Spero Therapeutics Announces Third Quarter 2023 Operating Results and Provides a Business Update Special Protocol Assessment Agreement with FDA for Phase 3 PIVOT-PO trial of tebipenem HBr; Trial expected to begin with Fi

Spero Therapeutics Announces Third Quarter 2023 Operating Results and Provides a Business Update

Special Protocol Assessment Agreement with FDA for Phase 3 PIVOT-PO trial of tebipenem HBr; Trial

expected to begin with First Patient, First Visit in 4Q 2023

Conference call and webcast at 4:30pm ET today

CAMBRIDGE, Mass., November 13, 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 third quarter ended

September 30, 2023, and provided a business update.

Having made substantial progress across our late-stage programs throughout 2023, we look

forward to important milestones before year-end, said Sath Shukla, President, and Chief Executive Officer of Spero. In our SPR720 program, enrollment for our Phase 2 clinical proof-of-concept trial, evaluating the product in non-tuberculous mycobacterial pulmonary disease, continues to advance. Enrollment of

our first patients in the Phase 3 PIVOT-PO clinical trial of tebipenem HBr is expected to begin in the fourth quarter. Further, we expect to file an IND for SPR206, in the fourth quarter of this year, as well,

with the goal of conducting a Phase 2 clinical trial in patients with hospital-acquired or ventilator-associated bacterial pneumonia.

Highlights and Upcoming Anticipated Milestones

Third Quarter 2023 Financial Results

net loss for the third quarter ended September 30, 2023, of $3.2 million or $0.06 per basic and diluted share of common stock, compared to a net loss of $11.7 million or $0.33 per basic and diluted share of common stock reported for

the same period in 2022.

Total revenues for the third quarter of 2023 were $25.5 million, compared with revenues of $2.0 million in the third

quarter of 2022. Revenues were approximately $23.5 million higher year over year primarily due to $23.2 million in collaboration revenue related to the license agreement with GSK in the third quarter of 2023.

Research and development expenses for the third quarter of 2023 were $16.4 million, compared with $7.4 million of research and development expenses

for the same period in 2022. This year over year increase, of approximately $9 million, was primarily due to higher direct costs related to the tebipenem HBr and SPR720 programs. These included increased clinical activity related to the ongoing

Phase 2a clinical trial of SPR720 as well as startup clinical activities and increased preclinical activities related to the planned Phase 3 clinical trial of tebipenem HBr.

General and administrative expenses for the third quarter of 2023 were $5.7 million compared with

$6.6 million in the same period in 2022. The decrease year over year was primarily a result of decreased personal related costs, as well as lower facility and other related expenses, offset in part by an increase in professional and consultant

An impairment expense was incurred in the third quarter of 2023, as the Company concluded that it no longer had need for commercial manufacturing

of tebipenem HBr, provided under a service agreement with Savior Lifetec Corporation. An impairment expense of $5.3 million was recorded as the Company fully impaired the long-term asset, related to the Savior service agreement.

As of September 30, 2023, Spero had cash and cash equivalents of $93.8 million. The Company believes that its cash and cash equivalents will be

sufficient to provide funding into the second half of 2025.

For further details on Spero s financials, including results for the nine-month period

ended September 30, 2023, refer to Spero s Quarterly Report on Form 10-Q, filed with the U.S. Securities and Exchange Commission (SEC) today.

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 13741831 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 HHSO100201800015C.

Government Agency Research

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 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 and its future value, the potential receipt of milestone payments and royalties on future sales under the

GSK license agreement, 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:

Vice President, Investor Relations and Strategic

Lora Grassilli, Health Media Relations

Spero Therapeutics, Inc.

Condensed Consolidated Balance Sheet Data

Spero Therapeutics, Inc.

Condensed Consolidated Statements of Operations

(in thousands, except share and per share data)