SecProbe.io

December 2, 2024
Christopher Whitten Bernard
Chief Executive Officer
Metsera, Inc.
3 World Trade Center
175 Greenwich Street
New York, New York 10007
Re:Metsera, Inc.
Draft Registration Statement on Form S-1
Submitted November 4, 2024
CIK No. 0002040807
Dear Christopher Whitten Bernard:
            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 revise here and on page 119 to explain what you mean when you say that your
lead candidate, MET-097i, is "BLA-eligible," and explain the significance of a
product candidate being so eligible with the FDA. Also, given that your disclosure
that MET-097i is in ongoing Phase 1/2 trials, revise to explain when companies
typically make a BLA application (e.g., following successful completion of all
required clinical trials and at same time the company seeks marketing approval).
We note your disclosure that you are advancing a "broad, scalable and combinable
portfolio of injectable and oral NuSH analog peptides" and that your pipeline includes 2.

December 2, 2024
Page 2
"clinical-stage" injectable and oral GLP-1 RA analog peptides, as well as multiple
complementary peptides that "can be combined with GLP-1 RAs." Here and
throughout where appropriate, please revise as follows:
•Clarify that your pipeline includes both clinical-stage and early preclinical stage
product candidates. Likewise, revise the subsections on pages 6 and elsewhere
throughout captioned "Other pipeline programs" to clarify that the programs
described are in preclinical stages.
•To the extent that the scalability and combinability of your product candidates is
currently aspirational, please so state. For example, we contrast certain of your
other disclosures that you "plan" to develop MET-233i to be administered in
combination with other peptides, including MET-097i if you are first able
to establish sufficient results in your Phase 1 trial of MET-233i as a monotherapy.
•If true, balance this disclosure by explaining that the data you have generated to
date from MET-097i "supporting combinability" is preliminary and limited to
preclinical data, and that you have yet to initiate any clinical trials of any
combination therapies.
•As appropriate, revise the Summary, Risk Factors and Business sections to
describe how the development of combination therapies differs from the
development of single agent therapies, and whether such development may
present more or different challenges than development of single agent therapies,
or otherwise advise.
3.We note your disclosure that MET-097i, your most advanced product candidate, is a
"subcutaneously injectable" GLP-1 RA that you are developing for the treatment of
obesity and overweight. In this regard:
•Please revise the Summary and Business where appropriate to explain how you
intend for MET-097i and any other of your subcutaneous injectable product
candidates to be delivered and administered. In this regard, we note certain
references throughout to "disposable injector devices" and "cartridge-based
injectable drug product units" that lack sufficient context.
•Revise to disclose whether you anticipate that any of your injectable product
candidates may be regulated by the FDA as drug-device combination products. As
appropriate, 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 or biologics
alone, or otherwise advise.
•If material, please add summary risk and risk factor disclosure discussing any
risks or challenges related to your development of MET-097i and any other
injectable product candidate if the FDA may consider such candidate(s) to be a
drug-device combination product, or otherwise advise.
In the appropriate places in the Summary and Business sections, please revise to
disclose the location(s) of all completed, ongoing, and planned clinical trials of your
product candidates. Also, as appropriate, revise your risk factor disclosure on pages
10 and 29 to clarify whether you are currently conducting trials outside the United
States. In this regard, we note your disclosure that you have initiated a Phase 1 4.

