Based on the Exchange Ratio formula and the anticipated size of the Slate Concurrent Investment, and giving effect to certain adjustments described in the Merger Agreement (including adjustments in respect of Fulcrum’s net cash at closing), pre-Merger Slate stockholders (excluding the Investors) are expected to own approximately 55.9%, the Investors are expected to own approximately 39.1%, and pre-Merger Fulcrum stockholders are expected to own approximately 5.0% of the Combined Company on a fully diluted basis. These percentages are based on an assumed valuation of $31.3 million for Fulcrum (subject to a dollar-for-dollar downwards adjustment to the extent Fulcrum’s net cash at closing is less than $20.3 million) and $350.0 million for Slate, exclusive of Concurrent Investment proceeds.

Shares of Fulcrum common stock are currently listed on Nasdaq under the symbol “FULC.” Fulcrum intends to file an initial listing application for the Combined Company with Nasdaq. After completion of the Merger, Fulcrum will be renamed “Slate Medicines, Inc.” and it is expected that the common stock of the Combined Company will trade on Nasdaq under the symbol “SLTE.” On     , 2026, the last trading day before the date of the accompanying proxy statement/prospectus, the closing sale price of Fulcrum common stock was $  per share.

Fulcrum stockholders are cordially invited to virtually attend the special meeting of Fulcrum stockholders (the “Fulcrum Special Meeting”). Fulcrum is holding the Fulcrum Special Meeting on    , 2026, at     Eastern Time, unless postponed or adjourned to a later date, in order to obtain the stockholder approvals necessary to complete the Merger and related matters. The Fulcrum Special Meeting will be held via the Internet at a virtual audio web conference at    . Fulcrum stockholders will be able to attend and participate in the Fulcrum Special Meeting virtually, where they will be able to ask questions and vote. At the Fulcrum Special Meeting, Fulcrum will ask its stockholders to:

As described in the accompanying proxy statement/prospectus, certain Fulcrum stockholders who in the aggregate owned approximately 1.0% of the outstanding shares of Fulcrum as of August 16, 2026, and certain Slate stockholders who in the aggregate owned approximately 78.65% of the outstanding shares of Slate capital stock as of August 16, 2026, are parties to stockholder support agreements with Fulcrum and Slate, respectively, whereby such stockholders have agreed to vote in favor of the approval of the transactions contemplated therein, including, with respect to Slate stockholders, adoption of the Merger Agreement and approval of the Merger and,

with respect to such Fulcrum stockholders, Proposal Nos. 1 – 5, subject to the terms of the support agreements. Following the effectiveness of the registration statement on Form S-4 of which the accompanying proxy statement/prospectus is a part and pursuant to the Merger Agreement, Slate stockholders holding a sufficient number of shares of Slate capital stock to adopt the Merger Agreement and approve the Merger and related transactions will be asked to execute written consents providing for such adoption and approval.

Further, prior to the First Effective Time, the Fulcrum board of directors will declare and set aside the aggregate cash amount to be paid in accordance with a pre-Closing special cash dividend (the “Pre-Closing Cash Dividend”) to holders of record of outstanding shares of Fulcrum common stock as of a record date prior to the First Effective Time, to be set by the Fulcrum board of directors as close as reasonably practicable to (but not later than) the anticipated Closing date. The ex-dividend date in respect of such Pre-Closing Cash Dividend will be determined by Nasdaq. Fulcrum stockholders of record who continue to hold their eligible shares of Fulcrum common stock until market open on the ex-dividend date will be entitled to payment of the Pre-Closing Cash Dividend. The Pre-Closing Cash Dividend will be equal in the aggregate to an amount mutually agreed in good faith by Fulcrum and Slate by reference to the amount by which Fulcrum’s Net Cash (as determined pursuant to the Merger Agreement) is expected to exceed $20,300,000 as of the closing of the Merger. The aggregate amount of the Pre-Closing Cash Dividend is expected to be approximately $270 million.

After careful consideration, each of the Fulcrum and Slate boards of directors have approved the Merger Agreement and have determined that it is advisable to consummate the Merger. Fulcrum’s board of directors has approved the proposals described in the accompanying proxy statement/prospectus and recommends that its stockholders vote “FOR” the proposals described in the accompanying proxy statement/prospectus.

More information about Fulcrum, Slate, the Merger Agreement and transactions contemplated thereby and the foregoing proposals is contained in the accompanying proxy statement/prospectus. Fulcrum urges you to read the accompanying proxy statement/prospectus carefully and in its entirety. IN PARTICULAR, YOU SHOULD CAREFULLY CONSIDER THE MATTERS DISCUSSED UNDER “RISK FACTORS” BEGINNING ON PAGE 25 OF THE ACCOMPANYING PROXY STATEMENT/PROSPECTUS.

Fulcrum and Slate are excited about the opportunities the Merger brings to Fulcrum’s and Slate’s stockholders and thank you for your consideration and continued support.

Sincerely,

Neither the Securities and Exchange Commission nor any state securities commission has approved or disapproved of these securities or passed upon the adequacy or accuracy of the accompanying proxy statement/prospectus. Any representation to the contrary is a criminal offense.

The accompanying proxy statement/prospectus is dated     , 2026, and is first being mailed to Fulcrum’s stockholders on or about     , 2026.

FULCRUM THERAPEUTICS, INC.

26 Landsdowne Street

Cambridge, Massachusetts 02139

(617) 651-8851

NOTICE OF SPECIAL MEETING OF STOCKHOLDERS

To the stockholders of Fulcrum Therapeutics, Inc.:

NOTICE IS HEREBY GIVEN that a special meeting of stockholders (the “Fulcrum Special Meeting”) will be held on   , 2026, at     Eastern Time, unless postponed or adjourned to a later date. The Fulcrum Special Meeting will be held via the Internet at a virtual audio web conference at.

The Fulcrum Special Meeting will be held for the following purposes:

Virtual Meeting: The Fulcrum Special Meeting will be a “virtual meeting” of stockholders, which will be conducted exclusively via the Internet at a virtual web conference. There will not be a physical meeting location, and stockholders will not be able to attend the Fulcrum Special Meeting in person. This means that you can attend the Fulcrum Special Meeting online, vote your shares during the online meeting and submit questions during and shortly before the online meeting. In order to attend the meeting and vote your shares electronically during the meeting, you must register in advance at   prior to the deadline of   , 2026, at     ,     Eastern Time. Upon completing your registration, you will receive further instructions via email, including your unique links that will allow you to attend the Fulcrum Special Meeting, vote your shares and submit questions.

Record Date: Fulcrum’s board of directors has fixed   , 2026 as the record date for the determination of stockholders entitled to notice of, and to vote at, the Fulcrum Special Meeting and any adjournment

or postponement thereof. Only holders of record of shares of Fulcrum common stock at the close of business on the record date are entitled to notice of, and to vote at, the Fulcrum Special Meeting. At the close of business on the record date, Fulcrum had      shares of common stock outstanding and entitled to vote.

Your vote is important. The affirmative vote of the holders of shares of stock having a majority in voting power of the votes cast by the holders of all of the shares of stock present or represented at the Fulcrum Special Meeting and voting affirmatively or negatively on such matter, assuming a quorum is present, is required for approval of Proposal Nos. 1, 2, 3, 4 and 5. Approval of each of Proposal No. 1 and Proposal No. 2 is a condition to the completion of the Merger. Therefore, the Merger cannot be consummated without the approval of Proposal Nos. 1 and 2.

Even if you plan to virtually attend the Fulcrum Special Meeting, Fulcrum requests that you sign and return the enclosed proxy or vote by mail or online to ensure that your shares will be represented at the Fulcrum Special Meeting if you are unable to virtually attend. You may change or revoke your proxy at any time before it is voted at the Fulcrum Special Meeting.

FULCRUM’S BOARD OF DIRECTORS HAS DETERMINED AND BELIEVES THAT EACH OF THE PROPOSALS OUTLINED ABOVE IS FAIR TO, IN THE BEST INTERESTS OF, AND ADVISABLE TO FULCRUM AND ITS STOCKHOLDERS AND HAS APPROVED EACH SUCH PROPOSAL. FULCRUM’S BOARD OF DIRECTORS RECOMMENDS THAT FULCRUM STOCKHOLDERS VOTE “FOR” EACH SUCH PROPOSAL.

Important Notice Regarding the Availability of Proxy Materials for the Stockholders’ Meeting to Be Held on   , 2026 at   Eastern Time at   .

The proxy statement/prospectus and annual report to stockholders are available at   .

By Order of Fulcrum’s Board of Directors,

Alex C. Sapir

Chief Executive Officer

    , 2026

REFERENCES TO ADDITIONAL INFORMATION

This proxy statement/prospectus incorporates important business and financial information about Fulcrum Therapeutics, Inc. that is not included in or delivered with this document. You may obtain this information without charge through the Securities and Exchange Commission website (www.sec.gov) or upon your written or oral request by contacting the Corporate Secretary of Fulcrum Therapeutics, Inc. by calling (617) 651-8851.

To ensure timely delivery of these documents, any request should be made no later than     , 2026 to receive them before the Fulcrum Special Meeting.

For additional details about where you can find information about Fulcrum, please see the section titled “Where You Can Find More Information” beginning on page 390 of this proxy statement/prospectus.

i

TABLE OF CONTENTS

ii

QUESTIONS AND ANSWERS ABOUT THE MERGER

Except where specifically noted, the following information and all other information contained in this proxy statement/prospectus does not give effect to the proposed reverse stock split described in Proposal No. 2 of this proxy statement/prospectus.

The following section provides answers to frequently asked questions about the Merger. This section, however, provides only summary information. For a more complete response to these questions and for additional information, please refer to the cross-referenced sections.

For a more complete description of the treatment of Slate securities in the Merger, please see the sections titled “The Merger Agreement — Merger Consideration,” and “The Merger Agreement — Exchange Ratio” beginning on pages 198 and 199, respectively, of this proxy statement/prospectus. For a description of the effect of the Slate Concurrent Investment on Slate’s current securityholders, please see the section titled “Agreements Related to the Merger — Securities Purchase Agreement” beginning on page 217 of this proxy statement/prospectus.

1

In addition, prior to the First Effective Time, Fulcrum’s board of directors expects to declare a special cash dividend (the “Pre-Closing Cash Dividend”) to stockholders of record of outstanding shares of Fulcrum common stock as of the record date prior to the First Effective Time, to be set by Fulcrum’s board of directors as close as reasonably practicable to (but not later than) the First Effective Time. The ex-dividend date in respect of such Pre-Closing Cash Dividend will be determined by Nasdaq. Fulcrum stockholders of record who continue to hold their eligible shares of Fulcrum common stock until market open on the ex-dividend date will be entitled to payment of the Pre-Closing Cash Dividend. The Pre-Closing Cash Dividend will be equal in the aggregate to an amount mutually agreed in good faith by Fulcrum and Slate by reference to the amount by which Fulcrum’s Net Cash (as determined pursuant to the Merger Agreement) is expected to exceed $20,300,000 as of the closing of the Merger. Fulcrum currently estimates that the aggregate amount of cash to be distributed to stockholders of record as of the record date for the Pre-Closing Cash Dividend will be approximately $270 million.

For a more complete description of the treatment of Fulcrum securities in the Merger, please see the sections titled “The Merger Agreement — Merger Consideration,” “The Merger Agreement — Exchange Ratio,” and “Market Price and Dividend Information” beginning on pages 198, 199 and 24, respectively, of this proxy statement/prospectus.

2

Immediately after the Merger, the shares of Slate common stock issued in the Slate Concurrent Investment are expected to represent approximately 39.1% of the outstanding shares of common stock of the Combined Company. Fulcrum, Slate and the investors participating in the Slate Concurrent Investment also entered into a registration rights agreement (the “Registration Rights Agreement”) at the closing of the Slate Concurrent Investment, pursuant to which, among other things, the Combined Company will agree to provide for the registration and resale of certain shares of Fulcrum common stock that are held by the investors participating in the Slate Concurrent Investment from time to time pursuant to Rule 415 under the Securities Act (“Rule 415”). The closing of the Slate Concurrent Investment is conditioned upon the satisfaction or waiver of the conditions to the Closing as well as certain other conditions.

For a more complete description of the Slate Concurrent Investment, please see the sections titled “Agreements Related to the Merger — Securities Purchase Agreement” and “Agreements Related to the Merger — Registration Rights Agreement” beginning on pages 217 and 218 of this proxy statement/prospectus, respectively.

3

Approval of each of Proposal Nos. 1 and 2 is a condition to completion of the Merger. The issuance (or reservation for issuance) of Fulcrum common stock in connection with the Merger and the change of control resulting from the Merger will not take place unless Proposal No. 1 is approved by Fulcrum stockholders and the Merger is consummated. The amendment to the restated certificate of incorporation of Fulcrum to effect a reverse stock split of Fulcrum’s issued and outstanding common stock will not take place unless Proposal No. 2 is approved by the requisite Fulcrum stockholders and the Merger is consummated.

In addition to the requirement of obtaining Fulcrum stockholder approval, the Closing is subject to the satisfaction or waiver of each of the other closing conditions set forth in the Merger Agreement. For a more complete description of the closing conditions under the Merger Agreement, please see the section titled “The Merger Agreement — Conditions to the Completion of the Merger” beginning on page 212 of this proxy statement/prospectus.

The presence, in person, by means of remote communication in a manner, if any, authorized by the Fulcrum board of directors in its sole discretion, or represented by proxy, at the Special Meeting of the holders of a majority in voting power of the shares issued and outstanding and entitled to vote at the Special Meeting is necessary to constitute a quorum at the meeting for the purpose of approving the Merger Proposals.

The approvals of Proposal Nos. 3, 4 and 5 are not conditions to the Merger.

The presence, in person, by means of remote communication in a manner, if any, authorized by the Fulcrum board of directors in its sole discretion, or represented by proxy, at the Special Meeting of the holders of a majority in voting power of the shares issued and outstanding and entitled to vote at the Special Meeting is necessary to constitute a quorum at the meeting for the purpose of approving the proposals.

Votes will be counted by the inspector of election appointed for the meeting, who will separately count “FOR” and “AGAINST” votes, abstentions and broker non-votes. Broker non-votes, if any, will not be treated as shares present for the purpose of determining the presence of a quorum for the transaction of business at the special meeting. Abstentions and broker non-votes, if any, will have no effect on any of the Proposals.

4

In the case of the Merger, based on the current estimated exchange ratio, Fulcrum expects to issue (or reserve for issuance) approximately 1.6 billion shares of Fulcrum common stock (including shares of Fulcrum common stock underlying the Slate warrants and Slate options assumed in the Merger, as well as shares issued to investors in the Slate Concurrent Investment, but in each case prior to adjusting for any reverse stock split), which shares will represent greater than 20% of its voting stock outstanding before the issuance. Accordingly, Fulcrum is seeking stockholder approval of the issuance pursuant to the Merger Agreement, including the Slate Concurrent Investment under the Nasdaq rules.

On    , 2026, the last trading day before the date of this proxy statement/prospectus, the closing sale price of Fulcrum common stock was $  per share.

5

For more information, please see the section titled “The Merger Agreement — Conditions to the Completion of the Merger” beginning on page 212 of this proxy statement/prospectus.

Stockholder of Record: Shares Registered in Your Name

If you are a stockholder of record, you may vote online at the Fulcrum Special Meeting, vote by proxy over the telephone, vote by proxy through the Internet or vote by proxy using a proxy card, the form of which is attached as Annex K. Whether or not you plan to virtually attend the meeting, you are urged to vote by proxy

6

to ensure your vote is counted. You may still virtually attend the meeting and vote online even if you have already voted by proxy.

Beneficial Owner: Shares Registered in the Name of Broker, Bank or Other Agent

If you are a beneficial owner of shares registered in the name of your broker, bank, or other agent, you should have received voting instructions from that organization rather than from Fulcrum. Simply follow the voting instructions provided to ensure that your vote is counted. You may vote by telephone or over the Internet as instructed by your broker, bank or other agent. To vote online at the Fulcrum Special Meeting, you must contact your broker, bank, or other agent and obtain a valid legal proxy in order to attend, participate in and vote at the Fulcrum Special Meeting. Follow the voting instructions from your broker, bank or other agent, or contact your broker, bank or other agent for instructions.

Online registration will begin on     , 2026, and you should allow ample time for the online registration. Upon completing your registration, you will receive further instructions via email, including your unique link that will allow you access to the meeting. Please be sure to follow the instructions you will receive once your registration is complete.

The Fulcrum Special Meeting will start at     , 2026, Eastern time, on     . You may log on to the virtual meeting starting 15 minutes before it begins. Fulcrum will have technicians standing by and ready to assist you with any technical difficulties you may have accessing the virtual meeting starting at     ,

7

Eastern time, on     , 2026. If you encounter any difficulties accessing the virtual special meeting, please contact technical support by following the instructions provided to you upon registration for the special meeting.

Broker non-votes, if any, will not be treated as shares present for the purpose of determining the presence of a quorum for the transaction of business at the Fulcrum Special Meeting. Broker non-votes, if any, will not be counted as votes cast and voting affirmatively or negatively and will therefore have no effect on any of the Proposals.

Your signed proxy card, telephonic proxy instructions, internet proxy instructions, or written notice must be received by     , 2026, at 11:59 p.m. Eastern Time to be counted.

8

If a Fulcrum stockholder who owns Fulcrum shares in “street name” has instructed a broker to vote its shares of Fulcrum common stock, the stockholder must follow directions received from its broker to change and/or revoke those instructions.

9

Fulcrum Therapeutics, Inc.

26 Landsdowne Street

Cambridge, Massachusetts 02139

Attn: Investor Relations

Telephone: (617) 651-8851

Email: coltmans@fulcrumtx.com

10

11

12

13

14

15

16

17

18

19

20

21

22

23

MARKET PRICE AND DIVIDEND INFORMATION

Fulcrum common stock is currently listed on The Nasdaq Global Market under the symbol “FULC.”

The closing price of the Fulcrum common stock on August 14, 2026, the last day of trading prior to the announcement of the Merger, as reported on The Nasdaq Global Market, was $3.74 per share.

Because the market price of the Fulcrum common stock is subject to fluctuation, the market value of the shares of the Slate common stock that the Fulcrum stockholders will be entitled to receive in the Merger may increase or decrease.

Assuming approval of Proposal Nos. 1 and 2 and successful application for initial listing with The Nasdaq Global Market, following the consummation of the Merger, the Fulcrum common stock will trade on The Nasdaq Global Market under Fulcrum’s new name, “Slate Medicines, Inc.,” and new trading symbol “SLTE.”

As of     , 2026, the Record Date for the Special Meeting, there were approximately registered holders of record of the Fulcrum common stock. As of    , 2026, Slate had     holders of record of Slate common stock and     holders of record of Slate preferred stock. For detailed information regarding the beneficial ownership of certain Fulcrum and Slate stockholders, see the sections of this proxy statement/prospectus titled “Principal Stockholders of Fulcrum” and “Principal Stockholders of Slate.”

