Spero Therapeutics Announces Second Quarter 2022 Operating Results and Provides Business Update Initiation of a Placebo-controlled Phase 2 Trial of SPR720 in Nontuberculous Mycobacterial Pulmonary Disease (NTM-PD) Expect

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

Initiation of a Placebo-controlled Phase 2 Trial of SPR720 in Nontuberculous Mycobacterial Pulmonary Disease

(NTM-PD) Expected in 4Q 2022

Initiation of a Phase 2 Cross-indication Resistant Pathogen

Trial of SPR206 Expected in 3Q 2023

Continued Engagement with FDA is Expected to Provide Key Insights into the Path Forward for

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

CAMBRIDGE, Mass., August 10, 2022 Spero Therapeutics, Inc. (Nasdaq: SPRO) today announced financial results for the second quarter

ended June 30, 2022 and provided a business update.

We believe Spero is well positioned to create value with a clear strategic focus, strong

clinical and preclinical data, and cash runway extending through key anticipated catalysts, said Ankit Mahadevia, M.D., Chief Executive Officer of Spero Therapeutics. These include the expected initiation of a Phase 2 clinical trial

of SPR720 in NTM-PD patients in the fourth quarter of this year, with a subsequent interim data readout in mid-2023. This study is designed to provide clinical proof-of-concept for SPR720 as a potential first-line therapy for the 75% of NTM-PD patients who are

non-refractory and lack approved treatment options. Given the permanent lung damage that often comes with refractory disease, we believe focusing on treatment for these patients with early-stage disease

represents the best strategy to improve clinical outcomes and quality of life.

Dr. Mahadevia continued, Alongside efforts with SPR720,

we continue to work to enable the advancement of our partnership-directed programs. We previously secured non-dilutive funding to fully support the development of SPR206 through Phase 2 and have requested and

completed a Type A meeting with the FDA, as we seek a path forward for tebipenem HBr. While receiving a Complete Response Letter for tebipenem s New Drug Application was disappointing, it does not change our view of the asset s value

proposition. Looking forward, we remain committed to being good stewards of capital and leveraging partnerships where appropriate as we work to address the unmet needs of patients with serious drug-resistant infections.

Program Highlights and Upcoming Milestones

Medical Congress Engagement:

Second Quarter 2022 Financial Results

net loss for the second quarter ended June 30, 2022 of $28.7 million or $0.87 per common share, compared to a net loss of $18.6 million or $0.63 per common share reported for the same period in 2021.

Total revenues for the second quarter of 2022 were $2.0 million, compared with revenues of $5.1 million in the second quarter of 2021. The revenue

decrease was primarily due to a $1.2 million decrease in qualified expenses incurred under Spero s BARDA contract for tebipenem HBr, a $1.0 million decrease in funding under Spero s DoD agreement relating to SPR206 and a decrease

in collaboration revenues related to the Pfizer license agreement, offset by an increase of $0.3 million under Spero s NIAID agreement related to SPR206

Research and development expenses for the second quarter of 2022 were $8.2 million, compared with

$14.5 million of research and development expenses for the same period in 2021. This year-over-year decrease was primarily due to reduced program activity for tebipenem HBr, as a result of Spero s strategic restructuring announced in May

2022, as well as reduced costs associated with Spero s SPR720 and SPR206 programs, and a decrease in research and development headcount costs after the restructuring.

General and administrative expenses for the second quarter of 2022 of $8.1 million were lower than the $9.2 million reported in the same period in

2021, primarily as a result of a decrease in headcount in Spero s commercial, general and administrative functions due to the strategic restructuring, as well as a decrease in professional and consultant fees.

Restructuring expenses of $11.8 million were incurred during the quarter. These expenses were primarily comprised of $8.7 million of severance and

other employee costs, $2.6 million of discontinuation costs such as contract termination fees, and $0.6 million of lease impairment expenses.

As of June 30, 2022, Spero had cash, cash equivalents, and marketable securities of $45.4 million. Based on the previously announced restructuring

and the cessation of commercialization activities for the tebipenem HBr program, 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 into 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 13731565. 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

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

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 SPR720, SPR206, and tebipenem HBr; 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 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; 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

Investor Relations Contact:

Vice President, Investor Relations and Strategic Finance

Media Inquiries: media@sperotherapeutics.com

Spero Therapeutics, Inc.

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Spero Therapeutics, Inc.

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