May 28, 2019

Robert J. Gould
President and Chief Executive Officer
Fulcrum Therapeutics, Inc.
26 Landsdowne Street
Cambridge, MA 02139

       Re: Fulcrum Therapeutics, Inc.
           Draft Registration Statement on Form S-1
           Submitted May 1, 2019
           CIK No. 0001680581

Dear Dr. Gould:

       We have reviewed your draft registration statement and have the
following comments. In
some of our comments, we may ask you to provide us with information so we may
better
understand your disclosure.

       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 our comments apply 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 these comments
and your
amended draft registration statement or filed registration statement, we may
have additional
comments.

Draft Registration Statement on Form S-1 filed May 1, 2019

Prospectus Summary
Overview, page 1

1.     We refer to your statement in the first paragraph that your proprietary
product engine
       identifies and validates cellular drug targets that can modulate gene
expression to treat the
       known root cause of genetically defined diseases. Please revise this
disclosure to avoid
       the implication that your proprietary product engine has generated
successful treatments
       for genetically defined diseases. Also revise the first sentence to
clarify that you are a
       clinical stage biopharmaceutical company.
 Robert J. Gould
FirstName LastNameRobert J. Gould
Fulcrum Therapeutics, Inc.
Comapany NameFulcrum Therapeutics, Inc.
May 28, 2019
May 28, 2019 Page 2
Page 2
FirstName LastName
2.       With reference to your disclosure on page 109, please revise the first
paragraph of the
         Overview to explain that you recently commenced a Phase 1 clinical
trial to establish the
         initial safety and tolerability of losmapimod in patients with FSHD.
Also, revise your
         product pipeline table on page 3 to depict clearly that your Phase 1
trial work is ongoing
         and to identify the next Phase 1 milestone in the last column.
3.       You state in the first full paragraph on page 2 that you believe you
may be able to apply
         for accelerated approval of losmapimod for the treatment of FSHD
because of prior safety
         data from GSK. Please balance your statement by noting that the FDA
may not agree
         with your proposed endpoints for accelerated approval, as you more
fully explain on
         pages 18-19 and 46, and that the FDA may raise questions regarding
your planned
         transition from GSK-manufactured tablets to tablets manufactured by
you or another
         party, and you may be required to conduct comparability assessments,
as you discuss on
         page 17.
Our Pipeline, page 3

4.       Please revise to remove the "Discovery Screening Indications" graphic
from your
         Summary presentation. Given that you have neither identified a drug
nor a drug target, it
         is premature to highlight this "screening" work prominently in your
Summary. For
         guidance, please refer to the Instruction to Item 503(a) of Regulation
S-K.
Risks Associated with Our Business, page 3

5.       Please expand the penultimate bullet to explain that the composition
of matter patent for
         losmapimod that is licensed to you expires in February 2023.
6.       Please revise the third bullet point on page 4 to identify the
"conditions and events." Also
         clarify that your auditors have issued a going concern opinion.
Implications of Being an Emerging Growth Company, page 5

7.       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.
Risk Factors
Our ability to use our NOLs and research and development tax credit
carryforwards. . ., page 14

8.       Please quantify the NOLs and other tax attributes that are subject to
limitation and clarify
         the factors that will determine the extent of the limitation.
 Robert J. Gould
FirstName LastNameRobert J. Gould
Fulcrum Therapeutics, Inc.
Comapany NameFulcrum Therapeutics, Inc.
May 28, 2019
May 28, 2019 Page 3
Page 3
FirstName LastName
Our internal computer systems, or those of our collaborators. . ., page 58

9.       You state that you make extensive use of cloud-based storage systems
and that you
         experienced a breach of one such system in October 2018. Although you
explain that the
         breach did not result in permanent loss of data, please expand your
disclosure, here or
         elsewhere as appropriate, to discuss the magnitude of the incident and
its consequences, as
         well as remediation steps you have taken.
Our certificate of incorporation that will become effective. . ., page 64