Dividends

Fulcrum has never declared or paid any cash dividends on the Fulcrum common stock and does not anticipate paying cash dividends on the Fulcrum common stock for the foreseeable future, except the Pre-Closing Cash Dividend that Fulcrum will declare and pay to the holders of record of outstanding shares of Fulcrum common stock as of a record date prior to the effective time of the Merger, to be set by the Fulcrum board of directors as close as reasonably practicable to (but not later than) the anticipated date of Closing (the “Closing Date”). The aggregate amount of the Pre-Closing Cash Dividend is expected to equal approximately $270 million, subject to certain adjustments depending on Fulcrum’s Net Cash. Notwithstanding the foregoing, any determination to pay cash dividends subsequent to the Merger will be at the discretion of the Combined Company’s then-current board of directors and will depend upon a number of factors, including the Combined Company’s results of operations, financial condition, future prospects, contractual restrictions, restrictions imposed by applicable law and other factors the then-current board of directors deems relevant.

Slate has never paid or declared any cash dividends on the Slate capital stock. If the Merger does not occur, Slate does not anticipate paying any cash dividends on the Slate capital stock in the foreseeable future, and Slate intends to retain all available funds and any future earnings to fund the development and expansion of its business. Any future determination to pay dividends will be at the discretion of the Slate board of directors and will depend upon a number of factors, including its results of operations, financial condition, future prospects, contractual restrictions, and restrictions imposed by applicable laws and other factors the Slate board of directors deems relevant.

24

RISK FACTORS

The Combined Company will be faced with a market environment that cannot be predicted and that involves significant risks, many of which will be beyond its control. In addition to the other information contained or incorporated by reference in this proxy statement/prospectus, you should carefully consider the material risks described below before deciding how to vote your shares of Fulcrum common stock. You should also read and consider the other information in this proxy statement/prospectus and additional information about Fulcrum set forth in its Quarterly Report on Form 10-Q for the fiscal quarter ended June 30, 2026, which is filed with the Securities and Exchange Commission (“SEC”), as updated by its Quarterly Reports on Form 10-Q and Annual Reports on Form 10-K, in each case incorporated by reference into this proxy statement/prospectus. Please see the section titled “Where You Can Find More Information” beginning on page 390 of this proxy statement/prospectus for further information regarding the documents incorporated by reference into this proxy statement/prospectus.

Risks Related to the Merger

Failure to complete, or delays in completing, the potential Merger with Slate, announced on August 17, 2026, could materially and adversely affect Fulcrum’s or Slate’s results of operations, business, financial results and may cause a decline in the market price of Fulcrum common stock.

On August 16, 2026, Fulcrum entered into the Merger Agreement with Slate, pursuant to which, if all the closing conditions are satisfied or waived, Merger Sub I, a direct, wholly owned subsidiary of Fulcrum, will merge with and into Slate, with Slate surviving as a wholly owned subsidiary of Fulcrum and the surviving corporation of the First Merger. Slate will then merge with and into Merger Sub II, a direct, wholly owned subsidiary of Fulcrum, with Merger Sub II being the surviving entity of the Second Merger. Consummation of the Merger is subject to certain closing conditions, a number of which are not within Fulcrum’s control. Any failure to satisfy or, to the extent permitted by applicable law, waive these required closing conditions may prevent, delay or otherwise materially adversely affect the consummation of the Merger. Fulcrum cannot predict with certainty whether or when any of the required conditions will be satisfied or, to the extent permitted by applicable law, waived, or if another uncertainty may arise and cannot assure you that Fulcrum will be able to successfully consummate the Merger as currently contemplated under the Merger Agreement or at all.

Fulcrum’s efforts to complete the Merger could cause substantial disruptions in, and create uncertainty surrounding, Fulcrum’s business, which may materially adversely affect Fulcrum’s results of operation and Fulcrum’s business. Uncertainty as to whether the Merger will be completed may affect Fulcrum’s ability to retain and motivate existing employees. Employee retention may be particularly challenging while the transaction is pending because employees may experience uncertainty about their roles following the transaction. Uncertainty as to whether the Merger will be completed could adversely affect Fulcrum’s business and Fulcrum’s relationship with collaborators, suppliers, vendors, regulators and other business partners. For example, vendors, collaborators and other counterparties may defer their decisions to work with Fulcrum or seek to change their existing business relationships with Fulcrum. Changes to, or termination of, existing business relationships could adversely affect Fulcrum’s results of operations and financial condition, as well as the market price of Fulcrum common stock. The adverse effects of the pendency of the transaction could be exacerbated by any delays in completion of the transaction or termination of the Merger Agreement.

The Exchange Ratio will not be adjusted based on the market price of Fulcrum common stock as the Exchange Ratio depends on Fulcrum’s Net Cash at the Closing and not the market price of Fulcrum common stock, so the Merger consideration at the Closing may have a greater or lesser value than at the time the Merger Agreement was signed.

At the First Effective Time, as described in the Merger Agreement, outstanding shares of Slate capital stock will be converted into shares of Fulcrum common stock. Based on Fulcrum’s and Slate’s capitalization as of

25

August 16, 2026, the Exchange Ratio is estimated to be equal to approximately 24.8186 shares of Fulcrum common stock for each share of Slate common stock. After applying the Exchange Ratio, the former Slate securityholders immediately before the Merger, excluding shares purchased in the Slate Concurrent Investment, are expected to own approximately 55.9% of the aggregate number of shares of Fulcrum common stock on a fully-diluted basis, shares issued in the Slate Concurrent Investment are expected to represent approximately 39.1% of the outstanding shares of Fulcrum common stock on a fully-diluted basis and Fulcrum securityholders immediately before the Merger are expected to own approximately 5% of the aggregate number of shares of Fulcrum common stock on a fully-diluted basis, subject to certain assumptions, including, but not limited to, Fulcrum’s Net Cash as of Closing being no less than $20,300,000. In the event Fulcrum’s Net Cash is below $20,300,000, the Exchange Ratio will be adjusted such that the number of shares issued to Slate’s pre-Closing securityholders will be increased, and Fulcrum stockholders will own a smaller percentage of the Combined Company.

Any changes in the market price of Fulcrum common stock before the completion of the Merger will not affect the Exchange Ratio or the number of shares Slate stockholders will be entitled to receive pursuant to the Merger Agreement. Therefore, if before the completion of the Merger, the market price of Fulcrum common stock increases from the market price on the date of the Merger Agreement, then Slate stockholders could receive Merger consideration with substantially more value for their shares of Slate capital stock than the parties had negotiated when they established the Exchange Ratio. Similarly, if before the completion of the Merger the market price of Fulcrum common stock declines from the market price on the date of the Merger Agreement, then Slate stockholders could receive Merger consideration with substantially lower value than the parties negotiated when they established the Exchange Ratio. The Merger Agreement does not include a price-based termination right.

The issuance of Fulcrum common stock to Slate stockholders pursuant to the Merger Agreement and the resulting change in control from the Merger must be approved by Fulcrum stockholders, and the Merger Agreement and transactions contemplated thereby must be approved by the Slate stockholders. Failure to obtain these approvals would prevent the Closing.

Before the Merger can be completed, Fulcrum stockholders must approve, among other things, the issuance of Fulcrum common stock to Slate stockholders pursuant to the Merger Agreement and the resulting change in control from the Merger, and Slate stockholders must adopt the Merger Agreement and approve the Merger and the related transactions. Failure to obtain the required stockholder approvals may result in a material delay in, or the abandonment of, the Merger. Any delay in completing the Merger may materially adversely affect the timing and benefits that are expected to be achieved from the Merger.

Failure to complete the Merger may result in either Fulcrum or Slate paying a termination fee to the other party, and could harm the common stock price of Fulcrum and future business and operations of each company.

If the Merger is not completed, Fulcrum and Slate are subject to the following risks:

If the Merger Agreement is terminated and the board of directors of Fulcrum or Slate determines to seek another business combination, there can be no assurance that either Fulcrum or Slate will be able to find another third party to transact a business combination with, yielding comparable or greater benefits.

26

If the conditions to the Merger are not satisfied or waived, the Merger may not occur.

Even if the Merger is approved by the stockholders of Slate and Proposal Nos. 1 and 2 as described in this proxy statement/prospectus are approved by the Fulcrum stockholders, specified conditions must be satisfied or, to the extent permitted by applicable law, waived to complete the Merger. These conditions are set forth in the Merger Agreement and each material condition to the completion of the Merger is described in the section titled “The Merger Agreement — Conditions to the Completion of the Merger” beginning on page 212 of this proxy statement/prospectus. Fulcrum and Slate cannot assure you that all of the conditions to the consummation of the Merger will be satisfied or waived. If the conditions are not satisfied or waived, the Merger may not occur or the Closing may be delayed.

The Merger may be completed even though a material adverse effect may result from the announcement of the Merger, industry-wide changes or other causes.

In general, neither Fulcrum nor Slate is obligated to complete the Merger if there is a material adverse effect affecting the other party between August 16, 2026, the date of the Merger Agreement, and the Closing. However, certain types of events and/or causes are excluded from the concept of a “material adverse effect.” Such exclusions include, but are not limited to, changes in general economic or political conditions, industry wide changes, changes resulting from the announcement of the Merger, natural disasters, pandemics, other public health events, other force majeure events, acts or threat of terrorism or war and changes in U.S. GAAP. Therefore, if any of these events were to occur and adversely affect Fulcrum or Slate, the other party would still be obligated to consummate the Closing notwithstanding such material adverse effects. If any such adverse effects occur and Fulcrum and Slate consummate the Closing, the stock price of the Combined Company may suffer. This, in turn, may reduce the value of the Merger to the stockholders of Fulcrum, Slate or both. For a more complete discussion of what constitutes a material adverse effect on Fulcrum or Slate, please see the section titled “The Merger Agreement — Representations and Warranties” beginning on page 203 of this proxy statement/prospectus.

If Fulcrum and Slate complete the Merger, the Combined Company will need to raise additional capital by issuing equity securities or additional debt or through licensing arrangements, which may cause significant dilution to the Combined Company’s stockholders or restrict the Combined Company’s operations.

On August 16, 2026, Slate entered into the Securities Purchase Agreement with certain investors, including existing investors of Slate, pursuant to which Slate agreed to sell, and the investors agreed to purchase, immediately prior to the consummation of the Merger, shares of Slate common stock for an aggregate purchase price of approximately $245 million in the Slate Concurrent Investment. The closing of the Slate Concurrent Investment is conditioned upon the satisfaction or waiver of the conditions to the Closing as well as certain other conditions. The shares of Slate common stock issued in the Slate Concurrent Investment will result in dilution to all securityholders of the Combined Company (i.e., both the pre-Merger Fulcrum securityholders and former pre-Merger Slate securityholders). The Slate Concurrent Investment is more fully described under the section titled “Agreements Related to the Merger — Securities Purchase Agreement” beginning on page 217 of this proxy statement/prospectus.

Additional financing may not be available to the Combined Company when it is needed or may not be available on favorable terms. To the extent that the Combined Company raises additional capital by issuing equity securities, such financing will cause additional dilution to all securityholders of the Combined Company, including Fulcrum’s pre-Merger securityholders and Slate’s former securityholders. It is also possible that the terms of any new equity securities may have preferences over the Combined Company’s common stock. Any debt financing the Combined Company enters into may involve covenants that restrict its operations. These restrictive covenants may include limitations on additional borrowing and specific restrictions on the use of the Combined Company’s assets, as well as prohibitions on its ability to create liens, pay dividends, redeem its stock or make investments. In addition, if the Combined Company raises additional funds through licensing arrangements, it may be necessary to grant licenses on terms that are not favorable to the Combined Company.

27

Some Fulcrum and Slate directors and executive officers have interests in the Merger that are different from yours.

Directors and executive officers of Fulcrum and Slate may have interests in the Merger that are different from, or in addition to, the interests of other Fulcrum stockholders generally. These interests with respect to Fulcrum’s directors and executive officers may include, among others, acceleration of stock option or restricted stock unit vesting, retention bonus payments, extension of exercisability periods of previously issued stock option grants, severance payments if employment is terminated in a qualifying termination in connection with the Merger and rights to continued indemnification, expense advancement and insurance coverage. These interests with respect to Slate’s directors and executive officers may include, among others, certain of Slate’s directors and executive officers have options, subject to vesting, to purchase shares of Slate common stock which, after the effective time of the Merger, will be converted into and become options to purchase shares of the common stock of the Combined Company; Slate’s executive officers are expected to continue as executive officers of the Combined Company after the effective time of the Merger; and all of Slate’s directors and executive officers are entitled to certain indemnification and liability insurance coverage pursuant to the terms of the Merger Agreement. In addition, certain of Fulcrum’s directors and Slate’s directors are affiliated with investment funds which hold an interest in the other party, and are participating in the Slate Concurrent Investment. Further, current members of Slate’s board of directors will continue as directors of the Combined Company after the effective time of the Merger, and, following the Closing, will be eligible to be compensated as non-employee directors of the Combined Company pursuant to the Fulcrum non-employee director compensation policy that is expected to remain in place following the effective time of the Merger. The directors and executive officers own options and/or, with respect to Fulcrum, restricted stock units, to purchase the shares of their respective companies.

The Fulcrum and Slate boards considered the interests in the Merger that the respective directors and officers may have that are different than yours, among other matters, in reaching their decisions to approve and adopt the Merger Agreement, approve the Merger, and recommend the approval of the Merger Agreement to Fulcrum and Slate stockholders.

For more information regarding the interests of Fulcrum and Slate directors and executive officers in the Merger, please see the sections titled “The Merger — Interests of Fulcrum Directors and Executive Officers in the Merger” and “The Merger — Interests of Slate Directors and Executive Officers in the Merger” beginning on pages 178 and 184, respectively, of this proxy statement/prospectus.

Fulcrum stockholders and Slate stockholders may not realize a benefit from the Merger commensurate with the ownership dilution they will experience in connection with the Merger, including the conversion of Slate common stock issued in the Slate Concurrent Investment.

If the Combined Company is unable to realize the full strategic and financial benefits currently anticipated from the Merger, Fulcrum stockholders and Slate stockholders will have experienced substantial dilution of their ownership interests without receiving any commensurate benefit, or only receiving part of the commensurate benefit to the extent the Combined Company is able to realize only part of the strategic and financial benefits currently anticipated from the Merger.

If the Merger is not completed, Fulcrum’s stock price may decline significantly.

The market price of Fulcrum common stock is subject to significant fluctuations. Market prices for securities of pharmaceutical, biotechnology and other life science companies have historically been particularly volatile. In addition, the market price of Fulcrum common stock will likely be volatile based on whether stockholders and other investors believe that Fulcrum can complete the Merger or otherwise raise additional capital to support Fulcrum’s operations if the Merger is not consummated and another strategic transaction cannot be identified, negotiated and consummated in a timely manner, if at all. The volatility of the market price

28

of Fulcrum common stock is exacerbated by low trading volume. Additional factors that may cause the market price of Fulcrum common stock to fluctuate include:

Moreover, the stock markets in general have experienced substantial volatility that has often been unrelated to the operating performance of individual companies. These broad market fluctuations may also adversely affect the trading price of Fulcrum common stock. In the past, following periods of volatility in the market price of a company’s securities, stockholders have often instituted class action securities litigation against such companies.

Fulcrum and Slate securityholders will generally have a reduced ownership and voting interest in, and will exercise less influence over the management of, the Combined Company following the completion of the Merger as compared to their current ownership and voting interests in the respective companies.

After the completion of the Merger, the current stockholders of Fulcrum and Slate will generally own a smaller percentage of the Combined Company than their ownership of their respective companies prior to the Merger. Based on the Exchange Ratio formula and the anticipated size of the Slate Concurrent Investment, and giving effect to certain adjustments described in the Merger Agreement (including adjustments in respect of Fulcrum’s net cash at closing), pre-Merger Slate stockholders (excluding the Investors) are expected to own approximately 55.9%, the Investors are expected to own approximately 39.1%, and pre-Merger Fulcrum stockholders are expected to own approximately 5.0% of the Combined Company on a fully diluted basis. These percentages are based on an assumed valuation of $31.3 million for Fulcrum (subject to a dollar-for-dollar downwards adjustment to the extent Fulcrum’s net cash at closing is less than $20.3 million) and $350.0 million for Slate, exclusive of Concurrent Investment proceeds. The Chief Executive Officer of Slate will serve as the Chief Executive Officer of the Combined Company following the completion of the Merger.

During the pendency of the Merger, Fulcrum and Slate may not be able to enter into a business combination with another party on more favorable terms because of restrictions in the Merger Agreement, which could adversely affect their respective business prospects.

Covenants in the Merger Agreement impede the ability of Fulcrum and Slate to make acquisitions during the pendency of the Merger, subject to specified exceptions. As a result, if the Merger is not completed, the parties may be at a disadvantage to their competitors during that period. In addition, while the Merger Agreement is in effect, each party is generally prohibited from soliciting, seeking, initiating or knowingly encouraging, inducing or facilitating the communication, making, submission or announcement of any acquisition proposal or acquisition inquiry or taking any action that could reasonably be expected to lead to certain transactions involving a third party, including a merger, sale of assets or other business combination, subject to specified exceptions. Any such transactions could be favorable to such party’s stockholders, but the parties may be unable to pursue them. For more information, please see the section titled “The Merger Agreement — Non-Solicitation” beginning on page 208 of this proxy statement/prospectus.

29

Certain provisions of the Merger Agreement may discourage third parties from submitting competing proposals, including proposals that may be superior to the transactions contemplated by the Merger Agreement.

The terms of the Merger Agreement prohibit each of Fulcrum and Slate from soliciting competing proposals or cooperating with persons making unsolicited takeover proposals, except in limited circumstances as described in further detail in the sections titled “The Merger Agreement — Non-Solicitation” beginning on page 208 of this proxy statement/prospectus. In addition, if Fulcrum terminates the Merger Agreement under specified circumstances, Fulcrum could be required to pay Slate a termination fee of $10 million, or Slate could be required to pay Fulcrum a termination fee of $15 million. This termination fee may discourage third parties from submitting competing proposals to Fulcrum, Slate or their respective stockholders, and may cause the Fulcrum or Slate board of directors to be less inclined to recommend a competing proposal.

Because the lack of a public market for Slate’s capital stock makes it difficult to evaluate the fair market value of Slate’s capital stock, the value of the Fulcrum common stock to be issued to Slate stockholders may be more or less than the fair market value of Slate’s capital stock.

The outstanding capital stock of Slate is privately held and is not traded in any public market. The lack of a public market makes it difficult to determine the fair market value of Slate’s capital stock. Because the percentage of Fulcrum equity to be issued to Slate stockholders was determined based on negotiations between the parties, it is possible that the value of the Fulcrum common stock to be issued to Slate stockholders will be more or less than the fair market value of Slate’s capital stock.

Lawsuits may be filed against Fulcrum, Slate, or any of the members of their respective boards of directors arising out of the Merger, which may delay or prevent the Merger.

Putative stockholder complaints, including stockholder class action complaints, and other complaints may be filed against Fulcrum, the Fulcrum board of directors, Slate, the Slate board of directors and others in connection with the transactions contemplated by the Merger Agreement. The outcome of litigation is uncertain, and Fulcrum or Slate may not be successful in defending against any such future claims. Lawsuits that may be filed against Fulcrum, the Fulcrum board of directors, Slate, or the Slate board of directors could delay or prevent the Merger, divert the attention of Fulcrum’s or Slate’s management and employees from their day-to-day business and otherwise adversely affect Fulcrum and Slate financially.

