the combination programs once the SPY001 license
agreement is
       executed, or otherwise revise.
9.     We note your response to prior comment 26, which we reissue with respect
to portions of
       the second bullet. In this subsection and in others as appropriate,
please further revise
       your discussion of completed preclinical studies to disclose when
preclinical studies were
       conducted, as well as the number of tests conducted in each study.
10.    Please review and revise the Figures includes in this section to ensure
that the text in each,
       including subscript or other notations, are clearly legible without need
for magnification.

Notes to the Financial Statements
8. Paragon Agreement, page F-58

11.    We acknowledge your response to comment 33. Please revise your
disclosure on pages F-
       56 and F-59 to clarify that the $22.0 million is also upon the
achievement of regulatory
       milestones as your current disclosure only refers to development and
clinical milestones.
General

12.    Please file the offer letter with Ms. King-Jones as an exhibit to the
registration statement,
       or tell us why you believe it is not required to be filed.
        We remind you that the company and its management are responsible for
the accuracy
and adequacy of their disclosures, notwithstanding any review, comments, action
or absence of
action by the staff.

       Refer to Rules 460 and 461 regarding requests for acceleration. Please
allow adequate
time for us to review any amendment prior to the requested effective date of
the registration
statement.

        Please contact Christine Torney at 202-551-3652 or Vanessa Robertson at
202-551-3649
if you have questions regarding comments on the financial statements and
related matters. Please
contact Lauren Sprague Hamill at 303-844-1008 or Jason Drory at 202-551-8342
with any other
questions.



                                                              Sincerely,
FirstName LastNameCameron Turtle
                                                              Division of
Corporation Finance
Comapany NameSpyre Therapeutics, Inc.
                                                              Office of Life
Sciences
February 16, 2024 Page 4
cc:       Branden Berns
FirstName LastName