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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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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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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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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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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 suppor