SPRO Spero Therapeutics Inc

Exhibit 10.1

675 Massachusetts Avenue, 14^th Floor

Cambridge, MA 02139

January 10, 2025    

Satayavrat Shukla

Dear Sath:

This letter confirms that you and Spero Therapeutics, Inc., a Delaware corporation (“Company”) have agreed that you will be placed on an administrative leave, commencing January 10, 2025. The Company and its Board of Directors (the “Board”) believes that you acted at all times in good faith and consistent with your obligations. The Company has taken this action solely to minimize any potential distractions pending the resolution of the Wells process. We appreciate your cooperation in connection with this administrative leave.

During your administrative leave you will not hold the positions of President and Chief Executive Officer or principal executive officer of the Company. The Board has appointed Esther Rajavelu to assume those responsibilities during your leave. As such, during your administrative leave, you will have no management or operational role at the Company. The Company appreciates your cooperation to remain available as a resource if specifically called upon by Ms. Rajavelu or the Board, but otherwise expects that all business will be directed on behalf of the Company by Ms. Rajavelu during your administrative leave, and you will not be a participant in Company operations during your leave (i.e., you may not take any action or engage in any conduct on behalf of the Company or as an agent of the Company, including, but not limited to, communicating in written or oral form with employees, consultants, clinical researchers, shareholders, vendors, or other business partners of the Company, without the prior written authorization of Ms. Rajavelu and/or the Board). Notwithstanding the foregoing, you will remain available to the Board and to Ms. Rajavelu at their request, including to respond to questions and to assist with transitioning your duties and responsibilities while you remain on leave. In addition, you will continue to serve as a member of the Board subject to the current terms of your directorship and may continue to provide your normal board service during your administrative leave.

During your administrative leave, you will continue to be entitled to all rights and benefits as a full-time employee under the Amended and Restated Executive Employment Agreement between you and the Company dated August 1, 2023 including, without limitation. receiving your full current base salary and continue to participate in the employee benefits plans sponsored by the Company in which you and your eligible dependents participate. In addition, you will be treated

as being continuously employed for purposes of the equity awards issued to you under the Company’s 2017 and 2019 Stock Incentive Plans, including without limitation with respect to vesting, and you remain in “good standing” for purposes of the Retention Bonus as defined in and payable to you under the Retention Bonus Agreement, dated as of November 13, 2024, by and between you and the Company, subject to the achievement of the milestones and other terms and conditions of the Retention Bonus Agreement. You are also entitled to all rights under the Indemnification Agreement between you and the Company dated December 9, 2020. In the interest of clarity, nothing herein or in any other agreements, documents or communications related to the administrative leave shall be construed as a waiver of any of your rights under any existing agreement between you and the Company.

Annual Performance Bonuses for executives are determined and approved by the Board. For the 2024 fiscal year, your Annual Performance Bonus will be paid to you in normal course according to the Company’s practices. For the period of your administrative leave, your Annual Performance Bonus for the 2025 fiscal year will be calculated at your current annual bonus target multiplied by the percent of company goal achievement for 2025, as determined by the Board and without respect to the administrative leave. For the avoidance of doubt your Annual Performance Bonus for the 2025 fiscal year will be governed by the terms of Section 3(b) of your Employment Agreement and will not be negatively impacted by the administrative leave.

Thank you for your cooperation with this matter. Please acknowledge your receipt, understanding and agreement to the terms of your administrative leave by signing below and returning the original executed copy to the Company.

Received, Understood and Agreed:

Exhibit 10.2

675 Massachusetts Avenue, 14^th Floor

Cambridge, MA 02139

January 10, 2025    

Esther Rajavelu

Dear Esther:

The Board of Directors (the “Board”) of Spero Therapeutics, Inc., a Delaware corporation (the “Company”), has asked you to serve, and you have agreed to serve, as the interim President and Chief Executive Officer of the Company during the period that Satyavrat Shukla remains on administrative leave commencing January 10, 2025 (the “Interim Period”). This letter agreement (this “Agreement”) supplements and amends your Employment Agreement with the Company, dated October 31, 2023 (the “Employment Agreement”).

