Spero Therapeutics Announces First Quarter 2022 Operating Results and Provides Business Update New Strategic Direction Focuses on Advancing the Clinical Stage Pipeline and Identifying Tebipenem s Optimal Path to Value Cr

Spero Therapeutics Announces First Quarter 2022 Operating Results and Provides Business Update

New Strategic Direction Focuses on Advancing the Clinical Stage Pipeline and Identifying Tebipenem s Optimal Path to Value Creation

Initiation of a Phase 2 Trial of SPR720 in Nontuberculous Mycobacterial-Pulmonary Disease Expected in 2H 2022

SPR206 s Phase 1 Data Support Further Development in Complicated Urinary Tract Infection, Hospital-acquired and Ventilator-associated

Bacterial Pneumonia, and Bloodstream Infections

Conference Call and Live Webcast at 4:30 p.m. ET Today

CAMBRIDGE, Mass., May 16, 2022 Spero Therapeutics, Inc. (Nasdaq: SPRO) today announced financial results for the first quarter

ended March 31, 2022 and provided a business update.

While our recent decision to restructure the company s operations was immensely

difficult, we remain optimistic about our future outlook, said Ankit Mahadevia, M.D., Chief Executive Officer of Spero Therapeutics. Our plan for Spero going forward is to focus on delivery of key clinical and regulatory milestones,

clarify and execute the path forward for tebipenem, and do so while being good stewards of capital and continuing to pursue creative partnerships. Both SPR720 and SPR206 seek to address pressing unmet needs for patients with serious drug-resistant

infections and are supported by robust clinical and preclinical datasets that we believe clearly differentiate them from competing approaches. We expect their advancement into Phase 2 trials in NTM-pulmonary

disease and multi-drug resistant Gram-negative infections, respectively, will provide us with a steady cadence of value inflection points moving forward.

Dr. Mahadevia continued, We also believe tebipenem HBr has the potential to deliver substantial clinical value to healthcare providers, payers, and

patients, if approved. We are pleased to maintain stewardship of the asset and are committed to pursuing a potential path forward to regulatory approval, either independently or with a partner. As we look ahead, we believe the diverse nature of our

multi-asset pipeline, together with cash runway through late 2023, leaves us positioned to execute on our strategic objectives.

Highlights and Upcoming Milestones

Medical Congress Engagement

First Quarter 2022 Financial Results

net loss for the first quarter ended March 31, 2022 of $32.8 million or $1.01 per common share, compared to a net loss of $19.4 million or $0.66 per common share reported for the same period in 2021.

Total revenues for the first quarter of 2022 were $2.1 million, compared with revenues of $7.3 million in the first quarter of 2021. The

revenue decrease was primarily due to a decrease in qualified expenses incurred under the BARDA contract for tebipenem HBr, a decrease in funding under the NIAID agreement related to SPR206, partially offset by an increase under the DOD agreement

relating to SPR206, and an increase in collaboration revenues related to the Pfizer agreement.

Research and development expenses for the first quarter of

2022 were $17.0 million, compared with $18.4 million, of research and development expenses for the same period in 2021. This year-over-year decrease was primarily due to the completion of significant activities to support the NDA for

tebipenem HBr, the Phase 2 clinical hold for SPR720, offset by direct costs related to the SPR206 program, and increase in personnel related costs.

General and administrative expenses for the first quarter of 2022 of $15.3 million were higher than the

$8.3 million reported in the same period in 2021, primarily due to an increase in headcount in our commercial, general and administrative functions.

As of March 31, 2022, Spero had cash, cash equivalents, and marketable securities of $122 million. Based on the previously announced restructuring

and the cessation of commercialization activities for the tebipenem HBr program and assuming the repayment of amounts under the company s Revenue Interest Financing Agreement with certain entities managed by HealthCare Royalty Management, LLC,

Spero believes that its existing cash, cash equivalents and marketable securities, together with other non-dilutive funding commitments, will be sufficient to fund its planned operating expenses and capital

expenditures pursuant to the priorities of its strategic refocusing through late 2023. During this period, the strategic refocusing prioritizes advancing SPR720 and SPR206 to key Phase 2 milestones.

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 1-877-704-4453 (domestic) or 1-201-389-0920 (international) and refer to conference ID 13729221. The conference call will also be webcast live and a link to the

webcast can be accessed here and on Spero Therapeutics website at www.sperotherapeutics.com in the Investors and Media section under Events and Presentations. 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; Office of the Assistant

Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority, under contract number HHSO100201800015C.

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.

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 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 potential regulatory path forward for tebipenem HBr and the potential approval of tebipenem HBr by the FDA and the timing thereof; the

potential value of tebipenem HBr; the potential for a partnership of the tebipenem HBr franchise; the future development and commercialization of SPR206 and SPR720; the design, initiation, timing, progress and results of Spero s preclinical

studies and clinical trials and its research and development programs; management s assessment of the results of such preclinical studies and clinical trials; and the expected cost-savings from the restructuring, Spero s anticipated

expenses and its anticipated 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 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 add costs for Spero, delay approval and/or reduce the commercial

prospects of tebipenem HBr; whether any third parties would be interested in partnering with Spero to pursue continued efforts to obtain FDA approval of tebipenem HBr, or acquiring rights to the tebipenem HBr program from Spero through a partnership

arrangement; the COVID-19 pandemic; Spero s need for additional funding; Spero s ability to successfully implement the restructuring; the impact of the restructuring on Spero s business,

including estimated costs related thereto; the risk that Spero may not be able to address the FDA s concerns with respect to tebipenem HBr; 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; 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 Specialty

Jacqueline Pomfret Kirby

Vice President, Corporate Affairs

Spero Therapeutics, Inc.

Condensed Consolidated Statements of Operations

(in thousands, except share and per share data)

Spero Therapeutics, Inc.

Condensed Consolidated Balance Sheet Data