Spero Therapeutics Announces First Quarter 2023 Operating Results and Provides a Business Update Phase 2 trial of SPR720 in nontuberculous mycobacterial pulmonary disease (NTM-PD) on track for top line data readout in 1H

Spero Therapeutics Announces First Quarter 2023 Operating Results and Provides a

trial of SPR720 in nontuberculous mycobacterial pulmonary disease (NTM-PD) on

line data readout in 1H 2024

Update on status of Special Protocol Assessment agreement for tebipenem HBr program

expected mid-year 2023; initiation of Phase 3 trial in complicated urinary tract infection (cUTI)

Conference call and webcast at 4:30 p.m. ET today

CAMBRIDGE, Mass., May 11, 2023 Spero Therapeutics, Inc. (Nasdaq: SPRO), a multi-asset clinical-stage biopharmaceutical company,

focused on identifying, developing and commercializing treatments in high unmet need areas involving rare diseases and multi-drug resistant (MDR) bacterial infections, today announced financial results for the first quarter ended March 31, 2023

and provided a business update.

Momentum continues to build across our late-stage programs, each of which targets a clear medical need in an

indication with a robust market and a favorable commercial landscape, ripe for innovation, said Ankit Mahadevia, M.D., Chief Executive Officer of Spero. SPR720 s Phase 2 clinical proof of concept trial in NTM-PD continues to advance, with a top line data readout expected in the first half of 2024. In parallel, we continue to engage with the FDA on a Special Protocol Assessment agreement for a pivotal Phase 3 trial of

tebipenem HBr in cUTI, expected to start later this year. We also expect to file an IND for SPR206 in the fourth quarter of this year, preparing for a Phase 2 trial in participants with hospital-acquired or ventilator-associated bacterial

Program Highlights and Upcoming Anticipated Milestones

Medical Congress Engagement

First Quarter 2023 Financial Results

Spero reported a net loss for the first quarter ended March 31, 2023 of $13.3 million or $0.25 per share of common stock, compared to a net loss of

$32.8 million or $1.01 per share of common stock reported for the same period in 2022.

Total revenues for the first quarter of 2023 were

$2.1 million, compared with revenues of $2.1 million in the first quarter of 2022. Although total revenues for the year-over-year comparison are approximately the same, grant revenue was approximately $493 thousand lower for 2023,

while collaboration revenue was approximately $493 thousand higher, due to recognition of revenue related to the GSK transaction.

Research and development expenses for the first quarter of 2023 were $9.0 million, compared with

$17.0 million of research and development expenses for the same period in 2022. This year-over-year decrease was primarily due to lower direct costs related to the tebipenem HBr program, decreased clinical activity related to the SPR206 program

and decreased research and development headcount associated with the strategic restructuring announced in May 2022.

General and administrative expenses

for the first quarter of 2023 of $7.3 million were lower than the $15.3 million reported in the same period in 2022, primarily as a result of decreased personnel related costs associated with a reduction in headcount in commercial, general

and administrative functions arising from the May 2022 strategic restructuring and a decrease in professional and consultant fees.

2023, Spero had cash and cash equivalents of $96.3 million. Based on its current operating plans, Spero believes that its cash and cash equivalents, together with other non-dilutive funding commitments,

will be sufficient to fund its operating expenses and capital expenditures beyond 2024.

Conference Call and Webcast

Spero will host a conference call and webcast today at 4:30 p.m. ET. To access the call, please dial 1-855-327-6837 (domestic) or 1-631-891-4304

(international) and refer to conference ID 10021779, or click on this link and request a return call. The conference call will also be webcast live and a link to the webcast can be accessed here and on

Spero s website at www.sperotherapeutics.com on the Events and Presentations page under the Connect tab. An archived webcast will be available on Spero s website for 30 days following the

Tebipenem HBr Research Support

tebipenem HBr studies have been funded in part with federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority, under

contract number HHSO100201800015C.

Government Agency Research Support

The views expressed in this press release are those of the authors and may not reflect the official policy or position of the Department of the Army,

Department of Defense, or the U.S. Government.

Department of Defense

Select SPR206 studies are supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Joint Warfighter Medical Research

Program under Award No. W81XWH 19 1 0295. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.

National Institute of Allergy and Infectious Disease

Select SPR206 studies have been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National

Institutes of Health, Department of Health and Human Services, under Contract No. 75N93021C00022.

About Spero Therapeutics

Spero Therapeutics, headquartered in Cambridge, Massachusetts, is a multi-asset, clinical-stage biopharmaceutical company focused on identifying, developing,

and commercializing novel treatments for bacterial infections, including multi-drug resistant bacterial infections and rare diseases.

For more information, visit https://sperotherapeutics.com.

Forward Looking Statements

This press release may

contain forward-looking statements. These statements include, but are not limited to, statements about the design, initiation, timing, progress and results of Spero s preclinical studies and clinical trials and its research and development

programs, statements about the regulatory path forward for tebipenem HBr and potential FDA approval, the potential receipt of milestone payments or royalties on under Spero s various license and collaboration agreements, and Spero s cash

runway. In some cases, forward-looking statements can be identified by terms such as may, will, should, expect, plan, aim, anticipate, could,

intent, target, project, contemplate, believe, estimate, predict, potential or continue or the negative of these terms or other similar

expressions. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including whether tebipenem HBr will advance through the clinical trial process on a timely basis, or

at all, taking into account the effects of possible regulatory delays, slower than anticipated patient enrollment, manufacturing challenges, clinical trial design and clinical outcomes; whether the results of such trials will warrant submission for

approval from the FDA or equivalent foreign regulatory agencies; whether the FDA will ultimately approve tebipenem HBr and, if so, the timing of any such approval; whether the FDA will require any additional clinical data or place labeling

restrictions on the use of tebipenem HBr that would delay approval and/or reduce the commercial prospects of tebipenem HBr; whether a successful commercial launch can be achieved and market acceptance of tebipenem HBr can be established; whether

Spero will satisfy all of the pre-conditions to receipt of the milestone payments under its various license and collaboration agreements; the lengthy, expensive, and uncertain process of clinical drug

development for SPR720 and SPR206; whether results obtained in preclinical studies and clinical trials will be indicative of results obtained in future clinical trials; Spero s reliance on third parties to manufacture, develop, and

commercialize its product candidates, if approved; Spero s need for additional funding; the ability to commercialize Spero s product candidates, if approved; Spero s ability to retain key personnel; whether Spero s cash resources

will be sufficient to fund its

continuing operations for the periods and/or trials anticipated; and other factors discussed in the Risk Factors set forth in filings that Spero periodically makes with the U.S.

Securities and Exchange Commission. The forward-looking statements included in this press release represent Spero s views as of the date of this press release. Spero anticipates that subsequent events and developments will cause its views to

change. However, while Spero may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so. These forward-looking statements should not be relied upon as representing Spero s

views as of any date subsequent to the date of this press release.

Investor Relations Contact:

Vice President, Investor Relations and Strategic

Lora Grassilli, Health Media Relations

Spero Therapeutics, Inc.

Condensed Consolidated Statements of Operations

(in thousands, except share and per share data)

Spero Therapeutics, Inc.

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