No provision of this Agreement may be modified, waived or discharged unless such waiver, modification or discharge shall be agreed to in a further writing and signed by you and the Company. No waiver by either party hereto at any time of any breach by the other party hereto of, or compliance with, any condition provision of this agreement to be performed by such other party shall be deemed a waiver of similar or dissimilar provisions or conditions at the same or at any prior or subsequent time. No agreements or representations, oral or otherwise, express or implied, with respect to the subject matter hereof have been made by either party that is not expressly set forth in this Agreement or the Employment Agreement. The laws of the Commonwealth of Massachusetts shall govern the validity, interpretation, construction and performance of this Agreement. This Agreement is binding on the Company’s successors and assigns.

If you agree with the foregoing, please sign this Agreement in the space provided below and return the original executed copy.

Accepted and agreed:

Exhibit 99.1

Corporate Presentation January 2025 

Forward-looking Statement This presentation contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended, including without limitation, statements regarding, among other things, the potential number of patients who could be treated by tebipenem HBr and market demand for tebipenem HBr generally; the potential regulatory path forward for tebipenem HBr, the potential approval of tebipenem HBr by the U.S. Food and Drug Administration (FDA) and the timing thereof; the potential commercialization of tebipenem HBr and its future value, the potential receipt of milestone payments and royalties on future sales of tebipenem HBr under the GlaxoSmithKline Intellectual Property (No. 3) Limited (GSK) license agreement; the effectiveness of tebipenem HBr and its potential impact on healthcare resource utilizations; the continued development and commercialization of SPR720 and SPR206; the initiation, timing, progress and results of the Company’s preclinical studies and clinical trials and its research and development programs, including management’s assessment of such results; the timing of t he availability of data from the Company’s clinical trials; the timing of the Company’s filings with regulatory agencies; product candidate benefits; competitive position; cash runway, business strategies; potential growth opportunities; potential market size; projected costs and the availability of additional non-dilutive funding from governmental agencies beyond any initially funded awards. 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. All statements other than statements of historical facts contained in this presentation are forward-looking statements. The Company may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various 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 the Company, delay approval and/or r educe the commercial prospects of tebipenem HBr; the Company’s need for additional funding; the lengthy, expensive, and uncertain process of clinical drug development; the Company’s reliance on third parties to manufacture, develop, and commercialize its product candidates, if approved; the ability to develop and commercialize the Company’s product candidates, if approved; the Company’s ability to retain key personnel; whether results obtained in preclinical studies and clinical trials will be indicative of results obtained in future clinical trials and whether preliminary data from the Company’s clinical trials will be predictive of final results from such trials; the Company’s dependence on raising capital and whether the Company’s product candidates will advance through the preclinical development a nd clinical trial process on a timely basis, or at all, taking into account such factors as the effects of possible regulatory delays, slower than anticipated patient enrollment, manufacturing challeng es, clinical trial design, clinical data requirements and clinical outcomes; whether the results of such clinical trials will warrant submission for approval from the FDA or equivalent foreign regulatory agencies; decisions made by the FDA and equivalent foreign regulatory agencies with respect to the development and commercialization of the Company’s product candidates; the commercial potential of the Company’s product candidates; the Company’s ability to obtain adequate third-party reimbursement for its product candidates; whether the Company will satisfy all of the pre-conditions to receipt of the milestone payments under its various license and collaboration agreements; the Company’s ability to implement its strategic plans; the Company’s ability to obtain, maintain and enforce int ellectual property and other proprietary rights for its product candidates; the risks and uncertainties related to market conditions; whether the Company’s cash resources will be sufficient to fund its con tinuing operations for the periods and/or trials anticipated; and other factors discussed in the “Risk Factors” section of the Company’s periodic reports filed with the U.S. Securities and Exchange Commiss ion (SEC), and risks described in other filings the Company may make with the SEC in the future. The forward-looking statements included in this presentation represent the Company’s views as of the date of this presentation. The Company anticipates that subsequent events and developments will cause its views to change. However, while the Company 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 the Company’s views as of any date subsequent to the date of this presentation.

