SecProbe.io

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

 FirstName LastNameCameron  Turtle
 Comapany NameSpyre Therapeutics, Inc.
 February 16, 2024 Page 2
 FirstName LastNameCameron  Turtle
Spyre Therapeutics, Inc.
February 16, 2024
Page 2
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-4ß7 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:

 FirstName LastNameCameron  Turtle
 Comapany NameSpyre Therapeutics, Inc.
 February 16, 2024 Page 3
 FirstName LastNameCameron  Turtle
Spyre Therapeutics, Inc.
February 16, 2024
Page 3
•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-4ß7 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

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