SPRO Spero Therapeutics Inc

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Exhibit 99.1

Spero Therapeutics Announces Second Quarter 2024 Operating Results

and Provides a Business Update

 

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Enrollment concluded in the Phase 2a proof-of-concept clinical trial evaluating SPR720 in nontuberculous mycobacterial pulmonary disease (NTM-PD); preliminary data expected in 4Q 2024

 

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New SPR720 in-vitro resistance data to be presented at IDWeek 2024 conference in October

 

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Company announces departure of Chief Medical Officer Kamal Hamed, MD, MPH, MBA; Appoints Board member and Chair of Development Committee John C. Pottage, Jr., M.D., as Special Advisor to oversee medical function; search ongoing for a new CMO

 

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Cash balance of $63.5 million as of June 30, 2024; reiterate expected cash runway into late 2025

 

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Conference call and webcast at 4:30pm ET today

CAMBRIDGE, Mass., August 5, 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 second quarter ended June 30, 2024, and provided a business update.

“Spero’s pipeline of both wholly-owned and partnered clinical-stage programs continues to advance as planned this year,” said Sath Shukla, President and Chief Executive Officer of Spero. “We recently concluded enrollment in the Phase 2a trial of SPR720 in treatment-naive and treatment-experienced non-refractory NTM-PD patients, and we anticipate reporting data in the fourth quarter of 2024. In addition, we remain on track with enrollment in the ongoing global Phase 3 PIVOT-PO clinical trial with tebipenem HBr. We are hopeful that both SPR720, with the potential to be the first approved oral agent in NTM-PD, and Tebipenem, with the potential to be the first oral carbapenem for complicated urinary tract infection (cUTI) and acute pyelonephritis (AP), could become meaningfully differentiated treatment options for patients and expand treatment choice for providers.”

Pipeline Update

SPR720

SPR720 is an investigational novel, oral, first-line treatment for NTM-PD.

 

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Enrollment has concluded, with 25 patients enrolled in the Phase 2a proof-of-concept clinical trial evaluating SPR720 in NTM-PD. The last patient received the first dose in July 2024. Preliminary data on SPR720’s early bactericidal activity, as assessed by the change in NTM bacterial load over the treatment course of 56 days, are expected in 4Q 2024. The rate of change in log10 Colony Forming Units per milliliter (CFU/mL), which is the trial’s primary endpoint, is being measured, along with the rate of change in Time to Positivity, which is a

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key secondary endpoint. The double-blinded, placebo-controlled, trial enrolled treatment-naïve and treatment-experienced patients with non-refractory NTM-PD due to Mycobacterium avium complex in 3 treatment groups (placebo, SPR720 500 mg and SPR720 1000 mg dosed QD). Additional secondary endpoints include assessments of pharmacokinetics and safety and tolerability. For more information on the trial, see ClinicalTrials.gov identifier NCT05496374.

 

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Dosing completed in two Phase 1 clinical studies evaluating SPR720 in healthy volunteers: 1) a bronchoalveolar lavage (BAL) study assessing intrapulmonary PK (epithelial lung fluid and alveolar macrophage) of SPR719, the active moiety of the prodrug SPR720 (NCT05955586), and 2) a study evaluating changes in plasma PK when SPR720 is co-administered with azithromycin and ethambutol (NCT05966688). Topline results from both studies are also expected to be disclosed in 4Q of 2024.

Upcoming Presentation

 

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Data from in vitro evaluation of the development of microbial resistance against SPR720 have been accepted for presentation at IDWeek, taking place October 16 to 19, 2024 in Los Angeles, CA.

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. Spero granted GSK an exclusive license to commercialize tebipenem HBr in all territories, except certain Asian territories.