Fulcrum is substantially dependent on Fulcrum’s remaining employees to facilitate the consummation of the Merger.

As of August 13, 2026, Fulcrum had only nine full-time employees. Fulcrum’s ability to successfully complete the Merger depends in large part on Fulcrum’s ability to retain certain remaining personnel. Despite Fulcrum’s efforts to retain these employees, one or more employees may terminate their employment with Fulcrum on short notice. The loss of the service of certain employees could potentially harm Fulcrum’s ability to consummate the Merger and run Fulcrum’s day-to-day business operations, as well as fulfill Fulcrum’s reporting obligations as a public company.

Risks Related to the Proposed Reverse Stock Split

The reverse stock split may not increase the Combined Company’s stock price over the long term.

The principal purpose of the reverse stock split is to increase the per-share market price of Fulcrum’s common stock to ensure it remains above the minimum bid price requirement under the Nasdaq rules so that the listing of Fulcrum and the shares of Fulcrum common stock being issued in the Merger on Nasdaq will be approved. It cannot be assured, however, that the reverse stock split will accomplish this objective for any meaningful period of time. While it is expected that the reduction in the number of outstanding shares of

30

common stock will proportionally increase the market price of Fulcrum’s common stock, it cannot be assured that the reverse stock split will increase the market price of its common stock by a multiple of the reverse stock split ratio mutually agreed by Fulcrum and Slate, or result in any permanent or sustained increase in the market price of Fulcrum’s common stock, which is dependent upon many factors, including Fulcrum’s business and financial performance, general market conditions and prospects for future success. Thus, while the stock price of Fulcrum might meet the listing requirements for Nasdaq initially, it cannot be assured that it will continue to do so.

The reverse stock split may decrease the liquidity of the Combined Company’s common stock.

Although the Fulcrum board believes that the anticipated increase in the market price of the Combined Company’s common stock resulting from the proposed reverse stock split could encourage interest in its common stock and possibly promote greater liquidity for its stockholders, such liquidity could also be adversely affected by the reduced number of shares outstanding after the reverse stock split. The reduction in the number of outstanding shares may lead to reduced trading and a smaller number of market makers for the Combined Company’s common stock. In addition, the reverse stock split may not result in an increase in the Combined Company’s stock price necessary to satisfy Nasdaq’s initial listing requirements for the Combined Company.

The reverse stock split may lead to a decrease in the Combined Company’s overall market capitalization.

Should the market price of the Combined Company’s common stock decline after the reverse stock split, the percentage decline may be greater, due to the smaller number of shares outstanding, than it would have been prior to the reverse stock split. A reverse stock split is often viewed negatively by the market and, consequently, can lead to a decrease in the Combined Company’s overall market capitalization. If the per share market price does not increase in proportion to the reverse stock split ratio, then the value of the Combined Company, as measured by its stock capitalization, will be reduced. In some cases, the per-share stock price of companies that have effected reverse stock splits subsequently declined back to pre-reverse split levels, and accordingly, it cannot be assured that the total market value of the Combined Company’s common stock will remain the same after the reverse stock split is effected, or that the reverse stock split will not have an adverse effect on the Combined Company’s stock price due to the reduced number of shares outstanding after the reverse stock split.

Risks Related to Fulcrum

Fulcrum may not be successful in consummating the Merger.

In June 2026, based upon meeting minutes received from end-of-phase interactions with the FDA following the completion of Fulcrum’s PIONEER Phase 1b clinical trial evaluating pociredir in SCD, Fulcrum announced its decision to discontinue clinical development of pociredir. Concurrently with such announcement, Fulcrum announced that it was undertaking a comprehensive review of strategic alternatives focused on maximizing stockholder value, which may include but are not limited to, the Merger or an alternative transaction or liquidation. Fulcrum has and expects to continue to devote substantial time and resources to exploring strategic alternatives that its board of directors believes will maximize stockholder value. There can be no assurances that the Merger will be successfully consummated or lead to increased stockholder value or that Fulcrum will make any additional cash distributions to its stockholders.

The process of completing the Merger may be very costly, time-consuming and complex and Fulcrum has incurred, and may in the future incur, significant costs related to the Merger, including legal and accounting fees and expenses and other related charges. Fulcrum may also incur additional unanticipated expenses in connection with the Merger, which will be incurred regardless of whether the Merger is completed. These expenses will decrease the remaining cash available for use in Fulcrum’s business.

31

Fulcrum is not currently pursuing further clinical development of pociredir. Resuming the development of pociredir and any potential commercialization would require substantial additional cash to fund the costs associated with conducting the necessary preclinical and clinical testing and obtaining regulatory approval. Consequently, if the Merger is completed, Slate may choose not to spend additional resources to continue development of pociredir and may attribute little or no value, in the Merger to pociredir. The Merger could have a variety of negative consequences, or yield unexpected results that adversely affects Fulcrum’s business and decreases the remaining cash available for use in Fulcrum’s business or the execution of its strategic plan. The completion of the Merger is dependent on a number of factors that may be beyond Fulcrum’s control, including, among other things, market conditions, industry trends and obtaining stockholder approval. Any failure of the Merger could significantly impair Fulcrum’s ability to enter into any future strategic transactions and may significantly diminish or delay any future distributions to Fulcrum’s stockholders.

If the Merger is not completed in a timely fashion, this may cause reputational harm with Fulcrum’s stockholders and the value of Fulcrum’s securities may be adversely impacted. In addition, speculation regarding the completion of the Merger and perceived uncertainties related to the future of Fulcrum could cause Fulcrum’s stock price to fluctuate significantly.

If Fulcrum is successful in completing a strategic transaction, Fulcrum may be exposed to other operational and financial risks.

Although there can be no assurance that the Merger will be completed, the negotiation and consummation of the Merger will require significant time on the part of Fulcrum’s management, and the diversion of management’s attention may disrupt Fulcrum’s business.

The negotiation and consummation of the Merger may also require more time or greater cash resources than Fulcrum anticipates and expose Fulcrum to other operational and financial risks, including:

Any of the foregoing risks could have a material adverse effect on Fulcrum’s business, financial condition and prospects.

If the Merger is not completed, Fulcrum’s board of directors may decide to pursue a dissolution and liquidation. In such an event, the amount of cash available for distribution to Fulcrum’s stockholders will depend heavily on the timing of such liquidation as well as the amount of cash that will need to be reserved for commitments and contingent liabilities.

If the Merger is not completed, Fulcrum’s board of directors may decide to pursue a dissolution and liquidation. In such an event, the amount of cash available for distribution to Fulcrum’s stockholders will depend heavily on the timing of such decision and, with the passage of time the amount of cash available for distribution will be reduced as Fulcrum continues to fund its operations. In addition, if Fulcrum’s board of directors were to

32

approve and recommend, and Fulcrum’s stockholders were to approve, a dissolution and liquidation, Fulcrum would be required under Delaware corporate law to pay its outstanding obligations, as well as to make reasonable provision for contingent and unknown obligations, prior to making any distributions in liquidation to Fulcrum’s stockholders. As a result of this requirement, a portion of Fulcrum’s assets may need to be reserved pending the resolution of such obligations and the timing of any such resolution is uncertain. In addition, Fulcrum may be subject to litigation or other claims related to a dissolution and liquidation. If a dissolution and liquidation were pursued, Fulcrum’s board of directors, in consultation with its advisors, would need to evaluate these matters and make a determination about a reasonable amount to reserve. Accordingly, holders of Fulcrum’s common stock could lose all or a significant portion of their investment in the event of a liquidation, dissolution or winding up.

Fulcrum’s ability to consummate the Merger depends on its ability to retain its employees required to consummate such transaction.

Fulcrum’s ability to consummate the Merger depends upon Fulcrum’s ability to retain its employees required to consummate such a transaction, the loss of whose services may adversely impact the ability to consummate such transaction. In connection with the evaluation of strategic alternatives and in order to extend resources, Fulcrum implemented workforce reduction plan, which resulted in the termination of nearly all of Fulcrum’s workforce (the “Workforce Reduction Plan”). Under the Workforce Reduction Plan, approximately 85% of Fulcrum’s workforce was terminated as of June 26, 2026. The Merger process is supported by Fulcrum’s deep and broad experience at the board of directors, executive management and supporting staff levels. Fulcrum’s cash conservation activities may yield unintended consequences, such as attrition beyond Fulcrum’s Workforce Reduction Plan and reduced employee morale, which may cause remaining employees to seek alternative employment. Fulcrum’s ability to successfully complete the Merger depends in large part on its ability to retain certain of its remaining personnel. If Fulcrum is unable to successfully retain its remaining personnel, Fulcrum is at risk of a disruption to the Merger process as well as business operations.

Fulcrum’s cash preservation activities, including the Workforce Reduction Plan, may not result in anticipated savings, could result in total costs and expenses that are greater than expected and could disrupt Fulcrum’s business.

In June 2026, Fulcrum implemented its Workforce Reduction Plan. In connection with the Workforce Reduction Plan, Fulcrum incurred costs of approximately $4.3 million, which are primarily one-time severance benefits. Fulcrum may not realize, in full or in part, the anticipated benefits, savings and improvements in its cost structure from its restructuring efforts due to unforeseen difficulties, delays or unexpected costs. If Fulcrum is unable to realize the expected operational efficiencies and cost savings from the restructuring, its operating results and financial condition would be adversely affected. Furthermore, Fulcrum’s Workforce Reduction Plan may be disruptive to its operations. For example, headcount reductions could yield unanticipated consequences, such as increased difficulties in implementing Fulcrum’s business strategy, including retention of remaining employees.

Due to Fulcrum’s limited resources, Fulcrum may not be able to effectively manage its operations, which may result in weaknesses in Fulcrum’s infrastructure, risks that Fulcrum may not be able to comply with legal and regulatory requirements, and loss of employees and reduced productivity among remaining employees. For example, Fulcrum’s limited resources and workforce reduction may negatively impact efforts to winddown Fulcrum’s clinical trial activities or expose Fulcrum to cybersecurity risks, which could result in unexpected costs and expenses and have a material adverse effect on Fulcrum’s business, financial condition and prospects.

Fulcrum may become involved in litigation, including securities class action litigation, that could divert management’s attention and harm Fulcrum’s business, and insurance coverage may not be sufficient to cover all costs and damages.

In the past, litigation, including securities class action litigation, has often followed certain significant business transactions, such as a merger, or the announcement of negative events, such as negative results from

33

clinical trials. These events may also result in investigations by the SEC. Fulcrum may be exposed to such litigation in connection with the Merger even if no wrongdoing occurred.

Furthermore, the stock market in general, and Nasdaq and biopharmaceutical companies in particular, have experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to the operating performance of these companies. In the past, companies that have experienced volatility in the market price of their stock have been subject to securities class action litigation. The market price of Fulcrum’s common stock may be volatile, and Fulcrum may be the target of this type of litigation in the future.

Litigation is usually expensive and diverts management’s attention and resources from other business concerns, which could adversely affect Fulcrum’s business and cash resources and its ability to consummate the Merger or the ultimate value Fulcrum’s stockholders receive in any such transaction.

Risks Related to Fulcrum’s Financial Position and Need for Additional Capital

Fulcrum has incurred significant losses since its inception. Fulcrum expects to incur losses over the next several years and may never achieve or maintain profitability.

Since inception, Fulcrum has incurred significant operating losses. Fulcrum’s net loss was $74.9 million for the year ended December 31, 2025, and $45.1 million for the six months ended June 30, 2026. As of June 30, 2026, Fulcrum had an accumulated deficit of $639.3 million. To date, Fulcrum has funded its operations primarily from the sale of shares of its capital stock and from upfront payments received under its collaboration and license agreements. Fulcrum has devoted substantially all of its financial resources and efforts to research and development, including clinical trials and preclinical studies. Fulcrum has not completed development of any product candidates. Fulcrum expects to continue to incur significant additional expenses and operating losses. Fulcrum’s net losses may fluctuate significantly from quarter to quarter and year to year.

In June 2026, Fulcrum announced the discontinuation of its pociredir program for the treatment of SCD and the initiation of a comprehensive review of strategic alternatives intended to maximize stockholder value, including, but not limited to, a merger, acquisition, business combination, or other strategic transactions involving the company or its assets. In connection with this review, Fulcrum initiated efforts to significantly reduce its operating expenses and preserve capital, including the approval of a restructuring plan to reduce its workforce by approximately 85%. Fulcrum has incurred and expects to continue to incur costs and expenditures in connection with the strategic alternatives process, including the proposed Merger, and will continue to incur costs associated with operating as a public company. The process of evaluating strategic transactions and pursuing the Merger is costly, time-consuming and complex, and Fulcrum is incurring significant costs related to these processes, such as legal, accounting and advisory fees and expenses and other related charges. A considerable portion of these costs will be incurred regardless of whether the Merger closes. Any such expenses will decrease the remaining cash available for use in Fulcrum’s business.

If Fulcrum resumes development of any future product candidates in the future, it anticipates that its expenses will increase substantially as it:

34

If Fulcrum resumes development of product candidates in the future, to become and remain profitable, it must succeed in developing, and eventually commercializing, a product or products that generate significant revenue. The ability to achieve this success will require Fulcrum to be effective in a range of challenging activities, including completing preclinical testing and clinical trials of its product candidates, discovering additional product candidates, obtaining regulatory approval for these product candidates and manufacturing, marketing and selling any products for which it may obtain regulatory approval. Fulcrum may never succeed in these activities and, even if it does, may never generate revenues that are significant enough to achieve profitability. Because of the numerous risks and uncertainties associated with pharmaceutical product development, Fulcrum is unable to accurately predict the timing or amount of increased expenses or when, or if, it will be able to achieve profitability. Fulcrum’s expenses will increase if, among other things:

Even if Fulcrum does achieve profitability, it may not be able to sustain or increase profitability on a quarterly or annual basis. Fulcrum’s failure to become and remain profitable would depress the value of the company and could impair its ability to raise capital, expand its business, maintain its research and development efforts, diversify its pipeline of product candidates or even continue its operations. A decline in the value of the company could also cause its stockholders to lose all or part of their investment.

Fulcrum’s decision to implement a restructuring plan may not result in the anticipated savings and may adversely affect its business.

In connection with Fulcrum’s decision to cease development of pociredir, its board approved a restructuring plan to significantly reduce its operating expenses and preserve capital. The restructuring plan, which was substantially completed during the second quarter, reduced its workforce by approximately 85%, from 57 full-time employees to nine full-time employees. Fulcrum may not realize, in full or in part, the anticipated benefits and savings in operating expenses from this decision. This workforce reduction may make it more challenging to pursue strategic alternatives. If Fulcrum is unable to realize the expected cost savings, its financial condition could be adversely affected, and it may be more difficult to complete a potential strategic transaction.

35

To the extent Fulcrum resumes development of any product candidates in the future, it will need substantial additional funding. If Fulcrum is unable to raise capital when needed, it could be forced to delay, reduce or eliminate its product development programs or commercialization efforts.

Although Fulcrum is currently pursuing the Merger to maximize stockholder value, if the Merger is not consummated and it determines to shift its focus to research and development and initiate additional clinical trials of, and seek regulatory approval for any future product candidates, it would need substantial additional funding. Fulcrum expects its expenses would increase substantially if it shifts its current activities back to advancing product candidates through preclinical and clinical development. In addition, if Fulcrum obtains regulatory approval for any of its product candidates, it expects to incur significant commercialization expenses related to product manufacturing, sales, marketing and distribution, particularly if it does not out-license its product candidate. Accordingly, Fulcrum will need to obtain substantial additional funding in connection with its continuing operations. Given current uncertainty in the capital markets and other factors, such funding may not be available on terms favorable to Fulcrum or at all. If Fulcrum is unable to raise capital when needed or on acceptable terms, it could be forced to delay, reduce or eliminate its research and development programs or any future commercialization efforts.

Fulcrum’s future capital requirements will depend on many factors, including:

As of June 30, 2026, Fulcrum had cash, cash equivalents, and marketable securities of approximately $318.8 million. Fulcrum believes that its cash, cash equivalents, and marketable securities as of June 30, 2026, will enable it to fund its operating expenses and capital expenditure requirements into 2029. However, Fulcrum has based this estimate on assumptions that may prove to be wrong, and its operating plan may change as a result of many factors currently unknown to it. As a result, Fulcrum could deplete its capital resources sooner than it currently expects.

36

Identifying potential product candidates and conducting preclinical testing and clinical trials is a time-consuming, expensive and uncertain process that takes years to complete, and Fulcrum may never generate the necessary data or results required to obtain regulatory approval and achieve product sales. For example, Fulcrum invested significant time and effort into developing losmapimod for facioscapulohumeral muscular dystrophy (“FSHD”) but did not demonstrate a statistically significant difference between losmapimod and placebo on the primary endpoint in the Phase 3 REACH trial, for which it announced topline data in September 2024, and it thereafter discontinued development. Fulcrum also invested significant time and effort into developing pociredir for the treatment of SCD, but discontinued development after end-of-phase I meeting minutes received in late May 2026 reflected heightened FDA concerns regarding pociredir’s benefit-risk profile in SCD, stemming from an unexpectedly high rate of secondary hematologic malignancies observed with Tazverik^® (tazemetostat), another PRC2 inhibitor. FDA concluded that any pharmacological intervention targeting the PRC2 complex carries equivalent malignancy risk regardless of the specific subunit engaged. FDA’s position is informed by pociredir’s previously disclosed preclinical malignancy observations and left no viable regulatory path forward for further clinical development of pociredir.

In addition, any future Fulcrum product candidates, if approved, may not achieve commercial success. Commercial revenues, if any, will not be derived unless and until Fulcrum can achieve sales of products, which it does not anticipate for several years, if at all. Accordingly, Fulcrum will need to continue to rely on additional financing to achieve its business objectives. Adequate additional financing may not be available to Fulcrum on acceptable terms, or at all, and may become even more difficult to obtain due to rising interest rates and the recent downturn in the U.S. capital markets and the biotechnology sector in general. In addition, Fulcrum may seek additional capital due to favorable market conditions or strategic considerations, even if it believes it has sufficient funds for its current or future operating plans. If adequate funds are not available to Fulcrum on a timely basis, it may be required to delay, limit, reduce or terminate preclinical studies, clinical trials or other development activities for one or more of its product candidates or discovery stage programs or delay, limit, reduce or terminate its establishment of sales and marketing capabilities or other activities that may be necessary to bring its product candidates to market. Fulcrum may also choose to further realign its operations to achieve additional operational efficiencies as it has done in the past.

Raising additional capital may cause dilution to Fulcrum’s stockholders, restrict its operations or require it to relinquish rights to its technologies or product candidates.

Until such time, if ever, as Fulcrum can generate substantial product revenues, it expects to finance its cash needs through a combination of equity offerings, debt financings, collaborations, strategic alliances and marketing, distribution or licensing arrangements. Fulcrum does not have any committed external source of funds. To the extent that Fulcrum raises additional capital through the sale of equity or convertible debt securities, its stockholders’ ownership interests will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect its stockholders’ rights as common stockholders. Debt financing and preferred equity financing, if available, may involve agreements that include covenants limiting or restricting Fulcrum’s ability to take specific actions, such as incurring additional debt, selling or licensing its assets, making capital expenditures or declaring dividends.

