Spero Therapeutics Announces Third Quarter 2024 Operating Results and Provides a Business Update Phase 3 PIVOT-PO trial of tebipenem HBr remains on track to complete enrollment in 2H 2025 Reiterate cash runway into mid-2

Spero Therapeutics Announces Third Quarter 2024 Operating Results

and Provides a Business Update

Phase 3 PIVOT-PO trial of tebipenem HBr remains on track to complete enrollment in 2H 2025

Reiterate cash runway into mid-2026; Q3 2024 ending cash balance of $76.3M

CAMBRIDGE, Mass., November 14, 2024 Spero Therapeutics, Inc. (Nasdaq: SPRO), a multi-asset

clinical-stage biopharmaceutical company, focused on identifying and developing novel treatments for rare diseases and multi-drug resistant (MDR) bacterial infections, today announced financial results for the third quarter ended September 30,

2024, and provided a business update.

Enrollment in the Phase 3 tebipenem HBr trial is progressing well, and we are on track to complete enrollment

in the second half of 2025. Further, our work on the Phase 2 ready SPR206 program continues, contingent on availability of non-dilutive funding, said Sath Shukla, President and Chief Executive Officer of

Spero. With SPR720 development plans now suspended while we complete a review of the full dataset from the Phase 2a trial, our extended cash runway into mid-2026 and streamlined operations position us

well to achieve our ultimate goal of delivering new therapies to patients in need.

Tebipenem HBr is an investigational

oral carbapenem antibiotic being developed for the treatment of complicated urinary tract infections (cUTI) including acute pyelonephritis (AP) to help patients potentially avoid hospitalizations or reduce duration of

in-patient therapy. Spero granted GSK an exclusive license to commercialize tebipenem HBr in all territories, except certain Asian territories.

SPR206 is an investigational, intravenously administered next-generation polymyxin that has shown antibiotic activity against MDR Gram-negative pathogens,

including carbapenem-resistant Enterobacterales, Acinetobacter baumannii and Pseudomonas aeruginosa in preclinical studies.

investigational oral, chemically stable phosphate ester prodrug that is converted rapidly in vivo to SPR719, the active moiety. SPR719 targets the ATPase site of DNA gyrase B in mycobacteria.

Third quarter 2024 Financial Results

For further details on Spero s financials, refer to Spero s Quarterly Report on Form 10-Q, filed with the

U.S. Securities and Exchange Commission (SEC) today.

About Spero Therapeutics

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

novel treatments for rare diseases and MDR bacterial infections with high unmet need. For more information, visit www.sperotherapeutics.com

Government Agency Research Support

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.

Tebipenem HBr Research Support

Select tebipenem HBr

studies have been funded in part with federal funds from the Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority, under contract number

Department of Defense

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.

Forward Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including,

without limitation, statements regarding the timing, progress and results of Spero s preclinical studies, clinical trials and research and development programs; the potential benefits of any of Spero s current or future product candidates

in treating patients; and Spero s strategy, goals and anticipated financial performance, milestones, business plans and focus. In some cases, forward-looking statements may be identified by terms such as may, will,

should, expect, plan, aim, anticipate, could, intent, target, project, contemplate, believe, estimate,

predict, potential or continue, the negative of these terms or other similar expressions. Any forward-looking statements in this press release are based on management s current expectations and beliefs and

are subject to a number of important risks, uncertainties and other factors that may cause actual results to differ materially from those indicated by such forward looking statements, including whether tebipenem HBr, SPR720 and SPR206 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 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; Spero s leadership

transitions; 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 SEC. The forward-looking statements included in this press release represent Spero s views only as of the date hereof and should not be relied upon as representing its views as of any subsequent date. Except as required by law,

Spero explicitly disclaims any obligation to update any forward-looking statements.

Investor Relations Contact:

Spero Therapeutics, Inc.

Condensed Consolidated Balance Sheet Data

Spero Therapeutics, Inc.

Condensed Consolidated Statements of Operations

(in thousands, except share and per share data)