 

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Enrollment on track in PIVOT-PO, the global Phase 3 clinical trial of tebipenem HBr in patients with cUTI. This randomized, double-blinded trial compares oral tebipenem HBr with intravenous imipenem cilastatin, in hospitalized adult patients with cUTI/AP. The primary endpoint is overall response (a combination of clinical cure and favorable microbiological response) at the Test-of-Cure (TOC) visit. Target enrollment for the trial is approximately 2,648 patients, with enrollment completion expected in the second half of 2025. For more information on PIVOT-PO, refer to ClinicalTrials.gov ID NCT06059846.

SPR206

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.

 

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The U.S. Food and Drug Administration (FDA) cleared the Company’s IND for a Phase 2 trial in participants with hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP). The Company maintains its guidance to initiate the trial, contingent on availability of non-dilutive funding.

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Corporate Update

 

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Kamal Hamed, MD, MPH, MBA, Chief Medical Officer, is departing the Company, effective August 29, 2024.

 

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John C. Pottage, Jr., M.D., a member of Spero’s Board of Directors since August 2018, with over 20 years of experience advancing therapeutics for infectious diseases, has been appointed Special Advisor to oversee the Company’s medical function, effective immediately, and will assume responsibility for oversight of Spero’s pipeline programs, including the ongoing clinical studies for SPR720 and Tebipenem HBr. Dr. Pottage has served as Senior Vice President and Chief Scientific and Medical Officer of ViiV Healthcare, where he oversaw research and development, regulatory, safety and medical affairs. Prior to that, Dr. Pottage served as Senior Vice President and Head of the Infectious Disease Medicine Development Center at GSK (formerly GlaxoSmithKline), and prior to that, as Vice President of Global Clinical Development of Antivirals at GSK. Earlier in his career he held senior clinical development roles at Achillion Pharmaceuticals and Vertex Pharmaceuticals, as well as various academic/ clinical positions at Rush University Medical Center. In connection with this appointment, Dr. Pottage has stepped aside from the Company’s audit committee, as he will not meet the independence requirements for service on the audit committee while serving as a Special Advisor to the Company.

Mr. Shukla added, “We wish to thank Kamal for his significant contribution to the development and advancement of Spero’s three clinical programs over the last two years. At the same time, we are pleased that our clinical programs will be under the extremely capable oversight of Dr. Pottage while we continue our ongoing search for a new Chief Medical Officer.”

Second quarter 2024 Financial Results

 

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Spero reported a net loss of $17.9 million, or ($0.33) per share of common stock, basic and diluted, for the second quarter ended June 30, 2024, compared with a net loss of $11.9 million, or ($0.23) per share of common stock, basic and diluted, for the second quarter ending June 30, 2023.

 

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Total revenue for the second quarter of 2024 was $10.2 million, compared with total revenue of $2.7 million for the second quarter of 2023. The revenue increase for the second quarter of 2024 was primarily due to an increase in collaboration revenue related to our agreement with GSK for tebipenem HBr and an increase in grant revenue related to our BARDA contract for tebipenem HBr, partially offset by a decrease under our NIAID agreement relating to SPR206 and collaboration revenue related to our agreement with Pfizer for SPR206.

 

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Research and development expenses for the second quarter of 2024 were $23.7 million, compared to $9.5 million of research and development expenses for the same period in 2023. The increase in research and development expenses year-over-year was primarily due to higher direct costs related to the pivotal Phase 3 trial for tebipenem HBr and the Phase 2a clinical trial for SPR720, partially offset by lower direct expenses related to SPR206 and lower R&D personnel-related costs.

 

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General and administrative (G&A) expenses for the second quarter of 2024 were $5.5 million, compared to $6.1 million of general and administrative expenses for the same period in 2023. This year-over-year decrease was primarily due to a decrease in G&A personnel-related costs, partially offset by increases in professional and consulting fees and facility-related expenses.

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As of June 30, 2024, Spero had cash and cash equivalents of $63.5 million. Based on its current operating plans, Spero expects that its cash and cash equivalents, together with other non-dilutive funding commitments, will be sufficient to fund its operating expenses and capital expenditure requirements into late 2025.

For further details on Spero’s financials, refer to Spero’s Quarterly Report on Form 10-Q, filed with the U.S. Securities and Exchange Commission (SEC) today.