If Fulcrum raises additional funds through collaborations, strategic alliances or marketing, distribution or licensing arrangements with third parties, it may have to relinquish valuable rights to its technologies, future revenue streams, research programs or product candidates or grant licenses on terms that may not be favorable to it. If Fulcrum is unable to raise additional funds through equity or debt financings when needed, it may be required to delay, limit, reduce or terminate its product development or future commercialization efforts or grant rights to develop and market product candidates that it would otherwise prefer to develop and market itself.

37

Fulcrum has in the past relied, and in the future may rely, in part on sales of its common stock through an at-the-market (“ATM”), offering program. Increased volatility and decreases in market prices of equity securities generally and of Fulcrum’s common stock in particular may have an adverse impact on its willingness and/or ability to continue to sell its common stock through its ATM offering program. Decreases in these sales could affect the cost or availability of equity capital, which could in turn have an adverse effect on Fulcrum’s business, including current operations, future growth, revenues, net income and the market prices of its common stock.

In February 2024, Fulcrum established a new ATM offering program to sell shares of its common stock having an aggregate offering price of up to $100.0 million from time to time. Given the overall volatility in the capital markets, Fulcrum may not be willing or able to continue to raise equity capital through its ATM offering program. Fulcrum may, therefore, need to turn to other sources of funding that may have terms that are not favorable to it, or reduce its business operations given capital constraints.

Alternative financing arrangements could involve issuances of one or more types of securities, including common stock, preferred stock, convertible debt, warrants to acquire common stock or other securities. These securities could be issued at or below the then prevailing market price for Fulcrum’s common stock. In addition, if Fulcrum issues debt securities, the holders of the debt would have a claim to its assets that would be superior to the rights of stockholders until the principal, accrued and unpaid interest and any premium or make-whole has been paid. In addition, if Fulcrum borrows funds and/or issues debt securities through a subsidiary, the lenders and/or holders of those debt securities would have a right to payment that would be effectively senior to Fulcrum’s equity ownership in the subsidiary, which would adversely affect the rights of holders of both its equity securities and, if any, its debt and debt securities.

Interest on any newly-issued debt securities and/or newly-incurred borrowings would increase Fulcrum’s operating costs and reduce its net income, and these impacts may be material. If the issuance of new securities results in diminished rights to holders of Fulcrum’s common stock, the market price of its common stock could be materially and adversely affected. Should the financing Fulcrum requires to sustain its working capital needs be unavailable or prohibitively expensive when it requires it, the consequences could result in a material adverse effect on its business, operating results, financial condition and prospects.

Fulcrum’s operations have primarily been focused on research and development and conducting clinical trials, which may make it difficult for stockholders to evaluate the success of its business to date and to assess its future viability.

Fulcrum commenced activities in 2015 and is a clinical-stage biotechnology company. Until its recent focus on evaluating strategic alternatives to maximize stockholder value, its operations had been limited to organizing and staffing the company, business planning, raising capital, establishing its intellectual property, building its discovery platform, identifying drug targets and potential product candidates, in-licensing assets, producing drug substance and drug product material for use in clinical trials and conducting preclinical studies and clinical trials. Fulcrum has not yet demonstrated its ability to successfully develop any product candidate, obtain regulatory approvals, manufacture a commercial scale product or arrange for a third party to do so on its behalf, or conduct sales and marketing activities necessary for successful product commercialization or arrange for a third party to do so on its behalf. Consequently, any predictions stockholders make about Fulcrum’s future success or viability may not be as accurate as they could be if Fulcrum had a history of successfully developing and commercializing products.

In addition, as Fulcrum’s business evolves, it may encounter unforeseen expenses, difficulties, complications, delays and other known and unknown factors, such as its recent announcement to discontinue its pociredir program and its September 2024 announcement that its Phase 3 REACH trial evaluating losmapimod for FSHD did not achieve its primary endpoint of change from baseline in relative surface area compared to placebo. If Fulcrum shifts its focus back to research and development, it will need to transition at some point from a company with a research and development focus to a company capable of supporting commercial activities. Fulcrum may not be successful in such a transition.

38

Fulcrum expects its financial condition and operating results to fluctuate significantly from quarter-to-quarter and year-to-year due to a variety of factors, many of which are beyond its control. Accordingly, stockholders should not rely upon the results of any quarterly or annual periods as indications of future operating performance.

Changes in tax laws or in their implementation or interpretation may adversely affect Fulcrum’s business and financial condition.

The rules dealing with U.S. federal, state, and local income taxation are constantly under review by persons involved in the legislative process and by the Internal Revenue Service and the U.S. Treasury Department. Changes to tax laws (which changes may have retroactive application), including with respect to net operating losses and research and development tax credits, could adversely affect Fulcrum or holders of its common stock. In recent years, many such changes have been made and changes are likely to continue to occur in the future. For example, legislation commonly referred to as the One Big Beautiful Bill Act (“OBBBA”) enacted in July 2025, made significant changes to the U.S. tax laws. While the OBBBA did not have a material impact on Fulcrum’s consolidated financial position and results of operations, future changes in tax laws could have a material adverse effect on Fulcrum’s business, cash flow, financial condition or results of operations. Fulcrum urges investors to consult with their legal and tax advisers regarding the implications of potential changes in tax laws on an investment in its common stock.

Fulcrum’s ability to use its net operating losses and research and development tax credit carryforwards to offset future taxable income may be subject to certain limitations.

As of December 31, 2025, Fulcrum had federal net operating loss carryforwards of $102.8 million, which may be available to offset future taxable income and do not expire, but are limited in their usage to an annual deduction equal to 80% of annual taxable income. As of December 31, 2025, Fulcrum had state net operating loss carryforwards of $96.9 million, which begin to expire in 2044. As of December 31, 2025, Fulcrum also had federal orphan drug credits of $7.5 million, which begin to expire in 2044. As of December 31, 2025, Fulcrum also had federal and state research and development tax credit carryforwards of $1.2 million and $0.2 million, respectively, which begin to expire in 2039. These net operating loss and tax credit carryforwards could expire unused and be unavailable to offset future income tax liabilities.

In general, under Section 382 of the Code (“Section 382”), and corresponding provisions of state law, a corporation that undergoes an “ownership change,” which is generally defined as a greater than 50% change, by value, in its equity ownership by certain stockholders over a three-year period, is subject to limitations on its ability to utilize its pre-change net operating losses and research and development tax credit carryforwards to offset future taxable income. Fulcrum conducted an analysis under Section 382 through December 31, 2024, and determined that for purposes of Section 382, it was deemed to have undergone an ownership change as of September 12, 2024. Accordingly, Fulcrum determined that all federal and state net operating loss carryforwards and research and development tax credit carryforwards generated before September 12, 2024 are limited. As a result, the federal and state carryforwards and research and development tax credit carryforwards generated before the deemed ownership change date of September 12, 2024 are not available for utilization and have been written off. The federal and state carryforwards as of December 31, 2025, were generated after the deemed ownership change. Fulcrum has not conducted a study to assess whether a change of control has occurred or whether there have been multiple changes of control since December 31, 2024, or if any strategic alternative it may pursue, including the proposed Merger, would be deemed an “ownership change.” If Fulcrum has experienced a change of control, as defined by Section 382, subsequent to December 31, 2024, utilization of the net operating loss carryforwards or research and development tax credit carryforwards would be subject to an annual limitation under Section 382. Any limitation may result in expiration of a portion of the net operating loss carryforwards or research and development tax credit carryforwards before utilization. Further, until a study is completed and any limitation is known, no amounts are being presented as an uncertain tax position.

39

Fulcrum has a history of cumulative losses and anticipates that it will continue to incur significant losses in the foreseeable future; thus, it does not know whether or when it will generate taxable income necessary to utilize its net operating losses or research and development tax credit carryforwards.

Adverse developments affecting the financial services industry, such as actual events or concerns involving liquidity, defaults or non-performance by financial institutions or transactional counterparties, could adversely affect Fulcrum’s current and projected business operations and financial condition and results of operations.

Events involving limited liquidity, defaults, non-performance or other adverse developments that affect financial institutions, transactional counterparties or other companies in the financial services industry or the financial services industry generally, or concerns or rumors about any events of these kinds or other similar risks, have in the past and may in the future lead to market-wide liquidity problems. In 2023, a number of banks were placed into receivership. Even though Fulcrum assesses its banking relationships as it believes necessary or appropriate, its access to funding sources and other credit arrangements in amounts adequate to finance or capitalize its current and projected future business operations could be significantly impaired by factors affecting the financial services industry or economy in general, such as these recent bank failures. These factors could also include, among others, liquidity constraints or failures, the ability to perform obligations under various types of financial, credit or liquidity agreements or arrangements, disruptions or instability in the financial services industry or financial markets, or concerns or negative expectations about the prospects for companies in the financial services industry and the supervision thereof. In addition, investor concerns regarding the United States or international financial systems could result in less favorable commercial financing terms, including higher interest rates or costs and tighter financial and operating covenants, or systemic limitations on access to credit and liquidity sources, thereby making it more difficult for Fulcrum to acquire financing on acceptable terms or at all. Any decline in available funding or access to its cash and liquidity resources could, among other risks, adversely impact Fulcrum’s ability to meet its operating expenses, financial obligations or fulfill its other obligations, result in breaches of its contractual obligations or result in violations of federal or state wage and hour laws, which could have material adverse effect on its liquidity and on its business, financial condition or results of operations.

Risks Related to the Discovery and Development of Fulcrum’s Product Candidates

Fulcrum is not actively pursuing research and development activities and does not have any product candidates in active clinical development. If Fulcrum were to resume such activities and is unable to commercialize directly or out-license to a third party any of its product candidates or experiences significant delays in doing so, its business would be materially harmed.

Fulcrum is no longer actively pursuing research and development activities and has advanced only two product candidates into clinical trials (the first of which did not meet its primary endpoint, and the second of which was recently discontinued from development due to FDA concerns regarding safety-benefit profile). As a result, Fulcrum currently does not have any product candidates in active clinical development. Fulcrum has invested substantially all of its efforts and financial resources in identifying and validating and conducting clinical trials on cellular drug targets that can potentially modulate gene expression to address the root cause of genetically-defined rare diseases. Fulcrum’s ability to generate product revenues, which it does not expect will occur for several years, if ever, will depend heavily on the successful development, regulatory approval and eventual commercialization of product candidates, should it resume such activities. The success of any of Fulcrum’s product candidates will depend on several factors, including the following:

40

If Fulcrum resumes its research and development focus and does not achieve one or more of these factors in a timely manner or at all, it could experience significant delays or an inability to successfully develop and commercialize any product candidates, which would materially harm its business.

Fulcrum may not be successful in its efforts to build a pipeline of product candidates.

Fulcrum’s strategy was focused on developing small molecules to improve the lives of patients with genetically defined rare diseases. Even if Fulcrum is successful in identifying drug targets and potential product candidates should it resume such strategy, such candidates that it identifies may not be suitable for clinical development, including as a result of being shown to have harmful side effects or other characteristics that indicate that they are unlikely to receive marketing approval and achieve market acceptance. Identifying, developing, obtaining regulatory approval for and commercializing additional product candidates will require substantial additional funding and is prone to the risks of failure inherent in product development. Fulcrum cannot provide stockholders any assurance that it will be able to successfully identify additional product candidates, advance any additional product candidates through the development process or successfully commercialize any such additional product candidates. Regulatory authorities have substantial discretion in the approval process and may cause delays in the approval or rejection of an application. As a result of these factors, it is difficult for Fulcrum to predict the time and cost of product candidate development. There can be no assurance that any development problems Fulcrum experiences in the future related to its discovery technologies or any future research or development programs will not cause significant delays or unanticipated costs, or that such development problems can be solved. If Fulcrum does not successfully identify, develop, obtain regulatory approval for and commercialize product candidates, it will not be able to generate product revenues.

Clinical drug development involves a lengthy and expensive process, with an uncertain outcome. The results of preclinical studies and early clinical trials may not be predictive of future results. Fulcrum may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization of its product candidates.

After the discontinuation of its pociredir program for the treatment of SCD, Fulcrum does not have any product candidates in active clinical development. The risk of failure for product candidates is high and it is impossible to predict when or if any of Fulcrum’s product candidates will prove effective or safe in humans or will receive regulatory approval. Before obtaining marketing approval from regulatory authorities for the sale of

41

any product candidate, Fulcrum must complete preclinical development and then conduct extensive clinical trials to demonstrate the safety and efficacy of its product candidate in humans. Fulcrum has not yet completed a pivotal clinical trial of any product candidate that demonstrated that its product candidate is safe and effective for its intended use. For example, in September 2024, Fulcrum announced that REACH, its Phase 3 trial evaluating losmapimod in patients with FSHD, did not successfully achieve its primary endpoint as compared to placebo, and it suspended further development of losmapimod. Additionally, Fulcrum recently announced the discontinuation of its pociredir program for the treatment of SCD. Pociredir is an EED inhibitor. EED is a member of the PRC2 complex, which also includes EZH2. There are approved products in the EZH2 class of medications and their approved labeling outlines safety risks, including an increased risk of malignancies. In late May 2026, Fulcrum received meeting minutes from recent end-of-phase interactions with the FDA that reflected heightened FDA concerns regarding pociredir’s benefit-risk profile in SCD, due to potential malignancy risk associated with pociredir’s inhibition of the PRC2 complex given the experience with Tazverik^® (tazemetostat), another PRC2 inhibitor, which was withdrawn from the global market in March 2026, leaving no viable regulatory path forward for further clinical development of pociredir. Even if potential future clinical trials are successful, changes in marketing approval policies during the development period, changes in or the enactment or promulgation of additional statutes, regulations or guidance or changes in regulatory review for each submitted product application may cause delays in the approval or rejection of an application.

Before Fulcrum can commence clinical trials for a product candidate, it must complete extensive preclinical testing and studies that support any planned INDs and other regulatory filings in the United States and abroad. Fulcrum cannot be certain of the timely completion or outcome of its preclinical testing and studies and cannot predict if the FDA or other regulatory agencies will accept its proposed clinical programs or if the outcome of its preclinical testing and studies will ultimately support the further development of any future product candidates. As a result, Fulcrum cannot be sure that it will be able to submit INDs or similar applications for any future preclinical programs on the timelines it expects, if at all, and it cannot be sure that submission of INDs or similar applications will result in the FDA or other regulatory authorities allowing clinical trials to begin or continue. For example, in February 2023, the FDA imposed a clinical hold on Fulcrum’s IND for pociredir in SCD (which was lifted in August 2023). Product candidates are subject to continued preclinical safety studies, which may be conducted concurrent with Fulcrum’s clinical testing. The outcomes of these safety studies may delay the launch of or enrollment in future clinical trials and could impact Fulcrum’s ability to continue to conduct its clinical trials.

Clinical testing is expensive, difficult to design and implement, can take many years to complete and is uncertain as to outcome. Fulcrum cannot guarantee that any clinical trials will be conducted as planned or completed on schedule, or at all. For example, Fulcrum revised the inclusion and exclusion criteria of its Phase 1b clinical trial of pociredir in SCD to address the clinical hold imposed by the FDA, and initially experienced some difficulty enrolling patients who meet the updated more stringent criteria. A failure of one or more clinical trials can occur at any stage of testing, which may result from a multitude of factors, including, but not limited to, flaws in study design, dose selection issues, placebo effects, patient enrollment criteria and failure to demonstrate favorable safety or efficacy traits. For example, in September 2024 Fulcrum suspended further development of losmapimod after topline data from the Phase 3 REACH trial indicated that it did not achieve its primary endpoint of change from baseline in relative surface area, a measure of reachable work space, compared to placebo. The outcome of preclinical testing and early clinical trials may not be predictive of the success of later clinical trials, and preliminary or interim results of a clinical trial do not necessarily predict final results. For example, Fulcrum’s product candidates may fail to show the desired safety and efficacy in clinical development despite positive results in preclinical studies or having successfully advanced through initial clinical trials. A lack of clinical benefit may be due to insufficient dosing or for other reasons. Many companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in late-stage clinical trials even after achieving promising results in preclinical testing and earlier-stage clinical trials, and Fulcrum cannot be certain that it will not face similar setbacks. Moreover, preclinical and clinical data are often susceptible to varying interpretations and analyses, and many companies that have believed their product candidates performed satisfactorily in preclinical studies and clinical trials have nonetheless failed to obtain marketing approval of their products.

42

Furthermore, the failure of any of Fulcrum’s product candidates to demonstrate safety and efficacy in any clinical trial could negatively impact the perception of its other product candidates and/or cause the FDA or other regulatory authorities to require additional testing before approving any of its product candidates.

Fulcrum may experience numerous unforeseen events during, or as a result of, clinical trials that could delay or prevent its ability to receive marketing approval or commercialize its product candidates, including:

43

Further, in February 2023, the FDA imposed a clinical hold on Fulcrum’s IND for pociredir in SCD, which halted its clinical trial until the FDA lifted the clinical hold in August 2023. In late May 2026, Fulcrum received end-of-phase I meeting minutes from the FDA reflecting heightened FDA concerns regarding potential malignancy risk associated with pociredir’s inhibition of the PRC2 complex, which left no viable regulatory path forward for further clinical development of pociredir.

If Fulcrum is required to conduct additional clinical trials or other testing of its product candidates beyond those contemplated, if it is unable to successfully complete clinical trials of any future product candidates or other testing, if the results of these trials or tests are not positive, such as its topline data from the Phase 3 REACH trial, or are only modestly positive or if there are safety concerns, Fulcrum may:

Fulcrum’s product development costs will also increase if it experiences delays in testing or in obtaining marketing approvals. Fulcrum does not know whether any preclinical studies or clinical trials will begin as planned, will need to be restructured or will be completed on schedule, or at all. Fulcrum may also determine to change the design or protocol of one or more future clinical trials, including to add additional patients or arms, which could result in increased costs and expenses and/or delays. Significant preclinical study or clinical trial delays also could shorten any periods during which Fulcrum may have the exclusive right to commercialize any future product candidates or allow its competitors to bring products to market before it does and impair its ability to successfully commercialize its product candidates and may harm its business and results of operations.

If Fulcrum resumes development of its product candidates in the future and experiences delays or difficulties in the enrollment of patients in clinical trials, its receipt of necessary regulatory approvals could be delayed or prevented.

Identifying and qualifying patients to participate in and complete clinical trials for Fulcrum’s product candidates is critical to its success. Successful and timely completion of clinical trials requires that Fulcrum enroll a sufficient number of patients that meet both the enrollment criteria, and who remain in the trial until its conclusion. For example, in its Phase 1b trial of pociredir, although Fulcrum enrolled six subjects in the initial cohort, only three subjects remained evaluable as of the initial data cutoff date. Subsequently, Fulcrum modified the study protocol to monitor subject adherence. However, if such protocols do not improve adherence and improve compliance, Fulcrum may not be able to generate meaningful data. Furthermore, Fulcrum may not be able to initiate or continue clinical trials for any future product candidates if it is unable to locate and enroll a sufficient number of eligible patients to participate in these trials as required by the FDA or similar regulatory authorities outside of the United States. Because of its historic focus on genetically-defined rare diseases, Fulcrum may have difficulty enrolling a sufficient number of eligible patients if it resumes its focus on such diseases.

