Spero Therapeutics Announces Fourth Quarter and Full Year 2023 Operating Results and Provides a Business Update On track for topline data from SPR720 Phase 2a proof-of-concept trial in treatment-naive and treatment-exper

Spero Therapeutics Announces Fourth Quarter and Full Year 2023

Operating Results and Provides a Business Update

CAMBRIDGE, Mass., March 13, 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 fourth quarter and full year ended December 31, 2023, and provided a

2023 was a productive year for Spero and we have been focused on execution across our programs said Sath Shukla, President,

and Chief Executive Officer of Spero. We are well poised to unveil top-line data for SPR720 Phase 2a, which is expected in 2H 2024, and our excitement is fueled by the hope it may bring for the rare

disease community grappling with nontuberculous mycobacterial pulmonary disease (NTM-PD). On tebipenem HBr, engaging with the FDA and in collaboration with our partner, GSK, we are actively enrolling patients

globally in our Phase 3 PIVOT-PO clinical trial. Positioned as the first oral broad-spectrum carbapenem in the United States for cUTI, we believe this product has the potential to change the treatment paradigm

for these patients and underscores Spero s commitment to innovation. We reiterate our expected cash runway into late 2025 based on our year-end cash balance, along with tebipenem HBr development milestone

payments from GSK and our disciplined capital allocation.

SPR720 is an investigational novel, oral,

first-line treatment for NTM-PD.

Tebipenem HBr is an investigational oral carbapenem antibiotic being developed for the treatment of complicated urinary tract infection (cUTI) including acute

pyelonephritis (AP) to help patients avoid hospitalizations or reduce duration of in-patient therapy.

SPR206 is an innovative,

investigational IV-administered direct-acting next generation polymyxin that has shown antibiotic activity against MDR Gram-negative pathogens, including carbapenem-resistant Enterobacteriaceae, Acinetobacter

baumannii and Pseudomonas aeruginosa in preclinical studies.

Corporate Highlights

Fourth Quarter and Full Year 2023 Financial Results

For further details on Spero s financials, refer to Spero s Annual Report on Form 10-K, filed with the U.S.

Securities and Exchange Commission (SEC) today.

Conference Call and Live Webcast Today at 4:30 pm EST

Spero will host a conference call and webcast today at 4:30 p.m. ET. To access the call, please dial 1-877-704-4453 (domestic) or 1-201-389-0920

(international) and refer to conference ID 13744458 or click on this Link and request a return call. The conference call will also be webcast live and can be accessed through this website link, 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 presentation.

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

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 and developing

novel treatments for rare diseases and MDR bacterial infections with high unmet need.

For more information, visit www.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, as well as the regulatory path forward for tebipenem HBr and potential FDA approval, the potential commercialization of tebipenem HBr, the potential receipt under the GSK license agreement of milestone payments and royalties on future

sales of tebipenem HBr, 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, 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 ongoing

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 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:

Managing Director, LifeSci Advisors, LLC

Spero Therapeutics, Inc.

Condensed Consolidated Balance Sheet Data

Spero Therapeutics, Inc.

Condensed Consolidated Statements of Operations

(in thousands, except share and per share data)