Developing Therapies for Rare and Multi-drug Resistant Infectious Diseases Clinical stage Tebipenem HBr in Strong financial portfolio Phase 3 for cUTI foundation • Indications with high • In development, with potential • Cash runway into mid-2026 unmet need in addressable to be the first and only oral enables delivery of key patient populations carbapenem for complicated milestones urinary track infections (cUTI) • Orphan drug and/or QIDP • Potential for additional designations • Phase 3 trial expected to regulatory and commercial complete enrollment in 2H 2025 milestones • Strong global intellectual • Phase 3 data readout and property regulatory submission (US) expected in 2H 20251 • GSK commercial partnership with strong economics

Maturing Pipeline with Differentiated Clinical Assets Asset Indication Preclinical Phase 1 Phase 2 Phase 3 Anticipated Milestone Partnered Assets Tebipenem HBr Complete Enrollment cUTI Worldwide Rights (ex. Asia) (2H 2025) SPR206 HABP/VABP Initiate Phase 21 China    OUS, ex. China Spero Retains Rights in United States Wholly Owned First-line SPR720 Program suspended2 NTM-PD Non-dilutive Funding Alliances NTM-PD: non-tuberculous mycobacterial pulmonary disease; cUTI: complicated urinary tract infection; HABP: hospital-acquired bacterial pneumonia; VABP: ventilator-associated bacterial pneumonia 1.Contingent on non-dilutive funding. 2. The company has elected to suspend its current development program for SPR720, as it completes Phase 2a data analysis. 4

Tebipenem HBr Oral Carbapenem for cUTI

Complicated Urinary Tract Infection (cUTI) Typically caused by an abnormality of the Complicated Uncomplicated • urinary tract or in the presence of Functional or anatomical No functional or anatomical abnormality of urinary tract abnormality of urinary tract catheterization • Characterized by pyuria1 and a documented microbial pathogen on culture of urine or blood, accompanied by local and systemic signs and symptoms, including fever, chills, and malaise Acute • Patients with pyelonephritis2, regardless of Pyelonephritis underlying abnormalities of the urinary tract, (complicated) are considered a subset of cUTI patients Acute Cystitis Complicated Uncomplicated cystitis cystitis

Overview of cUTI Therapeutic Landscape Resistance and lack of effective treatments Lack of effective oral treatment options has result in a large addressable cUTI patient resulted in increased –population • Outpatient visits • Emergency department visits nd IV Therapy/ • Outpatient IV use 2 line Oral 3rd line Oral • Hospitalizations (Resistant/ Failed) (Resistant/ Failed) • Hospital days • Home health and long-term care stays post-hospitalization All translating to patient suffering Annual cUTI treatment episodes and high financial burden estimated to be 3.4M1

Tebipenem HBr: Potential to Reduce Treatment Burden for cUTI Patients Potential first-to-market Global commercial Phase 3 enrolling oral carbapenem partnership • Potential treatment of • PIVOT-PO trial protocol • Out-licensed global complicated UTI in outpatient approved under FDA Special commercial rights ex-Asia to setting vs current hospitalized Protocol Assessment (SPA) GSK setting • Global trial with centers in the • Japan and certain other Asian • Robust IP through 2038 North and South America, countries retained by Meiji Europe, Africa, and Asia • QIDP designation • Robust financial terms • Enrollment expected to including developmental, complete in 2H 2025 regulatory, and commercial milestones, as well as tiered sales royalties