44

Patient enrollment is affected by a variety of other factors, including:

Fulcrum’s inability to locate and enroll a sufficient number of eligible patients for its clinical trials would result in significant delays, could require it to abandon one or more clinical trials altogether and could delay or prevent its receipt of necessary regulatory approvals.

Enrollment delays in clinical trials may result in increased development costs for any future product candidates, which could cause Fulcrum’s value decline and limit its ability to obtain additional financing.

If serious adverse events or unacceptable side effects are identified during the development of Fulcrum’s product candidates, it may need to abandon or limit its development of its product candidate.

If Fulcrum’s product candidates are associated with serious adverse events or undesirable side effects in clinical trials or have characteristics that are unexpected in clinical trials or preclinical testing, Fulcrum may need to abandon their development or limit development to more narrow uses or subpopulations in which the serious adverse events, undesirable side effects or other characteristics are less prevalent, less severe or more acceptable from a risk-benefit perspective.

For example, in February 2023, the FDA placed Fulcrum’s IND for pociredir on clinical hold based on hematological malignancies observed in nonclinical toxicology studies. The FDA noted that the hematologic malignancies observed in Fulcrum’s nonclinical studies were consistent with findings reported for other PRC2 inhibitors.. Although the FDA lifted the clinical hold in August 2023 and Fulcrum resumed the trial, in late May 2026 it received meeting minutes from recent end-of-phase interactions with the FDA that reflected heightened FDA concerns regarding pociredir’s benefit-risk profile in SCD, due to potential malignancy risk associated with pociredir’s inhibition of the PRC2 complex given the experience with Tazverik^® (tazemetostat), another PRC2 inhibitor, which was withdrawn from the global market in March 2026. FDA’s position is informed by pociredir’s previously disclosed preclinical malignancy observations and left no viable regulatory path forward for further clinical development of pociredir.

In pharmaceutical development, many compounds that initially show promise in early-stage or clinical testing are later found to cause side effects that delay or prevent further development of the compound.

45

Additionally, if results of Fulcrum’s clinical trials reveal unacceptable side effects, Fulcrum, the FDA or the IRBs at the institutions in which its studies are conducted could suspend or terminate its clinical trials or the FDA or comparable foreign regulatory authorities could order it to cease clinical trials or deny approval of its product candidates for any or all targeted indications. Treatment-related side effects could also affect patient recruitment or the ability of enrolled patients to complete any of Fulcrum’s clinical trials. If Fulcrum elects or is forced to suspend or terminate any clinical trial of its product candidates, the commercial prospects of such product candidate will be harmed, and its ability to generate product revenue from such product candidate will be delayed or eliminated. Any of these occurrences could materially harm Fulcrum’s business.

If any of Fulcrum’s product candidates receives marketing approval and Fulcrum, or others, later discovers that the drug is less effective than previously believed or causes undesirable side effects that were not previously identified, its ability to market the drug could be compromised.

Clinical trials of Fulcrum’s product candidates are conducted in carefully defined subsets of patients who have agreed to enter into clinical trials. Consequently, it is possible that Fulcrum’s clinical trials may indicate an apparent positive effect of a product candidate that is greater than the actual positive effect, if any, or alternatively fail to identify undesirable side effects. If one or more of Fulcrum’s product candidates receives regulatory approval, and Fulcrum, or others, later discovers that they are less effective than previously believed, or cause undesirable side effects, a number of potentially significant negative consequences could result, including:

Any of these events could prevent Fulcrum from achieving or maintaining market acceptance of a particular product candidate, if approved, and could significantly harm its business, financial condition, and results of operations.

Fulcrum may expend its limited resources to pursue a particular product candidate or indication and fail to capitalize on product candidates or indications that may be more profitable or for which there is a greater likelihood of success.

Because Fulcrum has limited financial and managerial resources, it is focusing its research and development efforts on rare neuromuscular, muscular, hematologic and central nervous system disorders. As a result, Fulcrum may forego or delay pursuit of opportunities with other product candidates or for other indications that later

46

prove to have greater commercial potential. Fulcrum’s resource allocation decisions may cause it to fail to capitalize on viable commercial products or profitable market opportunities. Fulcrum’s spending on any future research and development programs and product candidates for specific indications may not yield any commercially viable products. For example, Fulcrum devoted significant time, effort and capital on its losmapimod program but suspended further development when it did not meet its primary endpoint in the Phase 3 REACH trial. If Fulcrum does not accurately evaluate the commercial potential or target market for a particular product candidate, it may relinquish valuable rights to that product candidate through collaboration, licensing or other royalty arrangements in cases in which it would have been more advantageous for Fulcrum to retain sole development and commercialization rights to such product candidate. Failure to allocate resources or capitalize on strategies in a successful manner will have an adverse impact on Fulcrum’s business.

Risks Related to the Commercialization of Fulcrum’s Product Candidates

Even if any of Fulcrum’s product candidates receives marketing approval, it may fail to achieve the degree of market acceptance by physicians, patients, third-party payors and others in the medical community necessary for commercial success, and the market opportunity for any of Fulcrum’s product candidates, if approved, may be smaller than Fulcrum estimates.

If any of Fulcrum’s product candidates receives marketing approval, it may nonetheless fail to gain sufficient market acceptance by physicians, patients, third-party payors and others in the medical community. Efforts to educate the medical community and third-party payors on the benefits of Fulcrum’s product candidates may require significant resources and may not be successful. If Fulcrum’s product candidates do not achieve an adequate level of acceptance, Fulcrum may not generate significant product revenues and may not become profitable. The degree of market acceptance of Fulcrum’s product candidates, if approved for commercial sale, will depend on a number of factors, including:

Fulcrum’s assessment of the potential market opportunity for its product candidates is based on industry and market data that it obtained from industry publications and research, surveys and studies conducted by third parties, one of which Fulcrum commissioned. Industry publications and third-party research, surveys and studies generally indicate that their information has been obtained from sources believed to be reliable, although they do

47

not guarantee the accuracy or completeness of such information. While Fulcrum believes these industry publications and third-party research, surveys and studies are reliable, it has not independently verified such data. Fulcrum’s estimates of the potential market opportunities for its product candidates include several key assumptions based on its industry knowledge, industry publications and third-party research, surveys and studies, which may be based on a small sample size and fail to accurately reflect market opportunities. While Fulcrum believes that its internal assumptions are reasonable, no independent source has verified such assumptions. If any of Fulcrum’s assumptions or estimates, or these publications, research, surveys or studies prove to be inaccurate, then the actual market for its product candidate may be smaller than it expects, and as a result its product revenue may be limited and it may be more difficult for Fulcrum to achieve or maintain profitability.

If Fulcrum is unable to establish sales, marketing and distribution capabilities or enter into sales, marketing and distribution agreements with third parties, it may not be successful in commercializing its product candidates if and when they are approved.

Fulcrum does not have a sales or marketing infrastructure and has no experience in the sale, marketing or distribution of pharmaceutical products. To achieve commercial success for any product for which it has obtained marketing approval, Fulcrum will need to establish a sales, marketing and distribution organization, either itself or through collaborations or other arrangements with third parties.

In the future, Fulcrum may build a focused, specialty sales and marketing infrastructure to market one or more of its product candidates in the United States, if and when they are approved. There are risks involved with establishing its own sales, marketing and distribution capabilities. For example, recruiting and training a sales force is expensive and time-consuming and could delay any product launch. If the commercial launch of a product candidate for which Fulcrum recruits a sales force and establishes marketing capabilities is delayed or does not occur for any reason, it would have prematurely or unnecessarily incurred these commercialization expenses. These efforts may be costly, and Fulcrum’s investment would be lost if it cannot retain or reposition its sales and marketing personnel.

Factors that may inhibit Fulcrum’s efforts to commercialize its products on its own include:

If Fulcrum is unable to establish its own sales, marketing and distribution capabilities and enters into arrangements with third parties to perform these services, its product revenues and its profitability, if any, are likely to be lower than if it were to market, sell and distribute any products that it develops itself. Fulcrum likely will have little control over such third parties, and any of them may fail to devote the necessary resources and

48

attention to sell and market its products effectively. Further, there can be no guarantee that Fulcrum will be able to successfully enter into arrangements with third parties to perform sales, marketing or distribution services. If Fulcrum does not establish sales, marketing and distribution capabilities successfully, either on its own or in collaboration with third parties, it will not be successful in commercializing its product candidates.

If Fulcrum resumes development of its product candidates in the future, it may face substantial competition, which may result in others discovering, developing or commercializing products before or more successfully than Fulcrum does.

The development and commercialization of new drug products is highly competitive. Fulcrum will face competition with respect to any product candidates that it may seek to develop or commercialize in the future, from major pharmaceutical companies, specialty pharmaceutical companies and biotechnology companies worldwide. There are a number of large pharmaceutical and biotechnology companies that currently market and sell products or are pursuing the development of products for the treatment of many of the disease indications for which Fulcrum is developing its product candidates. Some of these competitive products and therapies are based on scientific approaches that are the same as or similar to Fulcrum’s approach, and others are based on entirely different approaches. Potential competitors also include academic institutions, government agencies and other public and private research organizations that conduct research, seek patent protection and establish collaborative arrangements for research, development, manufacturing and commercialization.

For example, Fulcrum is aware of several product candidates in clinical development that could be competitive with product candidates that it may successfully develop and commercialize. See “Fulcrum’s Business — Competition” for additional information.

Fulcrum’s commercial opportunity could be reduced or eliminated if its competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than any products that Fulcrum may develop. Fulcrum’s competitors also may obtain FDA or other regulatory approval for their products more rapidly than Fulcrum may obtain approval for its products, which could result in its competitors establishing a strong market position before Fulcrum is able to enter the market.. In addition, Fulcrum’s ability to compete may be affected in many cases by insurers or other third-party payors seeking to encourage the use of generic products. If Fulcrum’s product candidates achieve marketing approval, it expects that they will be priced at a significant premium over competitive generic products.

Many of the companies against which Fulcrum is competing or against which it may compete in the future have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products than Fulcrum does.

Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of Fulcrum’s competitors. Smaller and other early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These third parties compete with Fulcrum in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, its programs.

If the market opportunities for Fulcrum’s product candidates are smaller than it believes they are, its revenue may be adversely affected, and its business may suffer. Because certain of the target patient populations of Fulcrum’s product candidates are small, and the addressable patient population even smaller, Fulcrum must be able to successfully identify patients and capture a significant market share to achieve profitability and growth.

Fulcrum primarily focuses its research and product development on treatments for genetically-defined rare diseases. Given the small number of patients who have the rare diseases that Fulcrum is targeting, it is critical to

49

its ability to grow and become profitable that Fulcrum continues to successfully identify patients with these rare diseases. Fulcrum’s projections of both the number of people who have these diseases, as well as the subset of people with these diseases who have the potential to benefit from treatment with its product candidates, are based on its beliefs and estimates. These estimates have been derived from a variety of sources, including the scientific literature, surveys of clinics, patient foundations or market research that Fulcrum conducted, and may prove to be incorrect or contain errors. New studies may change the estimated incidence or prevalence of these diseases. The number of patients may turn out to be lower than expected. The effort to identify patients with diseases Fulcrum seeks to treat is in early stages, and it cannot accurately predict the number of patients for whom treatment might be possible. Additionally, the potentially addressable patient population for each of Fulcrum’s product candidates may be limited or may not be amenable to treatment with its product candidates, and new patients may become increasingly difficult to identify or gain access to, which would adversely affect its results of operations and its business. Further, even if Fulcrum obtains significant market share for its product candidates, because the potential target populations for many of the indications it is evaluating are very small, it may never achieve profitability despite obtaining such significant market share.

Further, the pricing and reimbursement of Fulcrum’s product candidates, if approved, is uncertain, but must be adequate to support commercial infrastructure. If Fulcrum is unable to obtain adequate levels of reimbursement, its ability to successfully market and sell any approved products will be adversely affected.

If Fulcrum resumes development of its product candidates in the future, it expects to rely on CMOs to manufacture its product candidates. If Fulcrum is unable to enter into such arrangements as expected or if such organizations do not meet its supply requirements, development and/or commercialization of its product candidates may be delayed.

Fulcrum does not have any manufacturing facilities and expects to rely on third parties to manufacture clinical supplies of its product candidates and to manufacture commercial supplies of its products, if and when approved for marketing by applicable regulatory authorities, as well as for packaging, sterilization, storage, distribution and other production logistics. If Fulcrum is unable to enter into such arrangements on the terms or timeline it expects, development and/or commercialization of its product candidates may be delayed.

If these third parties do not successfully carry out their contractual duties, meet expected deadlines or manufacture Fulcrum’s product candidates in accordance with regulatory requirements, if there are disagreements between Fulcrum and such parties or if such parties are unable to expand capacities to support commercialization of any of Fulcrum’s product candidates for which it obtains marketing approval, Fulcrum may not be able to fulfill, or may be delayed in producing sufficient product candidates to meet, its supply requirements, or it may be forced to manufacture the materials itself, for which it may not have the capabilities or resources, or enter into an agreement with a different manufacturer, which it may not be able to do on reasonable terms, if at all. In either scenario, its clinical trial supply could be delayed significantly as it establishes alternative supply sources. In some cases, the technical skills required to manufacture Fulcrum’s products or product candidates may be unique or proprietary to the original manufacturer and Fulcrum may have difficulty, or there may be contractual restrictions prohibiting it from, transferring such skills to a back-up or alternate supplier, or it may be unable to transfer such skills at all.

In addition, if Fulcrum is required to change manufacturers for any reason, it will be required to verify that the new manufacturer maintains facilities and procedures that comply with quality standards and with all applicable regulations. Fulcrum will also need to verify, such as through a manufacturing comparability study, that any new manufacturing process will produce its product candidate according to the specifications previously submitted to the FDA or another regulatory authority. The delays associated with the verification of a new manufacturer could negatively affect Fulcrum’s ability to develop product candidates or commercialize its products in a timely manner or within budget. Furthermore, a manufacturer may possess technology related to the manufacture of Fulcrum’s product candidate that such manufacturer owns independently. This would increase Fulcrum’s reliance on such manufacturer or require it to obtain a license from such manufacturer in order to have

50

another manufacturer manufacture its product candidates. In addition, changes in manufacturers often involve changes in manufacturing procedures and processes, which could require that Fulcrum conduct bridging studies between its prior clinical supply used in its clinical trials and that of any new manufacturer. Fulcrum may be unsuccessful in demonstrating the comparability of clinical supplies which could require the conduct of additional clinical trials. These facilities may also be affected by natural disasters, such as floods or fire, as well as public health issues (for example, an outbreak of a contagious disease such as COVID-19), or such facilities could face manufacturing issues, such as contamination or regulatory concerns following a regulatory inspection of such facility.

Fulcrum’s third-party manufacturers will be subject to inspection and approval by the FDA and other applicable regulatory authorities before Fulcrum can commence the manufacture and sale of any of its product candidates in the relevant jurisdiction, and thereafter will remain subject to inspection by such authorities from time to time. Failure by Fulcrum’s third-party manufacturers to pass such inspections or otherwise satisfactorily complete applicable regulatory approval requirements with respect to its product candidates may result in regulatory actions, including the issuance of inspectional observations (such as FDA Form 483s), warning letters, or injunctions or the loss of operating licenses.

Fulcrum or its third-party manufacturers may also encounter shortages in the raw materials or API necessary to produce its product candidates in the quantities needed for its clinical trials or, if its product candidates are approved, in sufficient quantities for commercialization or to meet an increase in demand, as a result of capacity constraints or delays or disruptions in the market for the raw materials or API, including shortages caused by the purchase of such raw materials or API by its competitors or others. The failure of Fulcrum or its third-party manufacturers to obtain the raw materials or API necessary to manufacture sufficient quantities of its product candidates, may have a material adverse effect on its business.

Fulcrum’s reliance on third parties increases the risk that it will not have sufficient quantities of its product candidates or if approved, products at an acceptable cost or quality, which could delay, prevent or impair its development or commercialization efforts.

Fulcrum does not have any manufacturing facilities and expects to rely on third parties for the manufacture of any future product candidates for preclinical and clinical testing. Fulcrum also expects to rely on third-party manufacturers or third-party collaborators for the manufacture of clinical supply, or if approved, commercial supply of any future product candidates. This reliance on third parties increases the risk that Fulcrum will not have sufficient quantities of its product candidates for clinical development, or if approved, products at an acceptable cost or quality, which could delay, prevent or impair its development or commercialization efforts.

In addition, legislative proposals are pending that, if enacted, could negatively impact U.S. funding for certain biotechnology providers having relationships with foreign adversaries or which pose a threat to national security. The potential downstream adverse impacts on entities having commercial relationships with any impacted biotechnology providers are unknown but may include supply chain disruptions or delays. Any products that Fulcrum may develop may compete with other product candidates and products for access to manufacturing facilities. There are a limited number of manufacturers that operate under cGMP regulations and that might be capable of manufacturing for Fulcrum.

Any performance failure on the part of Fulcrum’s future manufacturers could delay clinical development or marketing approval. Fulcrum does not currently have arrangements in place for redundant supply or a source for bulk drug substance. If any of its future contract manufacturers cannot perform as agreed, Fulcrum may be required to replace such manufacturers, and if so, could incur added costs and delays in identifying and qualifying any such replacement.

Fulcrum’s future dependence upon others for the manufacture of any future product candidates or products may adversely affect its future profit margins and its ability to commercialize any products that receive marketing approval on a timely and competitive basis.

51

Even if Fulcrum is able to commercialize any product candidates, the products may become subject to unfavorable pricing regulations, third-party coverage or reimbursement practices or healthcare reform initiatives, which could harm its business.

The regulations that govern marketing approvals, pricing, coverage and reimbursement for new drug products vary widely from country to country. Current and future legislation may significantly change the approval requirements in ways that could involve additional costs and cause delays in obtaining approvals. Some countries require approval of the sale price of a drug before it can be marketed. In many countries, the pricing review period begins after marketing or product licensing approval is granted. In some foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted. As a result, Fulcrum might obtain marketing approval for a product in a particular country, but then be subject to price regulations that delay its commercial launch of the product, possibly for lengthy time periods, and negatively impact the revenues it is able to generate from the sale of the product in that country. Adverse pricing limitations may hinder Fulcrum’s ability to recoup its investment in one or more product candidates, even if its product candidates obtain marketing approval. See “Fulcrum’s Business — Government Regulation and Product Approval — Pharmaceutical Insurance Coverage and Health Care Reform” for additional information.