Conference Call and Live Webcast

Spero will host a conference call and live audio webcast today at 4:30 p.m. to report its second quarter 2024 financial results and provide an update on its business and pipeline. To access the call, please dial 1-877-269-7751 (domestic) or 1-201-389-0908 (international) and refer to conference ID 13747505, or click on this link and request a return call. The audio webcast can be accessed live on this link and also on the “Investor Relations” page of the Spero Corporate Website at https://sperotherapeutics.com. The archived webcast will also be available on Spero’s website for 30 days following the call.

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.

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.

Department of Defense

Select SPR206 studies have been 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.

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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; and Spero’s strategy, goals and anticipated financial performance, milestones, business plans and focus. 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, 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 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 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.

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Investor Relations Contact:

Shai Biran, PhD

Spero Therapeutics

IR@Sperotherapeutics.com

Media Inquiries:

media@sperotherapeutics.com

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Spero Therapeutics, Inc.

Condensed Consolidated Balance Sheet Data

(in thousands)

(Unaudited)

 

		June 30,				December 31,
		2024				2023
Cash, cash equivalents and marketable securities		$	63,527			$	76,333
Other assets			86,354				106,057
Total assets		$	149,881			$	182,390
Total liabilities			69,381				75,496
Total stockholder’s equity			80,500				106,894
Total liabilities and stockholders’ equity		$	149,881			$	182,390

Spero Therapeutics, Inc.

Condensed Consolidated Statements of Operations

(in thousands, except share and per share data)

(unaudited)

 

		Three Months Ended June 30,								Six Months Ended June 30,
		2024				2023				2024				2023
Revenues:
Grant revenue		$	4,180			$	1,928			$	9,243			$	3,258
Collaboration revenue—related party			5,903				519				9,967				1,036
Collaboration revenue			114				269				254				492
Total revenues			10,197				2,716				19,464				4,786
Operating expenses:
Research and development			23,725				9,510				41,057				18,489
General and administrative			5,533				6,096				11,450				13,413
Total operating expenses			29,258				15,606				52,507				31,902
Loss from operations			(19,061	)			(12,890	)			(33,043	)			(27,116	)
Other income (expense)			1,199				976				2,512				1,936
Net loss		$	(17,862	)		$	(11,914	)		$	(30,531	)		$	(25,180	)
Net loss per share attributable to common shareholders per share, basic and diluted		$	(0.33	)		$	(0.23	)		$	(0.57	)		$	(0.48	)
Weighted average shares outstanding, basic and diluted:			53,957,766				52,571,813				53,740,901				52,549,538

Exhibit 99.2 Corporate Presentation August 2024

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Forward-looking Statement This presentation contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995 regarding, among other things, the potential regulatory path forward for tebipenem HBr and 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 Company’s cash runway; the future development and commercialization of SPR206 and SPR720; the potential number of patients who could be treated by tebipenem HBr and SPR720 and market demand for tebipenem HBr and SPR720 generally; the effectiveness of tebipenem HBr and its potential impact on healthcare resource utilizations; the anticipated shift in treating patients from intravenous to oral administration; 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 the availability of data from the Company’s clinical trials; the timing of the Company’s filings with regulatory agencies; product candidate benefits; competitive position; business strategies; objectives of management; potential growth opportunities; potential market size; reimbursement matters; possible or assumed future results of operations; 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 reduce 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 and 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 challenges, 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 intellectual 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 continuing 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 Commission (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. 2

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Developing Therapies for Rare and Multi-drug Resistant Infectious Diseases Diversified clinical-stage portfolio SPR720, positioned for near-term inflection • Potential novel, oral, first-line treatment for • Indications with high unmet need in addressable non-tuberculous mycobacterial pulmonary disease patient populations (NTM-PD) • Late-stage development pipeline • Rare disease with ~245,000 diagnosed patients in • Focused on oral, small molecule drugs 1 developed markets • Orphan drug and/or QIDP designations • No approved first-line therapies • Strong global intellectual property • Proof-of-concept data anticipated in 4Q 2024 Supported by world class partnerships Partnership milestones, cash and cash equivalents, expected to provide runway into late 2025 NTM-PD: non-tuberculous mycobacterial pulmonary disease; QIDP: qualified infectious disease product 3 1.Winthrop KL, et al. Ann Am Thorac Soc 2020; 17:178-85 and Spero internal analysis.