Compound Structures and Definitions Tebipenem Tebipenem Pivoxil Tebipenem Pivoxil Hydrobromide Active drug Orally bioavailable prodrug of Spero’s orally bioavailable prodrug + tebipenem (Orapenem® fine granules HBr salt, enabling high dosage and for pediatrics; Meiji Seika, Japan) room temperature-stable product • TBP-PI-HBr is an orally bioavailable carbapenem prodrug that rapidly converts in enterocytes to active moiety tebipenem • Tebipenem has in vitro activity against multidrug-resistant (MDR) Gram-negative pathogens, including extended-spectrum ß-lactamase (ESBL)-producing, fluoroquinolone-resistant, and TMP-SMX-resistant Enterobacterales

Clinical Experience Supports Safety, Efficacy of Tebipenem1 • 741 Adult subjects evaluated, across 17 efficacy and pharmacology trials Tebipenem Pivoxil evaluated in 23 • 440 pediatric subjects evaluated, across 6 efficacy and pharmacology trials trials enrolling over 1,300 subjects (Meiji-Seika experience) • Generally well tolerated, comparable to common, approved oral beta lactam antibiotics and IV carbapenems • Met its primary endpoint in 3 double blind controlled efficacy trials in pediatric pneumonia, otitis media, and sinusitis • Approved for pediatric pneumonia, otitis media, sinusitis, over 4 million patients dosed to date Tebipenem Pivoxil approved in • Extensive post-marketing safety and efficacy surveillance completed, covering 3,331 patients Japan since 2009 • No issues of safety were observed, and adequate efficacy was demonstrated • 964 subjects have received at least one dose of TBP-PI-HBr Tebipenem HBr evaluated in 10 trials enrolling over 950 subjects • 279 healthy volunteers or patients with renal impairment across Phase 1 studies till date (Spero experience) • 685 patients with cUTI/AP in a previous Phase 3 study (SPR994-301; ADAPT-PO) 1. Akash Jain, Luke Utley, Thomas R. Parr, Thomas Zabawa & Michael J. Pucci (2018): Tebipenem, the first oral carbapenem antibiotic, Expert Review of Anti-infective Therapy, DOI: 10.1080/14787210.2018.1496821 10

Activity of Tebipenem and Comparator Carbapenems against Gram-negative and -positive Uropathogens MIC90 (μg/mL) Pathogen N Tebipenem Imipenem Meropenem Ertapenem Enterobacterales (Surveillance US & EU, 2022) E. coli 1,444 0.03 ≤0.12 0.03 0.015 K. pneumoniae 404 0.12 0.5 0.06 0.25 P. mirabilis 170 0.25 4 0.12 0.015 E. cloacae (species complex) 72 0.25 0.5 0.12 2 K. oxytoca 69 0.06 0.25 0.03 0.03 K. aerogenes 40 0.12 1 0.06 0.25 S. marcescens 22 0.25 2 0.12 0.5 C. koseri 43 0.03 ≤0.12 0.03 0.008 Gram-positive uropathogens (NCRPT-0089) E. faecalis 30 0.5 NA 4 >4 S. aureus (MSSA) 20 0.03 NA 0.25 0.25 S. Saprophyticus (MS) 25 0.25 NA 0.25 1 * Spero data on file. MIC = Minimum Inhibitory Concentration; MSSA = Methicillin Susceptible Staph Aureus; MS = Methicillin Susceptible 11

Tebipenem is Active Against Clinically Important Resistant Enterobacterales UTI Pathogens from Europe and the USA in 2022 Organism/ MIC90 (μg/mL) Phenotype N phenotype Tebipenem Imipenem Meropenem Ertapenem Enterobacterales All 2,447 0.12 1 0.06 0.06 All 1,444 0.03 ≤0.12 0.03 0.015 E. coli ESBL* 205 0.03 0.25 0.03 0.12 Levofloxacin-NS* 317 0.03 0.25 0.03 0.06 TMP-SMX-R* 399 0.03 ≤0.12 0.03 0.03 All 404 0.12 0.5 0.06 0.25 K. pneumoniae ESBL* 96 0.12 0.5 0.12 1 Levofloxacin-NS* 74 0.25 0.5 0.12 1 TMP-SMX-R* 102 0.06 0.5 0.06 0.25 *Non-CRE (Imipenem-susceptible, MIC ≤1 μg/mL): 2022 European and US Surveillance Isolates (JMI Laboratories) * Spero data on file. ESBL = Extended spectrum beta-lactamases; TMP-SMX = Trimethoprim-Sulfoxazole; R = Resistant; NS= Non susceptible; CRE = Carbapenem Resistant Enterobacterales; MIC = Minimum Inhibitory Concentration 12