Fulcrum’s ability to commercialize any product candidates successfully also will depend in part on the extent to which coverage and adequate reimbursement for these products and related treatments will be available from government health administration authorities, private health insurers and other organizations. Government authorities and third-party payors, such as private health insurers and health maintenance organizations, decide which medications they will pay for and establish reimbursement levels. A primary trend in the U.S. healthcare industry and elsewhere is cost containment. Government authorities and third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications. Increasingly, third-party payors are requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged for medical products. Coverage and reimbursement may not be available for any product that Fulcrum commercializes and, even if these are available, the level of reimbursement may not be satisfactory. Reimbursement may affect the demand for, or the price of, any product candidate for which Fulcrum obtains marketing approval. Obtaining and maintaining adequate reimbursement for its products may be difficult. Fulcrum may be required to conduct expensive pharmacoeconomic studies to justify coverage and reimbursement or the level of reimbursement relative to other therapies. If coverage and adequate reimbursement are not available or reimbursement is available only to limited levels, Fulcrum may not be able to successfully commercialize any product candidate for which it obtains marketing approval. Coverage and reimbursement by a third-party payor may depend upon a number of factors, including the third-party payor’s determination that use of a product is:

There may be significant delays in obtaining coverage and reimbursement for newly approved drugs, and coverage may be more limited than the purposes for which the drug is approved by the FDA or similar regulatory authorities outside of the United States. Moreover, eligibility for coverage and reimbursement does not imply that a drug will be paid for in all cases or at a rate that covers Fulcrum’s costs, including research, development, manufacture, sale and distribution expenses. Interim reimbursement levels for new drugs, if applicable, may also not be sufficient to cover Fulcrum’s costs and may not be made permanent. Reimbursement rates may vary according to the use of the drug and the clinical setting in which it is used, may be based on reimbursement levels already set for lower cost drugs and may be incorporated into existing payments for other services. Net prices for

52

drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the United States. Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement policies. Fulcrum’s inability to promptly obtain coverage and adequate reimbursement rates from both government-funded and private payors for any approved products that it develops could have a material adverse effect on its operating results, its ability to raise capital needed to commercialize products and its overall financial condition.

There can be no assurance that Fulcrum’s product candidates, even if they are approved for sale in the United States or in other countries, will be considered medically reasonable and necessary for a specific indication or cost-effective by third-party payors, or that coverage and an adequate level of reimbursement will be available or that third-party payors’ reimbursement policies will not adversely affect Fulcrum’s ability to sell its product candidates profitably.

Fulcrum’s future growth depends, in part, on its ability to penetrate foreign markets, where it would be subject to additional regulatory burdens and other risks and uncertainties that, if they materialize, could harm its business.

Fulcrum’s future profitability will depend, in part, on its ability to commercialize its product candidates in markets outside of the United States and the European Union. If Fulcrum commercializes its product candidates in foreign markets, it will be subject to additional risks and uncertainties, including:

If risks related to any of these uncertainties materializes, it could have a material adverse effect on Fulcrum’s business.

53

Clinical trial and product liability lawsuits against Fulcrum could divert its resources and could cause it to incur substantial liabilities and to limit commercialization of any products that it may develop.

Fulcrum faces an inherent risk of clinical trial and product liability exposure related to the testing of any future product candidates in human clinical trials, and will face an even greater risk if it commercially sells any products that it may develop. While Fulcrum currently has no products that have been approved for commercial sale, the future use of any product candidates by Fulcrum in clinical trials, and the sale of any approved products in the future, may expose it to liability claims. These claims might be made by patients that use the product, healthcare providers, pharmaceutical companies or others selling such products. If Fulcrum cannot successfully defend itself against claims that any future product candidates or products caused injuries, it will incur substantial liabilities. Regardless of merit or eventual outcome, liability claims may result in:

Fulcrum currently holds $10 million in clinical trial liability insurance coverage in the aggregate, with a per incident limit of $10 million, which may not be adequate to cover all liabilities that it may incur. Fulcrum may need to increase its insurance coverage if it resumes clinical trials of any future product candidates or if it commences commercialization of any approved product. Insurance coverage is increasingly expensive. Fulcrum may not be able to maintain insurance coverage at a reasonable cost or in an amount adequate to satisfy any liability that may arise. If a successful clinical trial or product liability claim or series of claims is brought against Fulcrum for uninsured liabilities or in excess of insured liabilities, its assets may not be sufficient to cover such claims and its business operations could be impaired.

Risks Related to Fulcrum’s Dependence on Third Parties

Fulcrum relied, and expects to continue to rely, as necessary, on third parties to conduct its clinical trials, and those third parties may not perform satisfactorily, including failing to meet deadlines for the completion of such trials, which may harm its business.

Fulcrum has historically relied on third-party clinical research organizations (“CROs”), to conduct its clinical trials and plans to continue to do so in the future should it resume research and development activities and have clinical stage candidates. Fulcrum does not plan to independently conduct clinical trials of its product candidates. Fulcrum expects to continue to rely on third parties, such as CROs, clinical data management organizations, medical institutions and clinical investigators, to conduct any future clinical trials. These agreements might terminate for a variety of reasons, including a failure to perform by the third parties. If Fulcrum needs to enter into alternative arrangements, its product development activities might be delayed.

Fulcrum’s reliance on these third parties for research and development activities will reduce its control over these activities but will not relieve it of its responsibilities.

If these third parties do not successfully carry out their contractual duties, meet expected deadlines or conduct Fulcrum’s clinical trials in accordance with regulatory requirements or its stated protocols, Fulcrum will not be able to obtain, or may be delayed in obtaining, marketing approvals for its product candidates and will not

54

be able to, or may be delayed in its efforts to, successfully develop and commercialize its product candidates. Furthermore, these third parties may also have relationships with other entities, some of which may be Fulcrum’s competitors.

Fulcrum also relied, and expects to continue to rely, on other third parties to store and distribute drug supplies for any clinical trials. Any performance failure on the part of its distributors could delay clinical development or marketing approval of its product candidates or commercialization of its products, producing additional losses and depriving it of potential product revenue. For any violations of laws and regulations that occur during the conduct of its preclinical studies or clinical trials, Fulcrum could be subject to untitled letters, warning letters or other enforcement actions.

Fulcrum has entered into, and may in the future enter into, collaborations with third parties for the discovery, development or commercialization of its product candidates. If its collaborations are not successful, Fulcrum may not be able to capitalize on the market potential of these product candidates and its business could be adversely affected.

Fulcrum may in the future enter into development, distribution or marketing arrangements with third parties with respect to its other existing or future product candidates. Its likely collaborators for any such sales, marketing, distribution, development, licensing or broader collaboration arrangements include large and mid-size pharmaceutical companies, regional and national pharmaceutical companies and biotechnology companies. These third party arrangements generally do not provide Fulcrum with the ability to control the amount and timing of resources that its collaborators dedicate to the development or commercialization of its product candidates. Fulcrum’s ability to generate revenues from these arrangements will depend on its collaborators’ abilities and efforts to successfully perform the functions assigned to them in these arrangements.

Collaborations that Fulcrum enters into may not be successful, and any success will depend heavily on the efforts and activities of such collaborators. Collaborations pose a number of risks, including the following:

55

Collaboration agreements may not lead to development or commercialization of product candidates in the most efficient manner, or at all. If any collaborations that Fulcrum enters into do not result in the successful development and commercialization of products or if one of its collaborators terminates its agreement with Fulcrum, it may not receive any future research funding or milestone or royalty payments under the collaboration. If Fulcrum does not receive the funding it expects under these agreements, its development of its product candidates could be delayed and it may need additional resources to develop its product candidates. All of the risks relating to product development, regulatory approval and commercialization described herein also apply to the activities of Fulcrum’s collaborators.

Additionally, subject to its contractual obligations to Fulcrum, if a collaborator of Fulcrum’s is involved in a business combination, the collaborator might deemphasize or terminate the development or commercialization of any product candidate licensed to it by Fulcrum. If a collaborator terminates its agreement with Fulcrum, it may find it more difficult to attract new collaborators and its perception in the business and financial communities could be adversely affected.

If Fulcrum is not able to establish collaborations, it may have to alter any future development and commercialization plans and its business could be adversely affected.

For any future product candidates, Fulcrum may decide to collaborate with pharmaceutical or biotechnology companies for the development and potential commercialization of those product candidates. Fulcrum faces significant competition in seeking appropriate collaborators, and a number of more established companies may also be pursuing strategies to license or acquire third-party intellectual property rights that Fulcrum considers

56

attractive. These established companies may have a competitive advantage over Fulcrum due to their size, financial resources and greater clinical development and commercialization capabilities. In addition, companies that perceive Fulcrum to be a competitor may be unwilling to assign or license rights to it. Whether Fulcrum reaches a definitive agreement for a collaboration will depend, among other things, upon its assessment of the collaborator’s resources and expertise, the terms and conditions of the proposed collaboration and the proposed collaborator’s evaluation of a number of factors. Those factors may include the design or results of clinical trials, the likelihood of approval by the FDA or similar regulatory authorities outside the United States, the potential market for the subject product candidate, the costs and complexities of manufacturing and delivering such product candidate to patients, the potential of competing products, the existence of uncertainty with respect to Fulcrum’s ownership of technology, which can exist if there is a challenge to such ownership without regard to the merits of the challenge, and industry and market conditions generally. The collaborator may also consider alternative product candidates or technologies for similar indications that may be available to collaborate on and whether such a collaboration could be more attractive than the one with Fulcrum for its product candidate. Fulcrum may also be restricted under existing or future license agreements from entering into agreements on certain terms with potential collaborators.

Collaborations are complex and time-consuming to negotiate and document. In addition, there have been a significant number of recent business combinations among large pharmaceutical and biotechnology companies that have resulted in a reduced number of potential future collaborators.

If Fulcrum is unable to reach agreements with suitable collaborators on a timely basis, on acceptable terms or at all, it may have to curtail the development of a product candidate, reduce or delay its development program or one or more of its other development programs, delay its potential commercialization or reduce the scope of any sales or marketing activities, or increase its expenditures and undertake development or commercialization activities at its own expense. If Fulcrum elects to fund and undertake development or commercialization activities on its own, it may need to obtain additional expertise and additional capital, which may not be available to it on acceptable terms or at all. If Fulcrum fails to enter into collaborations and does not have sufficient funds or expertise to undertake the necessary development and commercialization activities, it may not be able to further develop its product candidates or bring them to market.

Risks Related to Fulcrum’s Intellectual Property

If Fulcrum is unable to obtain, maintain, enforce and protect patent protection for its technology and product candidates or if the scope of the patent protection obtained is not sufficiently broad, its competitors could develop and commercialize technology and products similar or identical to Fulcrum’s, and its ability to successfully develop and commercialize its technology and product candidates may be adversely affected.

Fulcrum’s success depended in large part on its ability to obtain and maintain protection of the intellectual property it may own solely and jointly with others or may license from others, particularly patents, in the United States and other countries with respect to any proprietary technology and product candidates it develops. Fulcrum sought to protect its proprietary position by filing patent applications in the United States and abroad related to its product candidates that are important to its business and by in-licensing intellectual property related to its technologies and product candidates. If Fulcrum is unable to obtain or maintain patent protection with respect to any proprietary technology or product candidate, its business, financial condition, results of operations and prospects could be materially harmed.

The patent prosecution process is expensive, time-consuming and complex, and Fulcrum may not be able to file, prosecute, maintain, defend or license all necessary or desirable patent applications at a reasonable cost or in a timely manner. It is also possible that Fulcrum will fail to identify patentable aspects of its research and development output before it is too late to obtain patent protection. Moreover, in some circumstances, Fulcrum does not have the right to control the preparation, filing and prosecution of patent applications, or to maintain, enforce and defend the patents, covering technology that it licenses from third parties. Therefore, these

57

in-licensed patents and applications may not be prepared, filed, prosecuted, maintained, defended and enforced in a manner consistent with the best interests of Fulcrum’s business.

The patent position of pharmaceutical and biotechnology companies generally is highly uncertain, involves complex legal and factual questions and has in recent years been the subject of much litigation. In addition, the scope of patent protection outside of the United States is uncertain and laws of foreign countries may not protect Fulcrum’s rights to the same extent as the laws of the United States or vice versa. For example, European patent law restricts the patentability of methods of treatment of the human body more than United States law does. With respect to both owned and in-licensed patent rights, Fulcrum cannot predict whether the patent applications it and its licensors are currently pursuing will issue as patents in any particular jurisdiction or whether the claims of any issued patents will provide sufficient protection from competitors. Further, Fulcrum may not be aware of all third-party intellectual property rights potentially relating to its product candidates. In addition, publications of discoveries in the scientific literature often lag behind the actual discoveries, and patent applications in the United States and other jurisdictions are typically not published until 18 months after filing, or in some cases not published at all. Therefore, neither Fulcrum nor its licensors can know with certainty whether either Fulcrum or its licensors were the first to make the inventions claimed in the patents and patent applications it owns or in-licenses now or in the future, or that either Fulcrum or its licensors were the first to file for patent protection of such inventions. As a result, the issuance, scope, validity, enforceability and commercial value of Fulcrum’s owned and in-licensed patent rights are highly uncertain. Moreover, Fulcrum’s owned and in-licensed pending and future patent applications may not result in patents being issued which protect its technology and product candidates, in whole or in part, or which effectively prevent others from commercializing competitive technologies and products. Changes in either the patent laws or interpretation of the patent laws in the United States and other countries may diminish the value of Fulcrum’s patents and its ability to obtain, protect, maintain, defend and enforce its patent rights, narrow the scope of its patent protection and, more generally, could affect the value or narrow the scope of its patent rights. For information relating to Fulcrum’s patent portfolio, see “Fulcrum’s Business — Intellectual Property.”

Moreover, Fulcrum or its licensors may be subject to a third-party preissuance submission of prior art to the United States Patent and Trademark Office (“USPTO”) or become involved in opposition, derivation, revocation, reexamination, inter partes review, post-grant review or interference proceedings challenging its patent rights or the patent rights of others. An adverse determination in any such submission, proceeding or litigation could reduce the scope of, or invalidate, Fulcrum’s patent rights, allow third parties to commercialize its technology or product candidates and compete directly with Fulcrum, without payment to it, or result in its inability to manufacture or commercialize drugs without infringing third-party patent rights. If the breadth or strength of protection provided by Fulcrum’s patents and patent applications is threatened, regardless of the outcome, it could dissuade companies from collaborating with Fulcrum to license, develop or commercialize current or future product candidates. If any such claims are invalidated or rendered unenforceable for any reason, Fulcrum will lose valuable intellectual property rights and its ability to prevent others from competing with it would be impaired.

Additionally, the coverage claimed in a patent application can be significantly reduced before the patent is issued, and its scope can be reinterpreted after issuance. Even if Fulcrum’s owned and in-licensed patent applications issue as patents, they may not issue in a form that will provide it with any meaningful protection, prevent competitors from competing with it or otherwise provide it with any competitive advantage. The issuance of a patent is not conclusive as to its inventorship, scope, validity or enforceability, and Fulcrum’s owned and in-licensed patents may be challenged in the courts or patent offices in the United States and abroad. Such challenges may result in loss of exclusivity or freedom to operate or in patent claims being narrowed, invalidated or held unenforceable, in whole or in part, which could limit Fulcrum’s ability to stop others from using or commercializing similar or identical technology and products, or limit the duration of the patent protection of its technology and product candidates. Such proceedings also may result in substantial cost and require significant time from Fulcrum’s management and employees, even if the eventual outcome is favorable to it. Given the amount of time required for the development, testing and regulatory review of new product candidates, patents

58

protecting such candidates might expire before or shortly after such candidates are commercialized. Furthermore, Fulcrum’s competitors may be able to circumvent its owned or in-licensed patents by developing similar or alternative technologies or products in a non-infringing manner. As a result, Fulcrum’s owned and in-licensed patent portfolio may not provide it with sufficient rights to exclude others from commercializing technology and products similar or identical to any of its technology and product candidates.

Patent terms may be inadequate to protect Fulcrum’s competitive position on its product candidates for an adequate amount of time.

Patents have a limited lifespan. In the United States, if all maintenance fees are timely paid, the natural expiration of a patent is generally 20 years from its earliest U.S. non-provisional filing date. Various extensions may be available, but the life of a patent, and the protection it affords, is limited. Even if patents covering Fulcrum’s product candidates are obtained, once the patent life has expired, it may be open to competition from competitive products, including generics or biosimilars. Given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting such candidates might expire before or shortly after such candidates are commercialized. As a result, Fulcrum’s owned and licensed patent portfolio may not provide it with sufficient rights to exclude others from commercializing products similar or identical to its own.

If Fulcrum is unable to obtain licenses from third parties on commercially reasonable terms or fails to comply with its obligations under such agreements, its business could be harmed.

It may be necessary for Fulcrum to use the patented or proprietary technology of third parties to commercialize its products, in which case it would be required to obtain a license from these third parties. If Fulcrum is unable to license such technology, or if it is forced to license such technology on unfavorable terms, its business could be materially harmed. If Fulcrum is unable to obtain a necessary license, it may be unable to develop or commercialize the affected product candidates, which could materially harm its business and the third parties owning such intellectual property rights could seek either an injunction prohibiting its sales or an obligation on its part to pay royalties and/or other forms of compensation. Even if Fulcrum is able to obtain a license, it may be non-exclusive, thereby giving its competitors access to the same technologies licensed to it.

If Fulcrum is unable to obtain rights to required third-party intellectual property rights or maintain the existing intellectual property rights it has, it may be required to expend significant time and resources to redesign its technology, product candidates, or the methods for manufacturing them or to develop or license replacement technology, all of which may not be feasible on a technical or commercial basis. If Fulcrum is unable to do so, it may be unable to develop or commercialize the affected technology and product candidates, which could harm its business, financial condition, results of operations and prospects significantly.

Additionally, if Fulcrum fails to comply with its obligations under license agreements, its counterparties may have the right to terminate these agreements, in which event it might not be able to develop, manufacture or market, or may be forced to cease developing, manufacturing or marketing, any product that is covered by these agreements or may face other penalties under such agreements. Such an occurrence could materially adversely affect the value of the product candidate being developed under any such agreement. Termination of these agreements or reduction or elimination of Fulcrum’s rights under these agreements, or restrictions on its ability to freely assign or sublicense its rights under such agreements when it is in the interest of its business to do so, may result in its having to negotiate new or reinstated agreements with less favorable terms, cause it to lose its rights under these agreements, including its rights to important intellectual property or technology or impede, or delay or prohibit the further development or commercialization of one or more product candidates that rely on such agreements.

Under Fulcrum’s license agreements, it may not have the final or sole decision on whether it is able to opt out certain of its in-licensed European patents and patent applications from the recently created Unified Patent

59

Court (the “UPC”) for the European Union. While its licensors have decided to opt out of the UPC, Fulcrum cannot guarantee that its in-licensed European patents and patent applications will be challenged for non-compliance during the opt-out procedure and if successful, brought under the jurisdiction of the UPC, nor can it guarantee that its licensors will decide to opt back into the UPC at a later time. Thus, Fulcrum cannot be certain that its in-licensed European patents and patent applications will not fall under the jurisdiction of the UPC. Under the UPC, a single European patent would be valid and enforceable in numerous European countries. A challenge to the validity of a European patent under the UPC, if successful, could result in a loss of patent protection in numerous European countries which could have a material adverse impact on Fulcrum’s business and its ability to commercialize or license its technology and product candidates.

If Fulcrum does not obtain patent term extension in the United States under the Hatch-Waxman Act and in foreign countries under similar legislation, its business may be materially harmed.