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Maturing Pipeline with Differentiated Clinical Assets Anticipated Milestone Wholly Owned Asset Indication Preclinical Phase 1 Phase 2 Phase 3 First-line Preliminary Data SPR720 NTM-PD (4Q 2024) Partnered Assets Tebipenem HBr Complete Enrollment cUTI (2H 2025) Worldwide Rights (ex. Asia) SPR206 1 Initiate Phase 2 HABP/VABP China OUS, excl. China Spero Retains Rights in United States 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 4 1. Contingent on non-dilutive funding availability.

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SPR720

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NTM-PD: Chronic Debilitating Disease with 5-year All-cause Mortality Rate of 35% NTM Species Patient Characteristics Sign/Symptom Frequency (%) M. avium complex (80-85%) Fatigue 83 M. abscessus Cough 78 Structural lung disease M. xenopi Sputum (phlegm) 67 M. fortuitum Short of breath 65 M. kansasii Night sweats 54 Exposure to Immuno- NTM bacteria compromised M. malmoense Fever 44 (e.g. water, soil) M. simiae Hemoptysis 29 Weight loss 3.7 ± 5.2 kg Progressive Lung Damage Patients Need an Effective Oral Therapy Early in Their Disease Journey NTM: non-tuberculous mycobacteria; NTM-PD: NTM pulmonary disease 6 Marras TK, et al. Respir Med 2018; 145:80-88. Kim RD, et al. Am J Respir Crit Care Med 2008; 178:1066-74; mortality rate represents midpoint of published range.

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NTM-PD Patient Journey To Diagnosis Leads to Sub-optimal Treatment Choices Guidelines-based 1L SOC aims to reduce microbial No approved oral first-line treatment for NTM-PD patients burden measured by SCC Arikayce® currently in Phase 3 study for inhaled administration Azythromycin + Non-cavitary Ethambutol + form (~80%) Rifampin Diagnosis primarily by Pre-existing risk factors Clinical manifestations Environmental pulmonologists (mostly at lead to MAC colonization in emerge and worsen exposure to MAC specialized treatment Azythromycin + pulmonary tissue over time centers) Cavitary Ethambutol + form (~20%) Rifampin +/- IV Amikacin Lack of Effective Outcomes Safety/Intolerability • Sputum culture conversion occurs in up to 67% of • Azithromycin: QT prolongation, GI intolerability patients receiving a susceptibility-based treatment (nausea, vomiting, bloating, abdominal pain), increasing resistance • Even when culture conversion is achieved, recurrence occurs in up to 50% of patients • Ethambutol: Optic neuritis, hepatotoxicity, peripheral neuropathy • Rifampin: Hepatotoxicity, GI intolerability, immunologic reactions, drug-drug interactions Unmet Medical Need: Better Tolerability and Effectiveness, Fewer Drug-Drug Interactions, Shorter Therapy Duration 1L: first line; GI: gastrointestinal; MAC: Mycobacterium avium complex; NTM-PD: nontuberculous mycobacterial pulmonary disease; SCC: sputum culture conversion (to negative); SOC: standard of care 7 Non-Tuberculous Mycobacterial (NTM) Lung Infection Public Meeting: October 15, 2015; Report Date: April 2016. Hamed KA and Tillotson G. Expert Rev Respir Med 2023;17:973-88.