Tebipenem Pharmacokinetic Profile • Prodrug rapidly converts to tebipenem in enterocytes of GI tract • Plasma Half-life ~1 hour • Dose-proportional PK relationship when administered fed or fasted state • Low potential for drug-drug interactions • No CYP450-dependent metabolism • No induction of CYP450 enzymes • Elimination through fecal and renal excretion • No dose adjustment for hepatic impairment • Dose adjustment for moderate and severe renal impairment • Oral bioavailability of tebipenem ~60%

Phase 3 Clinical Trial PIVOT-PO: Pivotal Design Study Tebipenem HBr (NCT06059846): Phase 3 Clinical Trial in cUTI A Phase 3, Randomized, Double-blind, Double-dummy, Multi-center Study to Assess the Efficacy and Safety of Orally Administered Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr), Compared to Intravenously Administered Imipenem-cilastatin in Patients with Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) Treatment Population Treatment Arms Endpoints Primary Endpoint: TBP-PI-HBR (600 mg) orally and “dummy” infusion IV, Overall response at TOC in Patients with a diagnosis every 6 hours, days 1-10, (n=1324) of cUTI (incl. AP) micro-ITT population Approximately 2648 R patients Primary Analysis: (stratified by age, baseline patients Imipenem-cilastatin (500 mg) IV and matched “dummy” Assessment of non-inferiority diagnosis, etc.) randomized tablets, orally every 6 hours, days 1-10, (n=1324) (NI) in micro-ITT population, 7-10 Days of Dosing 1:1 (blinded) based on a 10% NI margin Entered FDA Special Protocol Assessment Agreement (SPA): The FDA has indicated that positive and persuasive results from PIVOT-PO, along with previously completed studies1, could be sufficient to support approval of tebipenem HBr as a treatment for cUTI, including pyelonephritis, for a limited use indication. 1. supported by confirmatory evidence from PK/PD and breakpoint package AP: acute pyelonephritis; cUTI: complicated urinary tract infection; NI: non-inferiority; TBP-PI-HBr/tebipenem HBr: tebipenem pivoxil hydrobromide (formerly SPR994) 14

Exclusive License Agreement with GSK for Tebipenem HBr and Equity Investment Global Collaboration (ex-Asia) Financial Terms Received $66 Million upfront and $9 Million in common stock investment Received $30 Million upon SPA agreement with the FDA Spero is responsible for execution and costs of the Tebipenem HBr Phase 3 in Upon FPFD, Spero qualified to receive $95 Million in development milestones the United States payable in four equal installments over two years; $47.5M received in 2024 and remaining to be received in 2025 GSK received exclusive license to: Spero is eligible to receive up to $400 Million in additional potential regulatory, o Develop Tebipenem in territories outside commercial and sales milestone payments, as well as royalties of United States (not including Japan and o $25 Million to be paid upon GSK’s submission of tebipenem HBr’s New Drug certain other Asian countries where rights Application (NDA) are held by Meiji Seika); and Up in potential commercial o to $150 million milestones based on first o Obtain regulatory approval and commercial sales (US/EU) commercialize tebipenem HBr in all o Up to $225 million in sales related milestone payments territories, except Meiji Seika Territories o Spero to receive tiered low-single digit to low-double digit (if sales exceed $1 billion) tiered royalties on net product sales

