United States securities and exchange commission logo





                              December 19, 2023

       Amit Etkin
       Chief Executive Officer
       Alto Neuroscience, Inc.
       369 South San Antonio Road
       Los Altos, CA 94022

                                                        Re: Alto Neuroscience,
Inc.
                                                            Draft Registration
Statement on Form S-1
                                                            Submitted November
22, 2023
                                                            CIK No. 0001999480

       Dear Amit Etkin:

                                                        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 Submitted November 22, 2023

       Prospectus Summary
       Overview, page 1

   1.                                                   Here and throughout the
registration statement, please revise to disclose how you define
                                                        "late-stage" or remove
statements that any of your product candidates are in "late-stage"
                                                        clinical trials, as
these statements may imply that your products are farther along in the
                                                        development process
than they actually are.
   2.                                                   We note that a key
element of your strategy is to build and expand your pipeline of
                                                        product candidates,
including through your "differentiated biomarker-based approach"
                                                        that relies heavily on
insights derived from your proprietary Precision Psychiatry Platform
                                                        (the "Platform"). Here
and where appropriate throughout the prospectus, please expand
                                                        your discussion of your
Platform to describe how it was built and how it grows. For
                                                        instance, discuss the
scope of your data repository and explain whether lines of data are
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Alto Neuroscience, Inc.
Comapany19,
December  NameAlto
              2023 Neuroscience, Inc.
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         added through third-party data sets or libraries. Also, address the
"scalable" nature of
         your Platform. To the extent that the scalability of the Platform is
currently aspirational,
         please so state.
3.       Please balance your discussion of your Platform and biomarkers-based
approach to
         matching potential drug responders with therapeutic product
candidates. Explain that
         such approach is unproven and disclose, if true, that you anticipate
that you will be
         required to develop and obtain FDA approval of a companion diagnostic
for such
         therapeutic product candidates. Disclose whether or not you have had
any conversations
         with or received any input from the FDA to date regarding the use of
your Platform and/or
         your biomarkers-based approach to product development, and if so,
describe the
         outcome of such discussions.
4.       We note your statements of belief that your Platform-driven approach
to developing
         therapeutics will enable you to improve upon the high failure rates of
late-stage clinical
         trials and improve your product candidates    probability of clinical
success. Please balance
         these and other statements in your Summary by prominently highlighting
that:
             your Platform is unproven and clinical evidence to support your
approach is
              preliminary and limited at this time;
             there can be no guarantee that your candidates will have an
increased chance of
              approval.
         Make conforming revisions throughout, including in the Business
section, as appropriate.
5.       We note disclosure in the prospectus summary, in the section beginning
on page 125,
         and in other places throughout the prospectus regarding your pursuit
of a strategy to match
         patients to the right medication "quickly" or to quickly find patient
populations more
         likely to respond to a particular product candidate. Please revise
these and any similar
         disclosures throughout the prospectus to remove any implication that
you will be
         successful in obtaining necessary regulatory approvals or
commercializing your product
         candidates in a rapid or accelerated manner, as such statements are
speculative given your
         current stage of development. You may state, if true, that your goal
is to develop drug
         candidates more efficiently than current industry standards.
6.       We note your disclosure at the end of the second paragraph on page 1
that you estimate
         one or both of two independent biomarkers are present in approximately
three-quarters of
         the overall MDD population. We also note your disclosure in the table
on page 2 that
         30%-60% of patients are likely to be biomarker positive. Please revise
your disclosure so
         that investors can better understand how to reconcile these different
percentages.
Our Pipeline, page 3

7.       It appears that your current pipeline consists of clinical-stage
assets that have been
         acquired or in-licensed, and that in certain cases the originators of
such candidates
         progressed your candidates through certain phases of clinical
development. Please add
         footnotes to your pipeline table to show which columns relate to work
conducted by the
         company and which, if any, relate to the work of third parties. Also,
as appropriate, please
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         disclose where third party clinical trials were conducted and discuss
any interaction the
         company has had with the FDA regarding its ability to rely on such
trial data in the event
         any trials were not conducted in the United States.
8.       To the extent that your product candidates were previously known by
different names
         prior to being acquired or in-licensed by your company, please revise
your disclosure to
         include these names.
9.       We note that you disclose the potential timing of clinical trials you
expect to initiate
         without addressing whether you have active INDs for your
clinical-stage candidates in
         each indication you are studying. Please revise to clarify. If you do
not have active INDs
         for each candidate and indication, please disclose when you plan to
submit INDs.