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Strong NTM-PD Patient Community Voices Unmet Therapeutic Need If your treatment could change one thing about your “Less Coughing, less shortness of NTM lung infection, what would that be? breath, less fatigue” Improved Quality of Life 97% 97% “I am most concerned with TOTAL lung health … getting this infection under control means I am less likely Increased Energy/Less Fatigue 84% 84% to have exacerbations that in turn require additional antibiotics in the Culture Conversion 72% 72% future” Reduced Coughing 53% 53% “Get rid of the bleeding, get rid of the mucous, get rid of the NTM” Improvement of Dyspnea 42% 42% 1 N=465 US patients with NTM-PD NTM: non-tuberculous mycobacteria; NTM-PD: NTM pulmonary disease 8 1. Flume PA, et al. Chest 2021; 159:537-43.

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SPR720 For Treatment-naïve and Treatment-experienced Non-refractory Patients • Diagnosed patient opportunity estimated to be ~245,000 1 across US, Europe*, and Japan • Increasing prevalence estimated at 6−10% annually in the Once diagnosed, up to 50% of patients are treated with 2 2 guidelines-based therapy US 41% continue at 6 months Europe: ~15,000 US: ~95,000 18% continue at 12 months Japan: ~135,000 11% continue at 18 months SPR720 Aims to be the Principal Foundation to a First-line SOC Combination Drug Regimen for NTM-PD *Europe refers to Germany, United Kingdom, Italy, Netherlands and France. NTM-PD: non-tuberculous mycobacterial pulmonary disease; SOC: standard of care 9 1.Winthrop KL, et al. Ann Am Thorac Soc 2020; 17:178-85 and Spero internal analysis. 2. Hamed KA and Tillotson G. Expert Rev Respir Med 2023;17:973-88.

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SPR720 Well-positioned to Address Unmet Patient Needs in First-line Setting Improve first-line SOC regimen 1 ü Potency against multiple NTM pathogens, including MAC and M. abscessus ü Novel mechanism of action for NTM-PD, with no evidence of cross resistance against 1 marketed antibiotics 2 ü Low propensity for selection of resistance ü Data support potential for efficacy, lung macrophage penetration, and safety/tolerability ü May be administered with or without food ü Composition of matter patent through 2032 ü Granted Orphan Drug, QIDP and Fast Track designations M.: Mycobacterium; MAC: Mycobacterium avium complex; NTM: non-tuberculous mycobacteria; SOC: standard of care; QIDP: qualified infectious disease product 10 1. Brown-Elliott BA, et al. Antimicrob Agents Chemother. 2018; 62:e01503-18. 2. Aragaw WW, et al. Microbiol Spectr 2022;10:e0132121.

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SPR720 is an Aminobenzimidazole, a Novel Pharmacophore • Oral, small molecule Gyrase B inhibitor • Novel mechanism of action for NTM-PD, not Oral exploited by current antibiotics absorption • No cross resistance to current SOC agents • Low propensity for selection of resistance • Penetrates lung macrophages • Differentiated advantages • In vitro: Activity against MAC, MAB and other NTM species including macrolide-resistant MAC • In vivo: Reduction of MAC pulmonary burden, best when combined with SOC agents Active moiety Phosphate ester prodrug 11

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Novel Mechanism of Action Not Exploited by Existing Antibiotics for NTM-PD • SPR719, active moiety of SPR720 pro-drug, inhibits ATPase activity of bacterial DNA gyrase B • DNA gyrase B is distinct from gyrase A, the target of fluoroquinolones • Blocks introduction of negative supercoils in DNA and traps chromosome in a positively charged state that impacts cell physiology and division • Inhibits bacterial DNA synthesis resulting in death of bacterial cell GyrB inhibitors ATPase 2 ATP GyrB TOPRIM GyrA fluoroquinolones ATPase: F0F1-ATP Synthase; TOPRIM: Topoisomerase-primase domain 12 Winthrop KL, et al. Expert Rev Anti Infect Ther 2023; 21:1177-87.