In the United States, the patent term of a patent that covers an FDA-approved drug may be eligible for limited patent term extension of up to five years beyond the expiration of the patent. The length of the patent term extension is related to, among other factors, the length of time the drug is under regulatory review, but such patent extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval, and only one eligible patent may be extended. Similar provisions are available in Europe and certain other jurisdictions outside the United States. If and when Fulcrum’s product candidate receives FDA approval, Fulcrum expects to apply for patent term extensions where applicable, but there is no guarantee that the applicable governmental authorities will agree with its assessment of whether such extensions should be granted, and even if granted, the length of such extensions. Fulcrum may not be granted patent term extension either in the United States or in any foreign country because of, for example, failing to exercise due diligence during the testing phase or regulatory review process, failing to apply within applicable deadlines, failing to apply prior to expiration of relevant patents or otherwise failing to satisfy applicable requirements. If Fulcrum is unable to obtain any patent term extension or the term of any such extension is less than it requests, its competitors may obtain approval of competing products following the expiration of its patent rights, and its business, financial condition, results of operations and prospects could be materially harmed.

Further, for its licensed patents, Fulcrum may not have the right to control prosecution, including filing with the USPTO a petition for patent term extension thus if one of its licensed patents is eligible for patent term extension, it may not be able to control whether a petition to obtain a patent term extension is filed, or obtained, from the USPTO.

There are detailed rules and requirements regarding the patents that may be submitted to the FDA for listing in the Orange Book. Fulcrum may be unable to obtain patents covering its product candidates that contain one or more claims that satisfy the requirements for listing in the Orange Book. Even if Fulcrum submits a patent for listing in the Orange Book, the FDA may decline to list the patent, or a manufacturer of generic drugs may challenge the listing. If one of Fulcrum’s product candidates is approved and a patent covering that product candidate is not listed in the Orange Book, an ANDA applicant would not have to provide notice to Fulcrum with respect to that patent. See “Fulcrum’s Business — Intellectual Property” for additional information regarding patent laws and patent protection.

Fulcrum’s issued European patents could be subject to the jurisdiction of the UPC.

Fulcrum’s European patents and patent applications could be challenged in the UPC. Fulcrum decided to remove, i.e., opt out, its European patents and patent applications from the jurisdiction of the UPC. However, if certain formalities and requirements are not met, its European patents and patent applications could be challenged for non-compliance and brought under the jurisdiction of the UPC. Fulcrum cannot be certain that its European patents and patent applications will avoid falling under the jurisdiction of the UPC. Under the UPC, a granted European patent would be valid and enforceable in numerous European countries. Although such patent rights would apply to numerous European countries, a successful challenge to a European patent under the UPC

60

could result in loss of patent protection in numerous European countries. Accordingly, a single proceeding under the UPC addressing the validity and infringement of the European patent could result in loss of patent protection in numerous European countries rather than in each validated country separately as such patents always have been adjudicated. Such a loss of patent protection could have a material adverse impact on Fulcrum’s business and its ability to commercialize or license its technology and product candidates.

Changes to patent laws in the United States and other jurisdictions could diminish the value of patents in general, thereby impairing Fulcrum’s ability to protect its products.

Changes in either the patent laws or interpretation of patent laws in the United States, including patent reform legislation such as the Leahy-Smith America Invents Act (the “Leahy-Smith Act”), could increase the uncertainties and costs surrounding the prosecution of Fulcrum’s owned and in-licensed patent applications and the maintenance, enforcement or defense of its owned and in-licensed issued patents. The Leahy-Smith Act includes a number of significant changes to United States patent law. These changes include provisions that affect the way patent applications are prosecuted, redefine prior art, provide more efficient and cost-effective avenues for competitors to challenge the validity of patents, and enable third-party submission of prior art to the USPTO during patent prosecution and additional procedures to attack the validity of a patent at USPTO-administered post-grant proceedings, including post-grant review, inter partes review, and derivation proceedings. Assuming that other requirements for patentability are met, prior to March 2013, in the United States, the first to invent the claimed invention was entitled to the patent, while outside the United States, the first to file a patent application was entitled to the patent. After March 2013, under the Leahy-Smith Act, the United States transitioned to a first-to-file system in which, assuming that the other statutory requirements for patentability are met, the first inventor to file a patent application will be entitled to the patent on an invention regardless of whether a third party was the first to invent the claimed invention. As such, the Leahy-Smith Act and its implementation could increase the uncertainties and costs surrounding the prosecution of Fulcrum’s patent applications and the enforcement or defense of its issued patents, all of which could have a material adverse effect on its business, financial condition, results of operations and prospects.

In addition, the patent positions of companies in the development and commercialization of biologics and pharmaceuticals are particularly uncertain. Recent U.S. Supreme Court rulings have narrowed the scope of patent protection available in certain circumstances and weakened the rights of patent owners in certain situations. This combination of events has created uncertainty with respect to the validity and enforceability of patents once obtained. Depending on future actions by the U.S. Congress, the federal courts, and the USPTO, the laws and regulations governing patents could change in unpredictable ways that could have a material adverse effect on Fulcrum’s patent rights and its ability to protect, defend and enforce its patent rights in the future.

Although Fulcrum or its licensors are not currently involved in any litigation to protect or enforce its patent or other intellectual property rights, Fulcrum may become involved in such lawsuits, which could be expensive, time-consuming and unsuccessful.

Competitors and other third parties may infringe, misappropriate or otherwise violate Fulcrum’s or its licensor’s issued patents or other intellectual property. As a result, Fulcrum or its licensors may need to file infringement, misappropriation or other intellectual property related claims, which can be expensive and time-consuming. Any claims Fulcrum asserts against perceived infringers could provoke such parties to assert counterclaims against it alleging that it infringes, misappropriates or otherwise violates their intellectual property. In addition, in a patent infringement proceeding, such parties could counterclaim that the patents Fulcrum or its licensors have asserted are invalid or unenforceable. In patent litigation in the United States, defendant counterclaims alleging invalidity or unenforceability are commonplace. Grounds for a validity challenge could be an alleged failure to meet any of several statutory requirements, including lack of novelty, obviousness, or non-enablement. Grounds for an unenforceability assertion could be an allegation that someone connected with prosecution of the patent withheld relevant information from the USPTO, or made a misleading statement, during prosecution. Third parties may institute such claims before administrative bodies in the United States or abroad,

61

even outside the context of litigation. Such mechanisms include re-examination, post-grant review, inter partes review, interference proceedings, derivation proceedings, and equivalent proceedings in foreign jurisdictions (e.g., opposition proceedings). The outcome following legal assertions of invalidity and unenforceability is unpredictable.

An adverse result in any such proceeding could put one or more of Fulcrum’s owned or in-licensed patents at risk of being invalidated or interpreted narrowly, and could put any of its owned or in-licensed patent applications at risk of not yielding an issued patent. A court may also refuse to stop the third party from using the technology at issue in a proceeding on the grounds that Fulcrum’s owned or in-licensed patents do not cover such technology. Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of Fulcrum’s confidential information or trade secrets could be compromised by disclosure during this type of litigation. Any of the foregoing could allow such third parties to develop and commercialize competing technologies and products and have a material adverse impact on Fulcrum’s business, financial condition, results of operations and prospects.

Interference or derivation proceedings provoked by third parties or brought by Fulcrum or declared by the USPTO may be necessary to determine the priority of inventions with respect to its patents or patent applications. An unfavorable outcome could require Fulcrum to cease using the related technology or to attempt to license rights to it from the prevailing party. Fulcrum’s business could be harmed if the prevailing party does not offer it a license on commercially reasonable terms or at all, or if a non-exclusive license is offered and its competitors gain access to the same technology. Fulcrum’s defense of litigation or interference or derivation proceedings may fail and, even if successful, may result in substantial costs and distract its management and other employees. In addition, the uncertainties associated with litigation could have a material adverse effect on Fulcrum’s ability to raise the funds necessary to continue its clinical trials, continue its research programs, license necessary technology from third parties, or enter into development partnerships that would help it bring its product candidates to market.

Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of Fulcrum’s confidential information could be compromised by disclosure during this type of litigation. There could also be public announcements of the results of hearings, motions, or other interim proceedings or developments. If securities analysts or investors perceive these results to be negative, it could have a material adverse effect on the price of Fulcrum’s common stock.

Third parties may initiate legal proceedings alleging that Fulcrum is infringing, misappropriating or otherwise violating their intellectual property rights, the outcome of which would be uncertain and could have a material adverse effect on the success of its business.

Fulcrum’s commercial success depends upon its ability and the ability of its collaborators to develop, manufacture, market and sell its product candidates and use its proprietary technologies without infringing, misappropriating or otherwise violating the intellectual property and proprietary rights of third parties. There is considerable patent and other intellectual property litigation in the pharmaceutical and biotechnology industries. Fulcrum may become party to, or threatened with, adversarial proceedings or litigation regarding intellectual property rights with respect to its technology and product candidates, including interference proceedings, post grant review, inter partes review, and derivation proceedings before the USPTO and similar proceedings in foreign jurisdictions such as oppositions before the European Patent Office. Numerous U.S. and foreign issued patents and pending patent applications, which are owned by third parties, exist in the fields in which Fulcrum is pursuing development candidates. As the biotechnology and pharmaceutical industries expand and more patents are issued, the risk increases that Fulcrum’s technologies or product candidates that it may identify may be subject to claims of infringement of the patent rights of third parties.

The legal threshold for initiating litigation or contested proceedings is low, so that even lawsuits or proceedings with a low probability of success might be initiated and require significant resources to defend.

62

Litigation and contested proceedings can also be expensive and time-consuming, and Fulcrum’s adversaries in these proceedings may have the ability to dedicate substantially greater resources to prosecuting these legal actions than Fulcrum can. The risks of being involved in such litigation and proceedings may increase if and as Fulcrum’s product candidates near commercialization and as it gains the greater visibility associated with being a public company. Third parties may assert infringement claims against Fulcrum based on existing patents or patents that may be granted in the future, regardless of merit. Fulcrum may not be aware of all such intellectual property rights potentially relating to its technology and product candidates and their uses, or it may incorrectly conclude that third party intellectual property is invalid or that its activities and product candidates do not infringe such intellectual property. Thus, Fulcrum does not know with certainty that its technology and product candidates, or its development and commercialization thereof, do not and will not infringe, misappropriate or otherwise violate any third party’s intellectual property.

Third parties may assert that Fulcrum is employing their proprietary technology without authorization. There may be third-party patents or patent applications with claims to materials, formulations or methods, such as methods of manufacture or methods for treatment, related to the discovery, use or manufacture of the product candidates that Fulcrum may identify or related to its technologies. Because patent applications can take many years to issue, there may be currently pending patent applications which may later result in issued patents that the product candidates that Fulcrum may identify may infringe. In addition, third parties may obtain patents in the future and claim that use of Fulcrum’s technologies infringes upon these patents. Moreover, as noted above, there may be existing patents that Fulcrum is not aware of or that it has incorrectly concluded are invalid or not infringed by its activities. If any third-party patents were held by a court of competent jurisdiction to cover, for example, the manufacturing process of the product candidates that Fulcrum may identify, any molecules formed during the manufacturing process or any final product itself, the holders of any such patents may be able to block its ability to commercialize such product candidate unless it obtained a license under the applicable patents, or until such patents expire.

Parties making claims against Fulcrum may obtain injunctive or other equitable relief, which could effectively block its ability to further develop and commercialize the product candidates that it may identify. Defense of these claims, regardless of their merit, would involve substantial litigation expense and would be a substantial diversion of employee resources from Fulcrum’s business. In the event of a successful claim of infringement against Fulcrum, it may have to pay substantial damages, including treble damages and attorneys’ fees for willful infringement, pay royalties, redesign its infringing products or obtain one or more licenses from third parties, which may be impossible or require substantial time and monetary expenditure,

Fulcrum may choose to take a license or, if it is found to infringe, misappropriate or otherwise violate a third party’s intellectual property rights, it could also be required to obtain a license from such third party to continue developing, manufacturing and marketing its technology and product candidates. However, Fulcrum may not be able to obtain any required license on commercially reasonable terms or at all. Even if it were able to obtain a license, it could be non-exclusive, thereby giving its competitors and other third parties access to the same technologies licensed to it and could require it to make substantial licensing and royalty payments. Fulcrum could be forced, including by court order, to cease developing, manufacturing and commercializing the infringing technology or product. In addition, it could be found liable for significant monetary damages, including treble damages and attorneys’ fees, if it is found to have willfully infringed a patent or other intellectual property right and could be forced to indemnify its customers or collaborators. A finding of infringement could prevent Fulcrum from commercializing its product candidates or force it to cease some of its business operations, which could materially harm its business. In addition, Fulcrum may be forced to redesign its product candidates, seek new regulatory approvals and indemnify third parties pursuant to contractual agreements. Claims that Fulcrum has misappropriated the confidential information or trade secrets of third parties could have a similar material adverse effect on its business, financial condition, results of operations and prospects.

63

Intellectual property litigation or other legal proceedings relating to intellectual property could cause Fulcrum to spend substantial resources and distract its personnel from their normal responsibilities.

Even if resolved in its favor, litigation or other legal proceedings relating to intellectual property claims may cause Fulcrum to incur significant expenses, and could distract its technical and management personnel from their normal responsibilities. In addition, there could be public announcements of the results of hearings, motions or other interim proceedings or developments and if securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of Fulcrum’s common stock. Such litigation or proceedings could substantially increase its operating losses and reduce the resources available for development activities or any future sales, marketing or distribution activities. Fulcrum may not have sufficient financial or other resources to conduct such litigation or proceedings adequately. Some of its competitors may be able to sustain the costs of such litigation or proceedings more effectively than Fulcrum can because of their greater financial resources and may also have an advantage in such proceedings due to their more mature and developed intellectual property portfolios. Uncertainties resulting from the initiation and continuation of intellectual property litigation or other proceedings could compromise Fulcrum’s ability to compete in the marketplace.

Obtaining and maintaining patent protection depends on compliance with various procedural, document submission, fee payment and other requirements imposed by governmental patent agencies, and Fulcrum’s patent protection could be reduced or eliminated for non-compliance with these requirements.

Periodic maintenance, renewal and annuity fees and various other government fees on any issued patent and pending patent application must be paid to the USPTO and foreign patent agencies in several stages or annually over the lifetime of Fulcrum’s owned and in-licensed patents and patent applications. The USPTO and various foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other similar provisions during the patent application process. In certain circumstances, Fulcrum relies on its licensing partners to pay these fees to, or comply with the procedural and documentary rules of, the relevant patent agency. With respect to its patents, Fulcrum relies on an annuity service, outside firms and outside counsel to remind it of the due dates and to make payment after it instructs them to do so. While an inadvertent lapse can in many cases be cured by payment of a late fee or by other means in accordance with the applicable rules, there are situations in which noncompliance can result in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction. Non-compliance events that could result in abandonment or lapse of a patent or patent application include failure to respond to official actions within prescribed time limits, non-payment of fees and failure to properly legalize and submit formal documents. In such an event, potential competitors might be able to enter the market with similar or identical products or technology. If Fulcrum or its licensors fails to maintain the patents and patent applications covering its product candidates, it would have a material adverse effect on its business, financial condition, results of operations and prospects.

If Fulcrum fails to comply with its obligations in its intellectual property licenses and funding arrangements with third parties, or otherwise experiences disruptions to its business relationships with its licensors, it could lose intellectual property rights that are important to its business.

Fulcrum is party to license and funding agreements, and may enter into additional licensing and funding arrangements with third parties that impose or may impose diligence, development and commercialization timelines, milestone payment, royalty, insurance and other obligations on it. Under its existing licensing and funding agreements, Fulcrum is obligated to pay royalties on net product sales of product candidates or related technologies to the extent they are covered by the agreements. If Fulcrum fails to comply with such obligations under current or future license and funding agreements, its counterparties may have the right to terminate these agreements or require it to grant them certain rights. Such an occurrence could materially adversely affect the value of any product candidate being developed under any such agreement. Termination of these agreements or reduction or elimination of Fulcrum’s rights under these agreements may result in its having to negotiate new or reinstated agreements with less favorable terms, or cause it to lose its rights under these agreements, including its rights to important intellectual property or technology, which would have a material adverse effect on its business, financial condition, results of operations and prospects. Fulcrum also has licenses and agreements to

64

certain technologies that it uses in its discovery efforts, all of which are non-exclusive. While it still faces all of the risks described herein with respect to those agreements, it cannot prevent third parties from also accessing those technologies. In addition, its licenses may place restrictions on its future business opportunities.

Disputes may arise regarding intellectual property subject to a licensing agreement, including:

In addition, the agreements under which Fulcrum licenses intellectual property or technology from third parties are complex, and certain provisions in such agreements may be susceptible to multiple interpretations. The resolution of any contract interpretation disagreement that may arise could narrow what Fulcrum believes to be the scope of its rights to the relevant intellectual property or technology, or increase what it believes to be its financial or other obligations under the relevant agreement, either of which could have a material adverse effect on its business, financial condition, results of operations and prospects. Moreover, if disputes over intellectual property that Fulcrum has licensed prevent or impair its ability to maintain its current licensing arrangements on commercially acceptable terms, it may be unable to successfully develop and commercialize the affected technology and product candidates, which could have a material adverse effect on its business, financial conditions, results of operations and prospects.

Fulcrum’s current or future licensors may have relied on third-party consultants or collaborators or on funds from third parties such that its licensors are not the sole and exclusive owners of the patents and patent applications it in-licenses. If other third parties have ownership rights to patents or patent applications Fulcrum in-licenses, they may be able to license such patents to its competitors, and its competitors could market competing products and technology. This could have a material adverse effect on Fulcrum’s competitive position, business, financial conditions, results of operations and prospects.

In spite of its best efforts, Fulcrum’s licensors might conclude that it has materially breached its license agreements and might therefore terminate the license agreements, thereby removing its ability to develop and commercialize product candidates and technology covered by these license agreements. If these in-licenses are terminated, or if the underlying intellectual property fails to provide the intended exclusivity, competitors would have the freedom to seek regulatory approval of, and to market, products and technologies identical to Fulcrum’s. This could have a material adverse effect on its competitive position, business, financial condition, results of operations and prospects.

Fulcrum may not be able to protect its intellectual property and proprietary rights throughout the world.

Filing, prosecuting and defending patents on product candidates in all countries throughout the world would be prohibitively expensive, and the laws of foreign countries may not protect Fulcrum’s rights to the same extent as the laws of the United States. In addition, the laws of some foreign countries do not protect intellectual property rights to the same extent as federal and state laws in the United States, and even where such protection is nominally available, judicial and governmental enforcement of such intellectual property rights may be lacking. Consequently, Fulcrum may not be able to prevent third parties from practicing its inventions in all countries outside the United States, or from selling or importing products made using its inventions in and into

65

the United States or other jurisdictions. Competitors may use Fulcrum’s technologies in jurisdictions where it has not obtained patent protection to develop their own products and, further, may export otherwise infringing products to territories where Fulcrum has patent protection or licenses but enforcement is not as strong as that in the United States. These products may compete with Fulcrum’s products, and its patents or other intellectual property rights may not be effective or sufficient to prevent them from competing.

Many companies have encountered significant problems in protecting and defending intellectual property rights in foreign jurisdictions. The legal systems of certain countries, particularly certain developing countries and in Russia, do not favor the enforcement of patents, trade secrets, and other intellectual property protection, particularly those relating to biotechnology products, which could make it difficult for Fulcrum to stop the infringement of its patents or marketing of competing products in violation of its intellectual property and proprietary rights generally. In addition, certain jurisdictions do not protect to the same extent or at all inventions that constitute new methods of treatment.