10.      With respect to your study of ALTO-100 for PTSD:
             Please remove the reference in the pipeline table, and any other
similar references
             throughout the prospectus, to ALTO-100 for PTSD being "Phase 2b/3
ready" to
             remove any implication that the FDA has signed off on a
registrational trial for any of
             your product candidates in any indication.
             If true, include a footnote to the table disclosing, as you have
on page 4, that your
             plans to continue study of ALTO-100 for PTSD are dependent upon
generating
             positive Phase 2b data from the ongoing trial of ALTO-100 for
patients with MDD.
             Clarify that there is no guarantee that the results from the
ongoing trial will be
             positive.
11.      Please revise the narrative disclosure supporting the pipeline table
appearing on pages 3
         and 100 to support your statement that each of ALTO-101, ALTO-203 and
ALTO-202 are
         "Phase 2 ready." In this regard, we note that it is unclear from your
disclosure whether
         you have active INDs for your product candidates in the indications
you state you are
         currently pursuing.
ALTO-101, page 5

12.      Please revise this section to explain, if true, that ALTO-101 is being
developed as a
         combination product due its patch formulation. Explain the
implications of combination
         product status with respect to the regulatory approval process.
Disclose whether or
         not you have had any conversations with or received any input from the
FDA to date
         regarding the patch formulation of ALTO-101, and if so, describe the
outcome of such
         discussions.
Other Pipeline Programs, page 5

13.      We note that the prospectus contains minimal discussion of your
ALTO-202 program, and
         as such, it is not clear why this program is sufficiently material to
your current operations
         to warrant being highlighted in the pipeline table appearing on pages
3 and 100. To the
         extent that ALTO-202 is currently material to your business, please
expand your
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Alto Neuroscience, Inc.
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              2023 Neuroscience, Inc.
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         disclosure here and in your Business section to provide a more fulsome
discussion of
         that program, including a description of development activities you
have conducted to
         date, relevant clinical work conducted or in process, and the
remaining steps to develop
         and commercialize the product. In this regard, your disclosure
concerning clinical
         work should support the positioning of the progress arrow in your
pipeline table.

Risk Factor Summary, page 6

14.      We note your disclosure on page 145 that you have reformulated
ALTO-101 in a
         transdermal patch formulation, as well as your disclosure on page 162
regarding the
         regulation of patch formulations of drugs as combination products in
the United States. If
         material, please add summary risk and risk factor disclosure
discussing any risks or
         challenges related to your development of ALTO-101 and/or the approval
process if the
         FDA may consider ALTO-101 to be a drug/device combination product.
15.      Consistent with your disclosure on page 153, please revise your
summary risk and risk
         factor disclosure where appropriate to highlight that issued patents
covering the
         composition of ALTO-100, one of your lead product candidates, are due
to retire in 2024
         and patents covering the method of its manufacturing are due to expire
in 2030.
16.      We note your disclosure on page 148 with respect to the license
agreement with Stanford
         University that your rights under the Licensed Patents are exclusive
until December 2029,
         at which time it will become non-exclusive, and that your rights under
the Licensed
         Technology are non-exclusive. Please include related disclosure in
your risk factor
         summary and risk factor disclosure.
Our amended and restated certificate of incorporation will provide..., page 82

17.      Since you state that the exclusive forum provision will apply to
claims under the
         Securities Act, please revise here and in the Choice of Forum section
on page 211 to state
         that investors cannot waive compliance with the federal securities
laws and the rules and
         regulations thereunder. In that regard, we note that 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.

Capitalization, page 93

18.      Please revise to include your term loan as shown on your September 30,
2023 balance
         sheet at F-35 as part of your capitalization table. Also revise to
double-underline your cash
         and cash equivalent balance so it is clear that cash and cash
equivalent is not part of your
         total capitalization.
Business
Our Team, page 123
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FirstName LastNameAmit    Etkin
Alto Neuroscience, Inc.
Comapany19,
December  NameAlto
              2023 Neuroscience, Inc.
December
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FirstName LastName

19.      We note the references to your "scientific advisory board." If
material, please include
         disclosure in the appropriate section or sections of your prospectus
that:
             Describes the role or function of your scientific advisory board;
             Describes the composition of such board; and
             Describes the material provisions of any advisory contracts
between advisory board
              members and the Company, including how such board members are
compensated. In
              this regard, we note disclosure on page 69 that seemingly
indicates that you have
              entered into advisory agreements with certain physicians who are
paid, in part, in the
              form of stock or stock options.
Our Differentiated Approach and Capabilities, page 125

20.      You state: "We believe developing product candidates for
biomarker-characterized
         patient populations and likely drug responders could improve efficacy
within such
         populations, enabling us to conduct smaller more cost-efficient trials
without sacrificing
         statistical power." Please place this and any similar statements in
context by disclosing
         that the FDA or other regulatory authorities may disagree with your
clinical trial designs
         and interpretation of data or may not permit you to reduce the number
of patients
         required. Please also revise to clarify whether the FDA has permitted
you to reduce the
         number of patients in your currently active trials.