December 2, 2024
Page 3
trial prototype compound MET-002, a predecessor peptide to MET-224o, following
your Clinical Trial Application being approved by Health Canada in October 2024.
We also note your disclosure on page 25 stating that you and your collaborators are
"currently conducting" clinical trials in foreign countries.
The Obesity and Overweight Market, page 2
5.Please revise the Summary and Business sections where appropriate to:
•Disclose your development and regulatory approval plans for each of your
product candidates, including clarifying the initial estimated patient
population(s) for which you are developing each candidate in each indication
(e.g., adults versus children), and the jurisdiction where you plan to first seek
regulatory approval.
•Revise your discussion of the market opportunity for your product candidates by
separately disclosing your best estimate of prevalence and incidence figures for
obesity and overweight in the patient population(s) you intend to treat in any
jurisdiction(s) where you plan to seek regulatory approval. In this regard, we note
that on page 2, you provide prevalence figures for obesity and overweight
worldwide, in Southeast Asia and the Americas. You also provide an estimate that
in 2020, obesity and overweight "affected more than 70% of adults in the United
States," and that "nearly half of Americans are projected to have obesity by 2030.
The Evolving Obesity and Overweight Treatment Landscape, page 3
6.You state that the GLP-1 RA market has experienced rapid commercial success, is
expected to continue to grow in the future, and that third-party market research reports
estimate that GLP-1 RAs represented approximately $36 billion in global sales in
2023 and could reach $170 billion by 2030. In this regard:
•Please revise here and in Business to separately provide past and future estimated
sales figures for GLP-1 RAs in the patient population(s) you intend to treat in any
jurisdiction(s) where you plan to seek regulatory approval.
•Balance your statements here and elsewhere pertaining to market size by
disclosing that you do not have any products approved for commercial sale and
discussing the regulatory steps you must take before receiving such approvals.
Explain that your product candidates are in the early stages of U.S. clinical
development, that it will take years to develop and commercialize them, and that
even if you are successful in obtaining regulatory approval, there can be no
assurance as to your ability to penetrate the obesity and overweight market, and if
so, to what extent.
7.Please balance your statements here and elsewhere pertaining to the tolerability of
currently approved products with disclosure about the TEAEs that you have observed
in your Phase 1/2 clinical trial of MET-097i.
Our Approach, page 4
8.We note the statement that your MINT peptide library was developed through over 20
years of iterative and empirical discovery work. Please clarify which entities
conducted this discovery work.

December 2, 2024
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9.Please revise this section here and in Business as follows:
•Explain what prodrugs and antibody peptide conjugates are, and why you believe
developing these technologies could reduce injection frequency. Disclose the
status of your development of these technologies, and identify any material steps
that will need to be taken in order to utilize them either alone or in combination
with your product candidates.
•Explain what you mean by "dose titration" and "re-titration."
MET-097i, page 5
10.Please revise this section here and in Business as follows:
•On pages 6 and 124, you state your belief, based on preliminary results from your
ongoing Phase 1/2 clinical trial of MET-097i, that the observed half-life provides
"clinical validation" of your HALO half-life extending platform. Please revise to
clarify that this "validation" does not mean that your product candidates will
demonstrate safety or efficacy, and disclose that product candidates developed
with the HALO platform have yet to be evaluated in a completed clinical trial.
•On pages 6 and 125 you state your belief that observed change in body weight
from baseline in the same ongoing trial "is consistent with, or better than the
highest titrated study arms of similar Phase 1 trials for marketed and clinical-stage
GLP-1/GIP RA compounds." Please tell us whether any differences in the
"similar" third party Phase 1 trial protocols, patient populations, dosages, or other
factors could lead to material differences in measured change in body weight.
Also, balance your statement by explaining that there are risks in drawing
conclusions as to the performance of MET-097i relative to that of any other
therapy given the absence of head-to-head trials, and disclose that the results from
clinical trials of a competitor’s product candidate in the same class may not
predict the results of clinical trials of your product candidates.
Our Pipeline and Programs, page 5
We note that the pipeline table should graphically demonstrate the current status of
your product candidates and clearly show the material trial phases you will need to
complete before marketing your products. The table should be a reflection of the
narrative disclosure in the prospectus and should not be used to prematurely project or
imply successful completion of the stages required prior to regulatory approval and
commercialization. A narrative discussion is more appropriate for the next steps or
aspirational plans for your product candidates, such as the completion of a particular
trial phase.
•As appropriate, please revise to shorten the progress arrows, by product candidate
and indication, to reflect the actual status of your pipeline candidates as of the
latest practicable date. As currently drawn, the gray "in process" portion of the
arrows could inappropriately create the impression of further candidate progress.
Your disclosure on page 1 and in footnote 2 to the pipeline table appears to
indicate that you have two parallel oral peptide development programs underway:
(1) the ongoing Phase 1 formulation optimization trial of MET-244o (prototype
peptide formulation), and (2) IND- and CTA-enabling preclinical studies of MET-•11.