Proceedings to enforce Fulcrum’s intellectual property and proprietary rights in foreign jurisdictions could result in substantial costs and divert its efforts and attention from other aspects of its business, could put its patents at risk of being invalidated or interpreted narrowly, could put its patent applications at risk of not issuing, and could provoke third parties to assert claims against it. Fulcrum may not prevail in any lawsuits that it initiates, and the damages or other remedies awarded, if any, may not be commercially meaningful. Accordingly, Fulcrum’s efforts to enforce its intellectual property and proprietary rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that it develops or licenses.

Many countries have compulsory licensing laws under which a patent owner may be compelled to grant licenses to third parties. In addition, many countries limit the enforceability of patents against government agencies or government contractors. In these countries, the patent owner may have limited remedies, which could materially diminish the value of such patent. If Fulcrum or any of its licensors is forced to grant a license to third parties with respect to any patents relevant to its business, its competitive position may be impaired, and its business, financial condition, results of operations and prospects may be adversely affected.

Fulcrum may be subject to claims challenging the inventorship or ownership of its patents and other intellectual property.

Fulcrum or its licensors may be subject to claims that former employees, collaborators or other third parties have an interest in its owned or in-licensed patents, trade secrets or other intellectual property as an inventor or co-inventor. For example, Fulcrum or its licensors may have inventorship disputes arise from conflicting obligations of employees, consultants or others who are involved in developing its product candidates. Litigation may be necessary to defend against these and other claims challenging inventorship or Fulcrum’s or its licensors’ ownership of its owned or in-licensed patents, trade secrets or other intellectual property. If Fulcrum or its licensors fails in defending any such claims, in addition to paying monetary damages, it may lose valuable intellectual property rights, such as exclusive ownership of, or right to use, intellectual property that is important to its product candidates. Even if Fulcrum is successful in defending against such claims, litigation could result in substantial costs and be a distraction to management and other employees. Any of the foregoing could have a material adverse effect on Fulcrum’s business, financial condition, results of operations and prospects.

Fulcrum may be subject to claims by third parties asserting that its employees, consultants or contractors have wrongfully used or disclosed confidential information of third parties, or it has wrongfully used or disclosed alleged trade secrets of their current or former employers or claims asserting it has misappropriated their intellectual property, or claiming ownership of what Fulcrum regards as its own intellectual property.

Many of Fulcrum’s former employees, consultants and contractors were previously employed at universities or other pharmaceutical or biotechnology companies, including its competitors or potential competitors. Although Fulcrum tries to ensure that its employees, consultants and contractors do not use the proprietary

66

information or know-how of others in their work for it, Fulcrum may be subject to claims that these individuals or Fulcrum has used or disclosed intellectual property, including trade secrets or other proprietary information, of any such individual’s current or former employer. Litigation may be necessary to defend against these claims.

In addition, while it is Fulcrum’s policy to require its employees, consultants and contractors who may be involved in the development of intellectual property to execute agreements assigning such intellectual property to it, Fulcrum may be unsuccessful in executing such an agreement with each party who in fact develops intellectual property that it regards as its own. Its intellectual property assignment agreements with them may not be self-executing or may be breached, and Fulcrum may be forced to bring claims against third parties, or defend claims they may bring against it, to determine the ownership of what it regards as its intellectual property. Such claims could have a material adverse effect on its business, financial conditions, results of operations and prospects.

If Fulcrum fails in prosecuting or defending any such claims, in addition to paying monetary damages, it may lose valuable intellectual property rights or personnel, which could have a material adverse effect on its competitive business position and prospects. Such intellectual property rights could be awarded to a third party, and Fulcrum could be required to obtain a license from such third party to commercialize its technology or products, which license may not be available on commercially reasonable terms, or at all, or such license may be non-exclusive. Even if Fulcrum is successful in prosecuting or defending against such claims, litigation could result in substantial costs and be a distraction to its management and employees.

If Fulcrum is unable to protect the confidentiality of its trade secrets, its business and competitive position would be harmed.

In addition to seeking patents for its product candidates, Fulcrum also relies on trade secrets and confidentiality agreements to protect its unpatented know-how, technology and other proprietary information, to maintain its competitive position, including certain aspects of its discovery technology. Fulcrum seeks to protect its trade secrets and other proprietary technology, in part, by entering into non-disclosure and confidentiality agreements with parties who have access to them, such as its employees, corporate collaborators, outside scientific collaborators, CROs, CMOs, consultants, advisors and other third parties. Fulcrum also enters into confidentiality and invention or patent assignment agreements with its employees and consultants, but cannot guarantee that it has entered into such agreements with each party that may have or has had access to its trade secrets or proprietary technology. Despite these efforts, any of these parties may breach the agreements and disclose Fulcrum’s proprietary information, including its trade secrets, and it may not be able to obtain adequate remedies for such breaches. Detecting the disclosure or misappropriation of a trade secret and enforcing a claim that a party illegally disclosed or misappropriated a trade secret is difficult, expensive and time-consuming, and the outcome is unpredictable. In addition, some courts inside and outside of the United States are less willing or unwilling to protect trade secrets. If any of Fulcrum’s trade secrets were to be lawfully obtained or independently developed by a competitor or other third party, Fulcrum would have no right to prevent them, or those to whom they communicate it, from using that technology or information to compete with it. If any of its trade secrets were to be disclosed to or independently developed by a competitor or other third party, Fulcrum’s competitive position would be materially and adversely harmed.

Intellectual property rights do not necessarily address all potential threats.

The degree of future protection afforded by Fulcrum’s intellectual property rights is uncertain because intellectual property rights have limitations and may not adequately protect its business or permit it to maintain its competitive advantage. For example:

67

Should any of these events occur, they could have a material adverse effect on Fulcrum’s business, financial condition, results of operations and prospects.

Risks Related to Regulatory Approval of Fulcrum’s Product Candidates and Other Legal Compliance Matters

Even if Fulcrum completes the necessary preclinical studies and clinical trials, the marketing approval process is expensive, time-consuming and uncertain, and it may not obtain approvals for the commercialization of some or all of its product candidates. If Fulcrum is not able to obtain, or if there are delays in obtaining, required regulatory approvals, it will not be able to commercialize its product candidates, and its ability to generate revenue will be materially impaired.

Marketing approval of drugs in the United States requires the submission of a new drug application (“NDA”) to the FDA and Fulcrum is not permitted to market any drug candidate in the United States until it obtains approval of the NDA. An NDA must be supported by extensive clinical and preclinical data, as well as extensive information regarding pharmacology, chemistry, manufacturing and controls. Fulcrum has not submitted an application for or received marketing approval for any of its product candidates in the United States or in any other jurisdiction.

68

Fulcrum has only limited experience in filing and supporting the applications necessary to gain marketing approvals and expects to rely on third-party CROs or other third-party consultants or vendors to assist it in this process. Securing marketing approval requires the submission of extensive preclinical and clinical data and supporting information, including manufacturing information, to regulatory authorities for each therapeutic indication to establish the product candidate’s safety and efficacy. Fulcrum’s product candidates may not be effective, may be only moderately effective or may prove to have undesirable or unintended side effects, toxicities or other characteristics that may preclude its obtaining marketing approval or prevent or limit commercial use. If any of its product candidates receives marketing approval, the accompanying label may limit the approved use of its drug, which could limit sales of the product.

The process of obtaining marketing approvals, both in the United States and abroad, is expensive, may take many years, if approval is obtained at all, and can vary substantially based upon a variety of factors, including the type, complexity and novelty of the product candidates involved. Changes in marketing approval policies during the development period, changes in or the enactment of additional statutes or regulations, or changes in regulatory review for each submitted product application, may cause delays in the approval or rejection of an application. Regulatory authorities have substantial discretion in the approval process and may refuse to accept any application or may decide that Fulcrum’s data is insufficient for approval and require additional preclinical, clinical or other studies. In addition, varying interpretations of the data obtained from preclinical and clinical testing could delay, limit or prevent marketing approval of a product candidate. Any marketing approval Fulcrum ultimately obtains may be limited or subject to restrictions or post-approval commitments that render the approved product not commercially viable.

If Fulcrum experiences delays in obtaining approval or if it fails to obtain approval of its product candidates, the commercial prospects for its product candidates may be harmed and its ability to generate revenues will be materially impaired.

Disruptions at the FDA, the SEC and other government agencies could hinder their ability to hire and retain key leadership and other personnel, prevent new products and services from being developed or commercialized in a timely manner, or otherwise prevent those agencies from performing normal business functions, which could negatively impact Fulcrum’s business and its timelines.

The ability of the FDA to review and approve new products can be affected by a variety of factors, including government budget and funding levels, ability to hire and retain key personnel and accept the payment of user fees, shifting policy priorities as a result of changes in the presidential administration and political appointees tasked to oversee the agency, and statutory, regulatory, leadership, and policy changes. Average review times at the agency have fluctuated in recent years as a result. In addition, government funding of the SEC, and other government agencies on which Fulcrum’s operations may rely is subject to the impacts of political events, which are inherently fluid and unpredictable.

Disruptions at the FDA and other federal agencies, including substantial leadership departures, personnel cuts, and policy changes, may also slow the time necessary for new drugs to be reviewed and/or approved, which would harm Fulcrum’s business. Changes and cuts in FDA staffing also could result in delays in the FDA’s responsiveness or in its ability to review IND submissions or applications, issue regulations or guidance, or implement or enforce regulatory requirements in a timely fashion or at all.

For example, over the last several years, the U.S. government has shut down several times, including from October 1, 2025 through November 12, 2025, and from January 31, 2025 through February 3, 2026. In some circumstances, certain regulatory agencies, such as the FDA and the SEC, have had to furlough critical FDA, SEC and other government employees and stop critical activities. If a prolonged government shutdown occurs, it could significantly impact the ability of the FDA and the SEC to timely review and process Fulcrum’s submissions, which could have a material adverse effect on its business and its timelines.

69

Since the change in the U.S. presidential administration in 2025, there is uncertainty as to how and to what extent the current administration will continue to seek to modify or revise the requirements and policies of the FDA and other regulatory agencies with jurisdiction over Fulcrum’s product candidates and any products for which it obtains approval. This uncertainty could present new challenges and/or opportunities as Fulcrum navigates development and approval of its product candidates. Additionally, the current administration could issue or promulgate executive orders, regulations, policies or guidance that adversely affect Fulcrum or create a more challenging or costly environment to pursue the development of new therapeutic candidates.

Fulcrum may not be able to obtain or maintain orphan drug designation or exclusivity for its product candidates and, even if it does, that exclusivity may not prevent the FDA or the EMA from approving other competing products.

Regulatory authorities in some jurisdictions, including the United States and European Union, may designate drugs for relatively small patient populations as orphan drugs. Fulcrum may seek orphan drug designation, as appropriate, for any future product candidates.

Generally, if a product with an orphan drug designation subsequently receives the first marketing approval for the indication for which it has such designation, the product is entitled to a period of market exclusivity, which precludes the FDA or the EMA from approving another marketing authorization application for the same drug for a certain time period. The applicable period is seven years in the United States and ten years in the European Union. The exclusivity period in the European Union can be reduced to six years at the end of the fifth year if it is determined that a product no longer meets the criteria for orphan designation, including if the product is sufficiently profitable so that market exclusivity is no longer justified. Proposed amendments to European Union regulations regarding orphan medicines are under consideration which, if approved, could reduce the ten-year marketing exclusivity period.

Orphan drug exclusivity may be lost if the FDA or EMA determines that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantity of the drug to meet the needs of patients with the rare disease or condition.

Even if Fulcrum obtains orphan drug exclusivity for a product, that exclusivity may not effectively protect the product from competition because competing drugs containing a different active ingredient can be approved for the same condition. In addition, the FDA or the EMA can subsequently approve the same drug for the same condition if the FDA or the EMA concludes that the later drug is clinically superior to the first drug to obtain orphan drug exclusivity because it is shown to be safer, more effective or makes a major contribution to patient care. Moreover, if Fulcrum pursues and obtains approval for the same product for another indication for which it is not entitled to or does not have orphan drug exclusivity, its period of orphan exclusivity will not prevent third parties from obtaining approval for a competing drug containing the same active ingredient for use in this other, non-orphan indication. If that were to occur, the protection Fulcrum derives from orphan exclusivity may be adversely affected.

Designations by the FDA, such as fast track designation or breakthrough therapy designation, may not lead to a faster development or regulatory review or approval process, and do not increase the likelihood that Fulcrum’s product candidates will receive marketing approval.

Fulcrum may seek fast track designation as well as breakthrough therapy designation for some of its product candidates. If a drug is intended for the treatment of a serious or life-threatening condition and the drug demonstrates the potential to address unmet medical needs for this condition, the drug sponsor may apply for FDA fast track designation. The FDA has broad discretion whether or not to grant this designation, so even if Fulcrum believes a particular product candidate is eligible for this designation, it cannot assure stockholders that the FDA would decide to grant it. Even with fast track designation, Fulcrum may not experience a faster development process, review or approval compared to conventional FDA procedures. The FDA may withdraw

70

fast track designation if it believes that the designation is no longer supported by data from Fulcrum’s clinical development program.

A breakthrough therapy is defined as a drug that is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

Designation as a breakthrough therapy is within the discretion of the FDA. Accordingly, even if Fulcrum believes one of its product candidates meets the criteria for designation as a breakthrough therapy, the FDA may disagree and instead determine not to grant such designation. Even if Fulcrum receives breakthrough therapy designation, the receipt of such designation for a product candidate may not result in a faster development process, review or approval compared to drugs considered for approval under conventional FDA procedures and does not assure ultimate approval by the FDA. In addition, even if one or more of Fulcrum’s product candidates is granted breakthrough therapy designation, the FDA may later decide that such product candidates no longer meet the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

Even if the FDA agrees that Fulcrum may pursue an accelerated approval NDA submission, approval of the NDA is not assured, nor does submission of an accelerated approval NDA ensure that the product candidate will have a faster development or regulatory review process.

Fulcrum may seek approval, as applicable, of its product candidates using the FDA’s accelerated approval pathway. A product may be eligible for accelerated approval if it treats a serious condition, generally provides a meaningful advantage over available therapies, and demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality (“IMM”) that is reasonably likely to predict an effect on IMM or other clinical benefit (i.e., an intermediate clinical endpoint).

Prior to seeking such accelerated approval, Fulcrum will seek feedback from the FDA and otherwise evaluate its ability to seek and receive such accelerated approval.

There can be no assurance that, after feedback from FDA, Fulcrum will continue to pursue or apply for accelerated approval or any other form of expedited development, review or approval, even if it initially decides to do so. Furthermore, if Fulcrum decides to submit an application for accelerated approval or under another expedited regulatory designation, there can be no assurance that such submission or application will be accepted or that any expedited review or approval will be granted on a timely basis, or at all.

Moreover, as a condition of accelerated approval, the FDA likely would require that Fulcrum perform adequate and well-controlled post-marketing clinical trials to confirm the product’s clinical benefit. These confirmatory trials must be completed with due diligence. Under the Food and Drug Omnibus Reform Act of 2022 (“FDORA”), the FDA may require that a post-approval confirmatory study or studies be underway prior to approval or within a specified time period after the date of approval for a product granted accelerated approval. FDORA also requires sponsors to send updates to the FDA every 180 days on the status of such studies, including progress toward enrollment targets, and the FDA must promptly post this information publicly. FDORA also gives the FDA increased authority to withdraw approval of a drug or biologic granted accelerated approval on an expedited basis if the sponsor fails to conduct such studies in a timely manner, send the necessary updates to the FDA, or if such post-approval studies fail to verify the drug’s predicted clinical benefit. Under FDORA, the FDA is empowered to take action, such as issuing fines, against companies that fail to conduct with due diligence any post-approval confirmatory study or submit timely reports to the agency on their progress. In addition, the FDA generally requires pre-approval of promotional materials for products under consideration for accelerated approval, which could adversely impact the timing of the commercial launch of the product. Thus,

71

even if Fulcrum seeks to utilize the accelerated approval pathway for a product candidate, it may not experience a faster development or regulatory review or approval process for that product. In addition, receiving accelerated approval does not assure that the product’s accelerated approval will ultimately be converted to a traditional approval.

Failure to obtain marketing approval in foreign jurisdictions would prevent any product candidates from being marketed abroad.

In order to market and sell its products in the European Union and many other foreign jurisdictions, Fulcrum or its potential third-party collaborators must obtain separate marketing approvals and comply with numerous and varying regulatory requirements. The approval procedure varies among countries and can involve additional testing. The time required to obtain approval may differ substantially from that required to obtain FDA approval. The regulatory approval process outside of the United States generally includes all of the risks associated with obtaining FDA approval. In addition, in many countries outside of the United States, it is required that the product be approved for reimbursement before the product can be approved for sale in that country. Fulcrum or its potential third-party collaborators may not obtain approvals, including conditional authorization, from regulatory authorities outside of the United States on a timely basis, if at all. Approval by the FDA does not ensure approval by regulatory authorities in other countries or jurisdictions, and approval by one regulatory authority outside of the United States does not ensure approval by regulatory authorities in other countries or jurisdictions or by the FDA. However, a failure or delay in obtaining regulatory approval in one country may have a negative effect on the regulatory process in other countries. Fulcrum may not be able to file for marketing approvals and may not receive the necessary approvals to commercialize its products in any market.

Additionally, now that the United Kingdom is no longer part of the European Union, separate applications and procedures will be required to obtain regulatory approval for Fulcrum’s products in the United Kingdom and the European Union. Any delay in obtaining, or an inability to obtain, any marketing approvals could prevent Fulcrum from commercializing any product candidates in the United Kingdom and/or the European Union and restrict its ability to generate revenue and achieve and sustain profitability.

Any product candidate for which Fulcrum obtains marketing approval could be subject to post-marketing restrictions or withdrawal from the market under certain circumstances, and Fulcrum may be subject to substantial penalties if it fails to comply with regulatory requirements or if it experiences unanticipated problems with its products, when and if any of them are approved.

Any product candidate for which Fulcrum obtains marketing approval, along with the manufacturing processes, post-approval clinical data, labeling, advertising and promotional activities for such product, will be subject to continual requirements of and review by the FDA and other regulatory authorities. Even if marketing approval of a product candidate is granted, the approval may be subject to limitations on the indicated uses for which the product may be marketed or to the conditions of approval, including the requirement to implement a REMS. If any of Fulcrum’s product candidates receives marketing approval, the accompanying label may limit the approved use of its drug, which could limit sales of the product.

The FDA may also impose requirements for costly post-marketing studies or clinical trials and surveillance to monitor the safety or efficacy of the product, including the adoption and implementation of REMS. The FDA and other agencies, including the Department of Justice (the “DOJ”), closely regulate and monitor the post-approval marketing and promotion of drugs to ensure they are marketed and distributed only for the approved indications and in accordance with the provisions of the approved labeling. Violations of the FDCA and other statutes, including the False Claims Act, relating to the promotion and advertising of prescription drugs may lead to investigations and enforcement actions alleging violations of federal and state healthcare fraud and abuse laws, as well as state consumer protection laws.

72

In addition, later discovery of previously unknown adverse events or other problems with Fulcrum’s products, manufacturers or manufacturing processes, or failure to comply with regulatory requirements, may have various consequences, including: