Spyre Therapeutics, Inc.

PROPOSAL 4: APPROVAL OF THE AMENDED AND RESTATED 2016 EMPLOYEE STOCK PURCHASE PLAN

General

The Spyre Therapeutics, Inc. 2016 Employee Stock Purchase Plan was originally effective in April 2016 in connection with our initial public offering and subsequently amended effective June 7, 2018 and January 31, 2024 (the “2016 ESPP”). The 2016 ESPP was scheduled to terminate on April 6, 2026. In order to continue offering the ability to participate in an employee stock purchase plan uninterrupted, on September 3, 2025, the Board of Directors approved an amendment and restatement of the 2016 ESPP (the “A&R 2016 ESPP”) to be effective January 1, 2026, subject to stockholder approval.

The purpose of the A&R 2016 ESPP is to provide eligible employees with a means of acquiring an equity interest in the Company and to enhance such employees’ sense of participation in the Company’s affairs. The A&R 2016 ESPP, and the rights of participants to make purchases thereunder, is intended to qualify under Section 423 of the Code; however, offerings that do not meet the requirements of Section 423 of the Code may be established for the benefit of eligible employees of non-U.S. subsidiaries of the Company (the “Non-Section 423 Component”).

In addition to removing the expiration of the 2016 ESPP, the A&R 2016 ESPP provides for the reservation of 1,056,096 shares of common stock for issuance and incorporates other ministerial changes.

If the A&R 2016 ESPP is not approved, the ongoing offering period will be terminated and accumulated contributions will be returned to participants. If the A&R 2016 ESPP is approved, we will file with the SEC a registration statement on Form S-8 to register the shares available for issuance thereunder.

Summary of the A&R 2016 ESPP

The following description of the A&R 2016 ESPP is not intended to be complete and is qualified in its entirety by the complete text of the A&R 2016 ESPP, a copy of which is attached as Annex A to this proxy statement. Stockholders are urged to read the A&R 2016 ESPP in its entirety.

Administration

The A&R 2016 ESPP is administered by the Compensation Committee or another committee designated by the Board of Directors to administer, which is referred to herein as the “Administrator.” All questions of interpretation or application of the A&R 2016 ESPP are determined by the Administrator, whose decisions are final and binding upon all participants. The Administrator may adopt rules or procedures relating to the operation and administration of the A&R 2016 ESPP to accommodate the specific requirements of local laws and procedures, including for participants outside of the United States pursuant to the Non-Section 423 Component.

Stock Subject to ESPP

A total of 1,056,096 shares of common stock is reserved for issuance under the A&R 2016 ESPP, subject to certain adjustments in the event of a change in the Company’s capitalization. Shares of common stock issued under the A&R 2016 ESPP may be shares of authorized but unissued common stock, common stock held as treasury shares, or common stock acquired in an open-market transaction.

If the total number of shares to be purchased by all participants on any exercise date (as defined below) exceeds the number of shares remaining available for issuance under the A&R 2016 ESPP, the Administrator may make a pro rata allocation of the remaining available number of shares in as uniform a manner as possible and as the Administrator determines to be equitable.

The closing price of our common stock, as reported on Nasdaq as of April 2, 2026, was $47.58.

Eligibility

All employees of the Company or a participating subsidiary of the Company who customarily work for more than 20 hours per week and more than five months in any calendar year and satisfy the requirements set forth in the A&R 2016 ESPP will be eligible to participate in the A&R 2016 ESPP. However, any employee who would own (or pursuant to Section 424(d) of the Code would be deemed to own) more than 5% of the voting power or value of the common stock immediately after a grant under the A&R 2016 ESPP is not eligible to participate. The Administrator may also, in its discretion, establish additional requirements for participation, subject to the limitations set forth in Section 423 of the Code. No participant may purchase more than $25,000 of common stock in any one calendar year or more than the maximum number of shares established by the Administrator prior to the commencement of such offering period. For the initial offering, the maximum number of shares per participant is 2,000 shares. As of April 2, 2026, approximately 111 employees are eligible to participate in the A&R 2016 ESPP.

Offering Periods

The A&R 2016 ESPP is generally implemented by a series of “offering periods”. The first offering period began on January 1, 2026 and will end on June 30, 2026 with subsequent offering periods and purchase periods lasting for six months and ending every December 31 and June 30.

Payroll Deductions

For the initial offering period, all participants of the offering period under the 2016 ESPP that ended immediately prior to its amendment and restatement on January 1, 2026 were automatically enrolled unless the participant chose to withdraw from the A&R 2016 ESPP. To participate in a future offering period, an eligible employee must submit an enrollment agreement prior to the applicable enrollment date (or such earlier date as determined by the Administrator). Once enrolled in the A&R 2016 ESPP, a participant can purchase shares of common stock with payroll deductions at the end of the applicable offering period. Once an offering period is over, a participant is automatically enrolled in the next offering period unless the participant chooses to withdraw from the A&R 2016 ESPP.

Each enrollment agreement will request a deduction in an amount expressed as a whole percentage between 1% and 15% and all payroll deductions will be credited to the eligible employee’s account. No interest will be paid on any amount held in the account of any eligible employee.

Option Grant

On the first trading day of each offering period, each eligible employee automatically will be granted an option to acquire shares of common stock on the exercise date. All participants granted options under the A&R 2016 ESPP will have the same rights and privileges consistent with the requirements set forth in Section 423 of the Code. No eligible employee will be permitted to purchase more than shares of common stock during each purchase period.

Purchase Price

The price per share at which shares are purchased under the A&R 2016 ESPP is 85% of the lesser of the fair market value of the common stock on the first day of the offering period or the fair market value of the common stock on the last day of the offering period.

Exercise of Options

At the end of each offering period, unless the participant has withdrawn from the A&R 2016 ESPP, payroll deductions are applied automatically to purchase shares of common stock at the price described above. The number of shares purchased is determined by dividing the payroll deductions by the applicable purchase price, rounded down to the nearest whole share.

Any payroll deductions accumulated in a participant’s account that are not sufficient to purchase a full share will be returned to the participant, without interest; however, the Administrator may determine that such amounts may be carried forward into the next offering period. Any other amounts of payroll deductions in a participant’s account that are not used for the purchase of shares of common stock, whether because of the participant’s withdrawal, because the amount would enable the participant to purchase more than the maximum number of shares, or for any other reason, will be returned to the participant, without interest, as soon as administratively practicable after such withdrawal, exercise date or other event, as applicable.

Cancellation and Withdrawal

Participants may cancel all (but not less than all) of their options and terminate their enrollment by submitting a signed and completed withdrawal form before any deadline established by the Administrator for such offering period. Upon such withdrawal, the balance in the participant’s account will be returned to the participant, without interest.

Termination of Employment or Eligibility

Upon the termination of a participant’s employment with the Company (or a participating subsidiary, as applicable) for any reason or if a participant loses eligibility to participate in the A&R 2016 ESPP, the participant’s participation in the A&R 2016 ESPP is immediately terminated, the balance in the participant’s account will be returned to the participant (or his or her estate or designated beneficiary in the event of the participant’s death), without interest, as soon as administratively practicable, and the participant will have no other rights under the A&R 2016 ESPP.

Transferability

Rights to purchase common stock under the A&R 2016 ESPP and accumulated contributions may not be assigned, transferred, pledged or otherwise disposed of in any way (other than by will or the laws of descent and distribution) by a participant, and rights to purchase common stock under the A&R 2016 ESPP may be exercised during a participant’s lifetime only by the participant.

Adjustments Upon Capital Changes

In the event of any stock dividends, recapitalizations, stock splits, reverse stock splits, subdivisions, combinations, reclassifications or similar changes in the capital structure of the Company without consideration, the Administrator will appropriately adjust the number and class of shares available under the A&R 2016 ESPP, the share limits under the A&R 2016 ESPP and the applicable purchase price of such shares in any ongoing offering period.

Corporate Transactions

If we experience a corporate transaction, any offering period that commenced prior to the closing of the proposed change in control transaction will be shortened and terminated on a new purchase date. The new purchase date will occur prior to the closing of the proposed change in control transaction and our A&R 2016 ESPP will then terminate on the closing of the proposed change in control.

Amendment and Termination

The Administrator may amend, suspend or terminate the A&R 2016 ESPP at any time and, in the event of a termination of the A&R 2016 ESPP, may terminate all outstanding offering periods (and return each participant’s account balance to the participant) or allow outstanding offering periods to expire in accordance with their terms. The A&R 2016 ESPP will continue in effect until terminated by the Administrator.

Federal Income Tax Consequences

The following is a brief description of the federal income tax treatment that will generally apply to the grant and exercise of rights under the A&R 2016 ESPP that qualify under Section 423 of the Code, based on federal income tax laws in effect on the date of this proxy statement/prospectus. The exact federal income tax treatment of options under the A&R 2016 ESPP will depend on the specific nature of any such option and the individual tax attributes of the participant. The following summary is not intended to be exhaustive and, among other considerations, does not describe gift, estate, social security, state, local or international tax consequences. In addition, if an offering under the Non-Section 423 Component is established for employees of non-U.S. subsidiaries, the tax rules may be different than discussed below.

The A&R 2016 ESPP is intended to qualify as an “employee stock purchase plan” under Section 423 of the Code and, as a result, employees who participate in the A&R 2016 ESPP will be afforded favorable tax treatment subject to meeting certain requirements specified by the Code. In general, there are no federal income tax consequences to a participant upon the grant of the option to purchase shares under the A&R 2016 ESPP at the beginning of an option period or upon its exercise on the exercise date at the end of an option period. Upon the disposition of shares of common stock acquired upon exercise of an option, the participant will generally be subject to tax and the nature and amount of the tax will depend on whether the employee has satisfied the statutory holding period.

If the employee holds shares acquired under the A&R 2016 ESPP for at least two years from the grant date of his or her option and at least one year from the date he or she acquired the shares (referred to as the “statutory holding period”), any gain on the sale of the shares will be taxed as ordinary income to the extent of the lesser of (i) the amount by which the fair market value of the shares on the grant date (i.e., the first day of the option period) exceeded the exercise price for the option, or (ii) the amount by which the fair market value of the shares on the date of sale exceeds the exercise price of the option. Any additional gain or loss will be taxed as long-term capital gain or loss.

If the participant sells or otherwise disposes of the shares before the expiration of the statutory holding period, then in the year of such “disqualifying” disposition, the participant will be required to recognize ordinary income equal to the difference between the fair market value of the shares on the date of the exercise of the option and the exercise price of the option. Any additional gain or loss will be short-term or long-term capital gain or loss depending on the length of time the employee has held the shares.

The Company is not entitled to any deduction with respect to the difference between the fair market value of the common stock and the option exercise price if the participant satisfies the statutory holding period described above. If shares are sold before the statutory holding period is satisfied, the Company (or, if applicable, the affiliate employer) is entitled to a tax deduction for any ordinary income recognized by the participant.

2016 ESPP Benefits

The table below shows the number of shares purchased under the 2016 ESPP by the individuals and groups identified below since its inception (giving effect to our reverse stock split in September 2023). No non-employee directors have ever participated in the 2016 ESPP.

New Plan Benefits

The benefits that will be received by or allocated to eligible employees under the A&R 2016 ESPP cannot be determined at this time because the amount of payroll deductions contributed to purchase shares of common stock under the A&R 2016 ESPP is entirely within the discretion of each participant (subject to the limitations discussed above). With respect to the offering period that commenced on January 1, 2026, Heidy King-Jones and 37 other employees have elected to participate, but the number of shares of common stock that may be acquired is not determinable until the completion of the offering period on June 30, 2026.

For information about our equity compensation plans as of December 31, 2025, see “Securities Authorized for Issuance under Equity Compensation Plans” on page 49.