December 2, 2024
Page 5
244o (optimized formulation). Since you are not currently conducting a Phase 1/2
clinical trial of either oral formulation, please tell us whether presenting the
ongoing studies/trials for each oral formulation separately in the pipeline table
would be more appropriate. We note in this regard that the progress arrow for
"MET-244o/MET-002" could be interpreted as indicating that you have
completed all preclinical work for MET-244o, rather than that you "plan to
complete" such studies. Please ensure your arrows clearly align with your
narrative disclosure.
•Revise the heading of the eighth column to remove the reference to "current
status," as the progress arrows themselves should reflect the current status of each
product candidate. In this column, you may instead identify the single next
anticipated material milestone for each product candidate.
•Please revise to qualify your statement regarding the next anticipated milestone
with respect to the MET-097i + MET-233i combination program. In this regard,
we note that sufficient safety might not be established in the MET-233i Phase 1
trial.
•Please tell us your consideration of removing the columns captioned "HALO
Half-Life Extending Platform" and "Global Rights" from the pipeline table. We
do not object to discussion of these topics in the supporting narrative disclosure.

12.Please explain to us why your MET-AMYo oral amylin analog program, for which
you have not yet identified a lead candidate, is currently sufficiently material to your
operations so as to warrant being highlighted in the pipeline table. Similarly, explain
the same with respect to each of the "next-generation combination" programs. To the
extent that you believe these programs are material, please revise the Business section
to explain each program and the respective identified product candidate(s) in greater
detail, including a discussion of relevant pre-clinical work that has been conducted or
is in process. In this regard, your disclosure in the Business section concerning the
preclinical work should support the positioning of the arrows in your pipeline table, as
well as the next material step reflected in the "Anticipated Milestones" column.
Alternatively, revise to remove any pre-clinical program that is not currently material
to your business. We do not object to your narrative discussion of such programs in
the Summary and Business sections.
MET-233i, page 6
13.We note your statements here and on page 125 that MET-233i "has a potentially
class-leading half-life amongst known amylin analogs in development and is the only
candidate suitable for monthly dosing," as well as the statements on pages 8 and 127
that your goal is to develop "potentially best-in-class injectable and oral therapies."
Please remove these and any similar statements throughout, as such statements are
speculative in light of the current regulatory status of your product candidates and the
uncertainty involved in clinical development.  Further, such statements could be read
to imply that your product candidate is effective or likely to be approved, and such
determinations are solely within the authority of the FDA and comparable regulatory
bodies.

December 2, 2024
Page 6
Our Strategy, page 8
14.Please revise your disclosure in this section and in Business as follows:
•Balance your statement of belief that your product candidates "have the potential
to outperform current approved products and development-stage product
candidates on tolerability, efficacy, convenience, and scalability" by disclosing, if
true, that you have not conducted head-to-head clinical trials of any of your
product candidates against currently approved products, your product candidates
are in the early stages of U.S. clinical development, that it will take several years
to develop and commercialize them, and that even if you are successful in
obtaining regulatory approval, there can be no guarantees as to outperformance of
other therapies on any of tolerability, efficacy, convenience or scalability.
•Balance references to your team's "track record" in drug development and your
belief in your ability to "develop multiple product candidates to global regulatory
approvals, to manufacture at commercial scale, and to commercialize effectively
in major markets." Disclose, if true, that the past experience of your individual
team members is not necessarily predictive of the future success of your company,
that as an organization you have not successfully obtained regulatory approval or
commercialized any products in any jurisdiction, that you may not obtain
approval for any product candidates in any jurisdiction, and that even if you are
successful in obtaining any regulatory approvals, there can be no guarantees as to
your ability to manufacture your product candidates at commercial scale.
Risk Factors
We currently rely on thi