10.      We note that your forum selection provision identifies a state court
located within the
         State of Delaware (or, if the Court of Chancery of the State of
Delaware does not have
         jurisdiction, the federal district court for the District of Delaware)
as the exclusive forum
         for certain litigation, including any "derivative action." Please
disclose whether this
         provision applies to actions arising under the Securities Act or
Exchange Act. If so,
         please also state that there is uncertainty as to whether a court
would enforce such
         provision. If the provision applies to Securities Act claims, please
also state that
         stockholders will not be deemed to have waived the company's
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. To the extent the provision
does not apply to
         claims arising under the Securities Act and the Exchange Act, please
ensure the exclusive
         forum provision in your governing documents states this clearly.
Management's Discussion and Analysis
Critical Accounting Policies and Estimates
Stock-Based Compensation, page 86

11.      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 including stock
compensation and
         beneficial conversion features.
Business
Our Opportunity, page 94

12.      We refer to your statement that you have demonstrated the ability to
accurately model
         human disorders of gene mis-expression in vitro. Please revise to
discuss the work that
         supports this performance claim or tell us where you present this work
in the prospectus.
 Robert J. Gould
FirstName LastNameRobert J. Gould
Fulcrum Therapeutics, Inc.
Comapany NameFulcrum Therapeutics, Inc.
May 28, 2019
May 28, 2019 Page 4
Page 4
FirstName LastName
CRISPR Screening, page 97

13.      We refer to your statement that you use a "pooled, custom-designed"
CRISPR library.
         Please expand your disclosure to explain what you mean by "pooled."
Prior Clinical Development of Losmapimod by GSK, page 106

14.      You disclose that GSK conducted multiple trials, and your tables
disclose the number of
         serious adverse events that occurred in two different trials of
losmapimod conducted by
         GSK. Please revise your disclosure to explain all serious adverse
events that occurred.
Preclinical Studies, page 114

15.      You state that the graphic on the left on page 116 shows drug target
engagement in mouse
         blood cells after treatment, shown as a percentage of the average
vehicle-treated value.
         Please further explain the graphic, as it appears that the level of
target engagement is
         lower in the drug-treated cells.
Right of Reference and License Agreement with GlaxoSmithKline, page 119

16.      Please revise to disclose your royalty range within a ten-percent
range (e.g., 5% to 15% or
         single digit to mid-teens). In addition, please clarify the duration
of the royalty term and
         the term of the agreement by disclosing the expiration dates
underlying the patents to the
         extent not otherwise disclosed.
Intellectual Property, page 120

17.      You disclose the projected expiration date for any patents that may
issue from pending
         applications. Please also disclose the expiration date for any owned
patent(s). In addition,
         please expand your disclosure to identify the foreign jurisdictions
where you have filed
         patent applications.
Transactions with Related Persons
Consulting Services Provided by Third Rock Ventures, LLC, page 173

18.      Please disclose whether Third Rock will continue to provide you with
consulting and
         management services following the offering.
General

19.      Please provide us proofs of all graphics, visual, or photographic
information you will
         provide in the printed prospectus prior to its use, for example in a
preliminary prospectus.
         Please note that we may have comments regarding this material.
 Robert J. Gould
FirstName LastNameRobert J. Gould
Fulcrum Therapeutics, Inc.
Comapany NameFulcrum Therapeutics, Inc.
May 28, 2019
Page 5
May 28, 2019 Page 5
FirstName LastName
       You may contact Mary Mast at 202-551-3613 or Mark Brunhofer at
202-551-3638 if you
have questions regarding comments on the financial statements and related
matters. Please
contact Dorrie Yale at 202-551-8776 or Joe McCann at 202-551-6262 with any
other questions.



                                                        Sincerely,

                                                        Division of Corporation
Finance
                                                        Office of Healthcare &
Insurance