SPR206 Direct Acting IV Potentiator

SPR206: Ongoing Clinical Development Lends Potential to Address Significant Unmet Need • Innovative, investigational IV direct-acting polymyxin antibiotic • Destabilization of phospholipids and lipopolysaccharides (LPS) present in the outer membrane • Increased permeability, cell membrane disruption, bacterial cell death • Received FDA Fast Track designation Current standard of care involves drug combinations that are often associated with nephrotoxicity Preclinical SAD/MAD Bronchoalveolar Renal Impairment Studies Phase 1 Trial1 Lavage Phase 1 Trial2 Phase 1 Trial3 Support increased efficacy beyond No evidence of nephrotoxicity at Well-tolerated and achieved lung Supportive of renal dosing in subsequent traditional antibiotics and potential for predicted therapeutic dose levels exposures consistent with predicted trials for patients impacted by single agent activity therapeutic levels differences in renal function Next Steps: Phase 2 HABP/VABP Proof of Concept Study4 SPR206 has potential to fulfill unmet need for a well tolerated, efficacious therapeutic against carbapenem-resistant pathogens HABP: hospital-acquired bacterial pneumonia; MAD: multiple ascending dose; SAD: single ascending dose; VABP: ventilator -associated bacterial pneumonia. 1. Bruss J, et al. Antimicrob Agents Chemother 2021;65:e0073921; 2.Rodvold KA, et al. Antimicrob Agents Chemother 2023;67:e0042623. 3. Bruss JB, et al. Antimicrob Agents Chemother 2023;67:e0050523; 4. Contingent on non-dilutive funding availability. 17

SPR720 Oral Antibiotic for Non-Tuberculosis Mycobacterium Pulmonary Disease (NTM-PD) The company has suspended its current development for SPR720 

SPR720 is An Oral Small Molecule Gyrase B Inhibitor • Novel mechanism of action for NTM-PD not exploited by current antibiotics • May be administered with or without food • No evidence of cross resistance against marketed antibiotics based on in vitro trials • Low propensity for development of resistance as monotherapy and in combination with SOC antibiotics in vitro Preclinical SAD/MAD Bronchoalveolar Proof of Concept Studies Phase 1 Trial Lavage Phase 1 Trial1 Phase 2a study Support activity against a broad Good PK characteristics, including lack Well-tolerated and achieved lung Phase 2a did not meet primary endpoint spectrum of NTM-PD pathogens, as of a food effect, and a clean safety exposures consistent with predicted well as low propensity for profile therapeutic levels development of resistance Next steps: Company has suspended development efforts of SPR720, as it continues to analyze data to determine next steps for the program 1. Keith A. Rodvold et. Al., Antimicrobial Agents and Chemotherapy, https://doi.org/10.1128/aac.01103-24 19

Leadership Team Esther Rajavelu Timothy Keutzer James Brady Interim President and Chief Chief Operating Officer Chief Human Resource Officer Executive Officer • Previously, Spero’s Chief • Prior CHRO at uniQure Therapeutics; • Over two decades of life science Development Officer Vice President, Human Resources at sector experience, combining Intarcia Therapeutics • Prior VP Program and Portfolio equities research, investment Management, Cubist • Close to 30 years of senior human banking, and strategy consulting resources experience with over 17 • Extensive antibiotic development years in the life science space • Prior CFO at Fulcrum Therapeutics. experience from pre-clinical to Senior equity research analyst at approval UBS, Oppenheimer and Deutsche Bank. Healthcare Investment Banker • Over 30 years in the pharmaceutical at Bank of America Merrill Lynch industry

Thank You    

Exhibit 99.2

Spero Therapeutics Provides Business Update and Announces Interim Leadership Changes

Esther Rajavelu Appointed Interim President and Chief Executive Officer, Frank Thomas Appointed Chairman of the Board

Interim Changes to Leadership Follow the Company’s Response to a Wells Notice from the SEC Relating to Certain Public Disclosures Made in 2022

Phase 3 PIVOT-PO Trial of Tebipenem HBr Reaches Over 60% Enrollment as of December 31, 2024; Remains on Track to Complete Enrollment in 2H 2025

Cash Balance and Cash Runway Guidance Remains into mid-2026

CAMBRIDGE, Mass., Jan. 10, 2025 — Spero Therapeutics, Inc. (“Spero” or the “Company”) (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 provided a corporate update regarding interim changes to its leadership and Board as well as an enrollment update regarding the Phase 3 PIVOT-PO trial of Tebipenem HBr.

Effective today, the Board of Directors (“Board”) has appointed Esther Rajavelu to serve as Interim President and Chief Executive Officer, stepping in for Sath Shukla, who has agreed to a voluntary paid administrative leave for an interim period. During such leave, Mr. Shukla will continue to serve as a member of the Board. The Board has also appointed Director Frank Thomas to serve as Chairman of the Board, stepping in for Dr. Ankit Mahadevia. Dr. Mahadevia will continue to serve as a member of the Board. These leadership changes were implemented as part of the Company’s response to a “Wells Notice” from the Securities and Exchange Commission (the “SEC”), related to certain public disclosures by the Company from March 31, 2022 leading up to May 3, 2022. The Board’s independent directors took these actions as a matter of corporate governance best practices and to enable the Company to maintain focus on pursuing its business objectives. The Board believes that the Company, Dr. Mahadevia and Mr. Shukla acted in good faith and consistent with their duties and obligations.

“The Board is highly confident that Esther is well equipped to serve as Interim President and CEO and execute on the Company’s strategy to advance our pipeline during this period,” stated Frank Thomas, Chairman of the Board of Spero Therapeutics. “The Board maintains that the disclosures of the Company were appropriate. We thank Sath and Ankit for their continued service and for their cooperation in helping Spero remain focused on its programs during this process. We look forward to the satisfactory resolution of this matter.”

“We are entering an important year of progress for Spero, as we build momentum with our Phase 3 Tebipenem HBr PIVOT-PO trial,” said Ms. Esther Rajavelu, Interim President and Chief Executive Officer of Spero Therapeutics. “We have now surpassed 60% enrollment in the trial, and we’re on track to be fully enrolled in the second half of 2025. This marks significant progress in developing the first-of-its-kind oral carbapenem antibiotic for complicated urinary tract infections. Our cash runway into mid-2026 enables us to stay focused on our highest priority, the tebipenem clinical program and other ongoing activities.”

Leadership Bios

Esther Rajavelu has served as the Company’s Chief Financial and Business Officer since joining in November 2023. Prior to that, she was Chief Financial Officer at Fulcrum Therapeutics, a clinical stage biopharmaceutical company. Ms. Rajavelu also brings more than two decades of life sciences sector experience combining equities research, investment banking and strategy consulting.

Frank Thomas has been a member of the Board since July 2017 and is currently the Chair of its Audit Committee. Mr. Thomas also serves on the Board of Directors of Larimar Therapeutics, and he brings extensive commercial and operational management experience at several biopharmaceutical companies.

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2024 Pipeline Updates and 2025 Anticipated Milestones

Tebipenem HBr

Tebipenem HBr is an investigational oral carbapenem antibiotic being developed for the treatment of cUTI including acute pyelonephritis (AP) to help patients avoid hospitalizations or reduce duration of in-patient therapy.

SPR720

SPR720 is an 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, a mechanism that is distinct from that of other antibiotics in use for Non Tuberculous Mycobacterial-Pulmonary Disease (NTM-PD).

SPR206 for Bacterial Pneumonia

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.

Financial Guidance

As of December 31, 2024, Spero Therapeutics had cash and cash equivalents of $52.9 million (unaudited). The Company estimates that its existing cash and cash equivalents, together with earned and non-contingent development milestone payments from GSK, as well as other non-dilutive funding commitments, will be sufficient to fund its operating expenses and capital expenditures into mid-2026.