Methodical Approach to Curate Product Candidates, page 126

21.      Conclusions regarding the safety or efficacy of your drug candidates
are solely within the
         authority of the FDA and comparable regulatory bodies. As such, please
remove or revise
         the following statement on page 126, and any similar statements
throughout: "We have
         focused on acquiring or in-licensing novel chemical entities with
favorable safety results,
         clear biological rationale, and preliminary pharmacodynamic data
indicative of potential
         efficacy in biomarker-characterized patient groups."
Our Approach to Biomarker Discovery and Managing Development Risk, page 128

22.      You state that to power your biomarker approach, you run larger trials
than typical Phase
         1 or Phase 2a trials for CNS product candidates. Revise to provide
examples of the size of
         completed Phase 1 or Phase 2a trials you have conducted for your
product candidates as
         well as the "typical" size of such trials for CNS product candidates.
23.      Please revise the graphic on page 128 as follows:
             Define references to "bio +," "bio -," and "PBO; and
             In right-most column labeled "Phase 2B/3," please revise the
reference to "establish
             efficacy in Bio +" and to "Efficacy: Drug > PBO in Bio+" to remove
any implication
             that your process for discovery and development will demonstrate
the efficacy of any
             of your product candidates. In this regard, we note that
determinations of efficacy are
             solely within the authority of the FDA or equivalent foreign
regulator.
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              2023 Neuroscience, Inc.
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2) Biomarker Validation - "Test" Data, page 129

24.      You state: "We believe the independent prospective validation not only
directly
         demonstrates the robustness of the biomarkers we identify, but also
increases the
         probability of success for our pivotal clinical development plan,
representing substantially
         more knowledge about a product candidate than is typical at that stage
of CNS drug
         development." Please explain what you mean by "pivotal clinical
development plan" and
         explain the basis for your belief. Where appropriate, disclose whether
or not you have
         discussed your clinical study plans and designs with the FDA, and if
so, describe the
         outcome of such discussions.
Our Product Candidates
ALTO-100
Data from Prior ALTO-100 Clinical Trials in MDD, page 130

25.      Please revise this section to explain who completed the multiple
preclinical models of
         ALTO-100 referenced on page 132. Also, please identify the
"originator" that studied
         ALTO-100 in two previous clinical trials for patients with MDD, when
such trials were
         completed, and disclose the primary and secondary endpoints of such
studies as well as
         the results as they relate to those endpoints.
ALTO-101, page 143

26.      You state on page 143 that ALTO-101 has been studied across multiple
Phase 1 trials, in
         which the product candidate demonstrated human brain penetration and
was well
         tolerated. Please revise to clarify the number of such prior Phase 1
trials conducted by
         third parties, and when such trials were conducted.
ALTO-101 Phase 1 Clinical Data, page 144

27.      It appears based on your disclosure that prior to your acquisition of
ALTO-101, this
         product candidate was studied in a human positron emission tomography
study and a total
         of nine Phase 1 trials involving healthy subjects and Parkinson's
disease patients. Please
         revise to explain whether you intend to rely on such prior PET study
and Phase 1
         clinical trial data to support your trial design for your intended
Phase 2 proof-of-concept
         trial in which you plan to evaluate ALTO-101 for patients with
cognitive impairment
         associated with schizophrenia, or CIAS.
28.      Please revise your graphics on page 145, and any other tables or
graphics throughout your
         filing where appropriate, to ensure that the text in each, including
subscript or other
         notations are clearly legible.
29.      We note that you are collaborating with MedRX to reformulate ALTO-101
from its initial
         oral delivery method and are currently conducting a second Phase 1
trial in healthy human
         subjects studying transdermally delivered ALTO-101. You state on page
145 that
         you observed successful transdermal drug delivery at the desired
concentrations in mini-
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              2023 Neuroscience, Inc.
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         pig studies. Please revise to present more detailed information
regarding these animal
         studies, such as the number of animal models used, the number of tests
conducted, the
         range of results or effects observed in these tests and how such
results were measured.
         Alternatively, explain to us why this disclosure would not be
material.
ALTO-203, page 146

