September 5, 2024

Jeffrey Finer, M.D, Ph.D.
President and Chief Executive Officer
Septerna, Inc.
250 East Grand Avenue
South San Francisco, CA 94080

       Re: Septerna, Inc.
           Draft Registration Statement on Form S-1
           Submitted on August 2, 2024
           CIK No. 0001984086
Dear Jeffrey Finer M.D, Ph.D.:

       We have reviewed your draft registration statement and have the
following comments.

        Please respond to this letter by providing the requested information
and either submitting
an amended draft registration statement or publicly filing your registration
statement on EDGAR.
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 the information you provide in response to this letter
and your amended
draft registration statement or filed registration statement, we may have
additional comments.

Draft Registration Statement on Form S-1
Prospectus Summary
Overview, page 1

1.     Please delete the overly speculative statements included in the Summary
and throughout
       your filing. Given the early stage of your candidates    development,
your unproven, novel
       technologies, the limited evidence supporting the feasibility of
developing therapeutic
       treatments based on your platform, and the number of other companies
focused on GPCRs
       and platform technologies, these statements are do not appear
supportable. Illustrative
       examples include:
           we have transformed GPCR oral small molecule drug discovery to an
industrialized
           and iterative structure-based drug design approach to expand the
landscape of
           druggable GPCR targets with novel oral small molecule medicines for
patients.
           we believe our team, scientific and technical advisors, and our
proprietary Native
           Complex PlatformTM uniquely positions us to become the leading
GPCR-focused
 September 5, 2024
Page 2

           biotechnology company.
           we believe we are at the forefront of industrial-scale GPCR drug
discovery and
           development.
           we are advancing cutting-edge science and rigorously developing a
broad and deep
           portfolio of GPCR-targeted programs for patients.
       We note there are other companies with platforms focused on GPCR drug
discovery,
       which are led by teams with extensive experience in the
pharmaceutica/biotechnology
       industry.

2.     Your summary presents an unbalanced discussion of your business and
potential
       opportunity by providing limited information that can put your
statements in the proper
       context and isolating such information towards the end of the Summary.
Please revise
       your summary to include balance by including equally prominent
disclosure of
       information about your status as a company with no commercial products,
information
       about the competitive conditions in the industry, and the status of your
product
       candidates. For example:

             Balance the statement that SEP-786 is the only clinical stage,
oral small molecule
           agonist targeting Parathyroid Hormone 1 Receptor for the treatment
of
           hypoparathyroidism with statements that there are other product
candidates in
           development that target PTH1R for hypoparathyroidism, including a
candidate that is
           in Phase 3 and has recently been granted fast track status by the
FDA.
             Balance your belief that your team, scientific and technical
advisors, and our
           proprietary Native Complex PlatformTM uniquely positions you to
become the
           leading GPCR-focused biotechnology company to clarify that there are
other
           companies that have developed platforms in use to develop
GPCR-focused product
           candidates, some of which are led by leadership teams with extensive
experience in
           the pharmaceutical/biotechnology field. Many of these companies are
private
           companies, therefore there may not be a lot of information publicly
available about
           their platforms, product candidates and current stage of
development.
             Balance your belief that you are at the forefront of
industrial-scale GPCR drug
           discovery and development with information that there are other
companies with
           platforms that are focused on GPCR drug discovery




3.     Please refer to Item 503 of Regulation S-K and note that the Summary
should be brief,
       should not contain all the detailed information in the prospectus and
should focus on
       providing a brief overview of the key aspects of the offering without
merely repeating the
       text of the prospects. As currently drafted the first eight pages of
your Summary are
       repeated almost word for word on the first eight pages of your Business
section, and much
       of the information was also repeated in Management   s Discussion and
Analysis of
       Financial Condition and Results of Operations and Management. The only
subsections
       that were summarized were the discussions of your strategy and risk
factors. Please revise
 September 5, 2024
Page 3

        your summary to eliminate the repetitive information from within the
Summary and avoid
        merely repeating detailed discussions from the prospectus. To the
extent you decide to
        keep both graphics summarizing your pipeline on pages 2 and 5. Please
why both are
        necessary as most of the information in the graphic on page 2 is also
in the graphic on
        page 5.
4.      We note your explanation of your Native Complex Platform. We understand
that there are
        other companies focused on developing GPCR-targeting drugs using
alternate
        technologies, given the difficulty in isolating GCPRs. Please explain
why the "unique
        position" of your technology will be sufficient to make up for the
competitive advantage
        other companies, who may be further along developing similar drugs.
5.      Please define agonists, antagonists and allosteric modulators the first
time the terms are
        used.
Our Pipeline and Programs, page 4

6.      Please remove the "Other Therapeutic Areas of Interest/Focus" from your
pipeline table.
        The pipeline table should only include references to your currently
material product
        candidates and programs.
SEP-786 - Oral Small Molecule PTH1R Agonist for Hypoparathyroidism, page 5

7.      Please remove statements about your conclusions from your preclincial
studies from the
        summary. Such statements should be accompanied by a description of the
studies, which
        is more appropriate for the Business section. Similarly revise the
descriptions of your
        other product candidates and programs.
Our future ability to utilize our net operating loss carryforwards and certain
other tax attributes
may be limited., page 47