The following information should be considered in connection with this preliminary result: The Company’s audited, consolidated financial statements as of December 31, 2024, are not yet available. Accordingly, the information presented above reflects the Company’s preliminary estimate, subject to the completion of the Company’s financial closing procedures and the annual audit of its financial statements by its auditors. As a result, this preliminary estimate may differ from the actual results that will be reflected

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in the Company’s audited, consolidated financial statements for the fiscal year ended December 31, 2024, when they are completed and publicly disclosed. This preliminary estimate may change, and that change may be material. The Company’s independent registered public accounting firm have not audited, reviewed, examined, or compiled nor applied agreed upon procedures with respect to such preliminary estimate and accordingly do not express an opinion or any other form of assurance with respect thereto.

Background on Wells Notice

As the Company disclosed today in a Form 8-K filing, on January 9, 2025, the Company responded to a “Wells Notice” from the SEC staff regarding a preliminary determination to recommend to the Commissioners of the SEC a civil enforcement action or administrative proceeding against the Company, Dr. Mahadevia, and Mr. Shukla. The Wells Notice relates to certain public disclosures by the Company from March 31, 2022 leading up to the Company’s announcement on May 3, 2022, that it had determined to cease commercialization of Tebipenem HBr based on feedback from the Food and Drug Administration (the “FDA”), and whether the Company’s disclosures may have violated the federal securities laws.

The Company, Dr. Mahadevia, and Mr. Shukla are cooperating with the SEC, and they maintain that the Company’s disclosures were appropriate. The Company, Dr. Mahadevia and Mr. Shukla intend to pursue the Wells Notice process and vigorously defend against this matter, including submitting a formal response to the SEC explaining their views and engaging in further dialogue with the SEC Staff.

A Wells Notice is neither a formal charge of wrongdoing nor a final determination that the recipient has violated any law, but is a preliminary determination by the SEC staff to recommend to the Commissioners of the SEC that a civil enforcement action or administrative proceeding be brought against the recipients. The results of the investigation and the Wells Notice process and any corresponding enforcement action against the Company and/or any of the identified individuals, and the costs, timing and other potential consequences of responding and complying therewith are unknown at this time.

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

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.

About Tebipenem HBr and the Phase 3 PIVOT-PO Trial

Spero Therapeutics, in collaboration with GSK through a global licensing agreement established in 2022, continues to advance Tebipenem HBr, an investigational first-in-class oral carbapenem antibiotic for treating complicated urinary tract infections (cUTI), including acute pyelonephritis. If approved, it would provide an oral alternative to IV antibiotics, addressing unmet medical needs and potentially reducing hospitalizations. The company received written agreement from the FDA under a Special Protocol Assessment (SPA) on the design and size of the pivotal Phase 3 clinical trial, named PIVOT-PO, for Tebipenem HBr in patients with cUTI, including acute pyelonephritis. The PIVOT-PO trial is a global Phase 3 randomized, double-blind study comparing the efficacy of oral Tebipenem HBr with intravenous imipenem cilastatin in hospitalized adults with complicated urinary tract infections (cUTI), including acute pyelonephritis (AP). The trial, which began enrolling patients in January 2024, aims to enroll approximately 2,648 participants, with enrollment completed in the second half of 2025.

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.

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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.

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; the potential future resolution of the Wells Notice process; and Spero’s strategy, goals, cash runway and anticipated financial performance, milestones and business plans. 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 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 need for additional funding; the ability to commercialize Spero’s product candidates, if approved; Spero’s ability to retain key personnel; Spero’s interim leadership transitions; whether Spero’s cash resources will be sufficient to fund its continuing operations for the periods and/or trials anticipated; the possible delisting of our common stock from the Nasdaq GS, the outcome of the Wells Notice process and any corresponding enforcement action or administrative proceeding; 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:

Shai Biran, PhD

Spero Therapeutics

IR@Sperotherapeutics.com

Media Inquiries:

Edelman Smithfield

Spero@edelmansmithfield.com

Spero Therapeutics

media@sperotherapeutics.com

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