30.      Please revise this section to:
             Identify the "originator" that studied ALTO-203 in prior Phase 1
trials, disclose the
             number of prior Phase 1 trials conducted, disclose the
indication(s) for which ALTO-
             203 was studied in such trials, and when such trials were
conducted.
             Revise to present more detailed information regarding the
originator's preclinical
             study of dopamine release with ALTO-203 referenced on page 147,
such as
             the date(s) of the studies, scope and size, dosage and duration,
and the range of
             results or effects observed in these tests and how such results
were
             measured. Alternatively, explain to us why this disclosure would
not be material.
             Explain whether you intend to rely on the originator's preclinical
and/or prior Phase 1
             clinical trial data to support your trial design for your intended
Phase 2 proof-of-
             concept trial in which you plan to evaluate ALTO-203 for patients
with MDD and
             higher levels of anhedonia.

License and Other Agreements, page 148

31.      We note your disclosure that unless terminated earlier, the license
agreements with Sanofi,
         Cerecor and MedRx will expire with respect to each licensed product,
on a country-by-
         country basis, upon the expiration of a Royalty Term. Here and in the
section beginning
         on page 101, please revise to clarify when the patents underlying such
Royalty Terms are
         expected to expire. Likewise, revise to clarify when the patents
underlying the royalty
         term under the Teva Asset Purchase Agreement are expected to expire.
License Agreement with Sanofi, page 149

32.      We note your disclosure that if you achieve regulatory approval for
one or more Licensed
         Products, you will owe Sanofi certain commercial milestone payments
for the
         achievement of specified levels of aggregate, annual worldwide net
sales of all Licensed
         Products, up to an aggregate amount in the "very low triple digit
millions for all Licensed
         Products." Please quantify the potential aggregate payments for
commercial milestones.
Teva Asset Purchase Agreement, page 151

33.      We note your disclosure that if you successfully achieve regulatory
approval, then
         beginning with first commercial sale, on a Product-by-Product and
country-by-country
         basis, you will be required pay Teva tiered royalties on worldwide
annual net sales of
         Products at percentages ranging from the mid-single-digit to the very
low-double-digits.
         Please revise your description of this royalty range so that the upper
bound of the range is
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         more specific.
Product Candidate Patent Portfolio, page 153

34.      Please include a discussion of the patents and patent applications
related to ALTO-202,
         including whether such patents or patent applications cover
composition of matter of
         ALTO-202.
ALTO-101, page 154

35.      Please disclose the jurisdiction in which you co-own one pending
foreign priority patent
         application with MedRx that is directed to an ALTO-101 formulation.
Principal Stockholders, page 203

36.      Please revise your disclosure to identify the natural person(s) who
have sole or shared
         voting or investment power for the securities beneficially owned by
entities affiliated with
         Aperion Investment Group Ltd., entities affiliated with Lightswitch
Capital, and Alpha
         Wave Venutres II, LP.

Notes to the Audited Consolidated Financial Statements
9. Asset Purchase and License Agreements, page F-19

37.      For each agreement, including the MedRx agreement entered into in
September 2023,
         please revise to separately disclose the milestone payments the
company may be required
         to make, broken down by the nature of the milestone such as
development, regulatory, and
         commercial. Also, please quantify the annual license fee you will be
required to pay under
         the Stanford license agreement.
Unaudited Condensed Consolidated Financial Statements as of and for the Nine
Months Ended
September 30, 2023 and 2022
Note 2. Summary of Significant Accounting Policies and Basis of Presentation
6. Stock Based Plans, page F-46

38.      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 IPO 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.
General

39.      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,
         have presented or expect to present to potential investors in reliance
on Section 5(d) of the
 Amit Etkin
Alto Neuroscience, Inc.
December 19, 2023
Page 9
      Securities Act, whether or not they retain copies of the communications.
       Please contact Li Xiao at 202-551-4391 or Mary Mast at 202-551-3613 if
you have
questions regarding comments on the financial statements and related matters.
Please contact
Lauren Hamill at 303-844-1008 or Tim Buchmiller at 202-551-3635 with any other
questions.



                                                           Sincerely,
FirstName LastNameAmit Etkin
                                                           Division of
Corporation Finance
Comapany NameAlto Neuroscience, Inc.
                                                           Office of Life
Sciences
December 19, 2023 Page 9
cc:       Divakar Gupta
FirstName LastName