8.      Please quantify your current net operating loss carryforward.
We are conducting, and will conduct, clincial trials for our current product
candidates outside of
the United States..., page 48

9.      We note your disclosure on page 143 that you have submitted a CTN in
Australia. Please
        revise to clarify your plans to conduct trials in Australia and
indicate whther you currently
        have plans to conduct trials in other jurisdictions.
We may not be able to obtain orphan drug designation for our product
candidates..., page 52

10.     Please clarify which candidates, if any, may qualify for orphan drug
status. Similarly
        revise the risk factor titled "While we may in the future seek
designations for our product
        candidates with the FDA, EMA and other comparable foreign regulatory
authorities that
        are intended to confer benefits..." to identify other candidates that
may qualify for
        programs providing for an accelerated regulatory pathway or regulatory
excusivity.
We currently depend and in the future may continue to depend on single or
limited-source
suppliers..., page 68

11.     We note you currently depend on single and limited source suppliers.
Please clarify
        whether you have supply agreements in place. If you do, please file
such agreements as
 September 5, 2024
Page 4

       exhibits pursuant to Item 601(b)(10)(ii)(B) of Regulation S-K.
We intend to rely on third parties to conduct, supervise and monitor our
preclinical studies...,
page 68

12.    We note your disclosure that if your relationships with your CROs
terminates, you may
       not be able to enter into arrangements with alternative CROs or do so on
commercially
       reasonable terms. Please identify any CROs you are substantially
dependent on and file
       agreements with these parties as exhibits to the registration statement.
In an appropriate
       location in your registration statement, include descriptions of the
material terms of these
       agreements.
Risks Related to Intellectual Property, page 69

13.    Please revise your discussion of risk relating to intellectual property
to include a
       disclosure, as mentioned on page 157, that your proprietary Native
Complex Platform is
       not patented. Specifically, discuss the additional risk associated with
protecting this
       intellectual property with things such as confidentiality agreements in
lieu of patent
       protection.
Our insurance policies are expensive and only protect us from some business
risks ..., page 95

14.    Please expand the discussion to identify commonly insured risks for
which you are
       currently not carrying insurance coverage. To the extent that you are
aware that you are
       maintaining a policy with a coverage amount that is less than adequate,
please provide
       information about the risk and quantify the shortfall.
Use of Proceeds, page 100

15.    We note your intention to advance the development of your two lead
product candidates
       with the proceeds of this offering. Please expand on this discussion to
disclose how far
       along in the development process you expect to get with the proceeds of
this offering.
Management's Discussion and Analysis of Financial Condition and Results of
Operations
Critical Accounting Estimates, Significant Judgments and Use of Estimates
Stock-based compensation, page 120

16.    Once you have an estimated offering price or range, please explain to us
how you
       determined the fair value of the common stock underlying your equity
issuances and the
       reasons for any differences between the recent valuations of your common
stock leading
       up to the initial public offering and the estimated offering price. This
information will
       help facilitate our review of your accounting for equity issuances.
Please discuss with the
       staff how to submit your response.
Our Solution: Oral Small Molecule MRGPRX2 NAM, page 144

17.    Please remove statements here and elsewhere that SEP-631 has the
potential to be an
       "insurmountable" NAM. Given the development stage of this treatment,
such statements
       appear to be premature and inappropriately assume regulatory approval at
this stage.
Our solution: Oral Small Molecule Single- and Multi-Incretin Receptor Agonists,
page 153

18.    Please include a textual description explaining what the table in Figure
14 is intended to
 September 5, 2024
Page 5

       convey.
Government Regulation, page 159

19.    We note that you have submitted a CTN in Australia to conduct your
SEP-786 Phase 1
       clincial trial. To the extent you are planning to seek approval of this
candidate in
       Australia, please discuss the applicable review and approval process or
clarify that it is
       not your intention to seek approval in Australia.
Employees and Human Capital Resources, page 178

20.    Please revise to quantify the number of full-time employees.
Management, page 180

21.    Please disclose where Ms. Sharp has been employed since October 2020.
Principal Stockholders, page 211

22.    Please identify in a footnote to the table all natural persons who have
voting and/or
       investment power over the shares held by Samsara BioCapital, L.P., Invus
Public
       Equities, L.P., and Deep Track Biotechnology Master Fund, Ltd.
General

23.    Please supplementally provide us with copies of all written
communications, as defined in
       Rule 405 under the Securities Act, that you, or anyone authorized to do
so on your behalf,
       present to potential investors in reliance on Section 5(d) of the
Securities Act, whether or
       not they retain copies of the communications.
       Please contact Ibolya Ignat at 202-551-3636 or Angela Connell at
202-551-3426 if you
have questions regarding comments on the financial statements and related
matters. Please
contact Tamika Sheppard at 202-551-8346 or Suzanne Hayes at 202-551-3675 with
any other
questions.



                                                             Sincerely,

                                                             Division of
Corporation Finance
                                                             Office of Life
Sciences