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In vitro Data Demonstrate Potent Activity Against Range of NTM Species NTM Species N SPR719 MIC (mg/L) Amikacin MIC (mg/L) 90 90 M. avium complex 41 2 32 M. abscessus subsp. abscessus 30 4 16 M. abscessus subsp. massiliense 10 2 16 M. chelonae 10 4 32 M. fortuitum group 10 1 ≤1 M. immunogenum 10 8 16 M. simiae 10 2 16 MIC : minimum inhibitory concentration at which 90% of isolates were inhibited; NTM: non-tuberculous mycobacteria; SPR719 is the active moiety of the prodrug SPR720 and is used for in vitro testing. 90 13 Brown-Elliott BA, et al. Antimicrob Agents Chemother 2018; 62:e01503-18.SPR720, Investigator Brochure Edition 5; 07Apr2022.

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In Vivo Data Demonstrate Increased Potency When Combined with SOC SPR720 as monotherapy and in combination with SOC agents • SPR720 monotherapy activity and dose response • Improved efficacy of current SOC combination regimen BID: twice daily; CFU: colony forming units; CLR: clarithromycin; EMB: ethambutol; SOC: standard of care; QD: once daily 14 Cotroneo N, et al. J Antimicrob Chemother 2024; doi: 10.1093/jac/dkae046. Online ahead of print. Untreated

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Phase 1 SAD/MAD: Dose Response Observed With No Evidence Of Food Effect Mean plasma concentration-time curves following single ascending dosing (SAD) of SPR720 MAD: multiple ascending dose; SAD: single ascending dose 15 Talley AK, et al. Antimicrob Agents Chemother 2021; 65:e0120821.

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Phase 1 SAD/MAD Study in 96 HV: Favorable Safety/Tolerability Profile • SAD (100 to 2000 mg) • MAD evaluated over 7 days (500 and 1000 mg) and over 14 days (500, 1000 and 1500 mg) • Dose-dependent increase in plasma exposure observed • No SAEs reported; generally well tolerated at doses up to 1000 mg • One discontinuation of study drug at 1500 mg dose: Grade 2 pancreatic enzyme elevation that was asymptomatic, monitorable and reversible SPR720 is Generally Well-tolerated with Predicted Therapeutic Exposures Attainable with 500 to 1000 mg HV: Healthy Volunteers; GI: gastrointestinal; MAD: multiple ascending dose; SAD: single ascending dose; SAE: serious adverse event 16 Talley AK, et al. Antimicrob Agents Chemother 2021; 65:e0120821.

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Phase 2a Designed to Achieve Proof-of-Concept Study SPR720-202 (NCT05496374): Phase 2a study in NTM-PD A Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of SPR720, as Compared With Placebo for the Treatment of Participants With Mycobacterium avium Complex (MAC) Pulmonary Disease Treatment Population Five Treatment Arms Endpoints Primary Endpoint: Placebo patients 1. The rate of change in log Colony Forming Units randomized 10 SPR720 (500 mg) 1:1:1 per milliliter (CFU/ml) Treatment-naïve/experienced (non-refractory) (blinded) SPR720 (1000 mg) patients with NTM due to M. avium complex Secondary Endpoints: 1. The rate of change in time to positivity (TTP) 25 patients enrolled SPR720 (1000 mg) Intense PK sub-study 56 Days of Dosing 2. Safety & tolerability (open label) SPR720 (500 mg BID) 3. Plasma PK 17 BID: twice daily; MAC: Mycobacterium avium complex; NTM-PD: non-tuberculous mycobacterial pulmonary disease; PK: pharmacokinetics

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Comprehensive Data Set Anticipated in 4Q 2024 We anticipate a robust dataset to inform the registrational path for SPR720 as first-line therapy for NTM-PD • Microbiological response to demonstrate anti-NTM activity in patients • PK in patients • Intrapulmonary PK from bronchoalveolar lavage (BAL) study, in healthy volunteers • Determine PK of co-administered SPR720, azithromycin and ethambutol in healthy volunteers • Expand safety/tolerability profile demonstrated in prior studies 18 BAL: bronchoalveolar lavage; NTM: non-tuberculous mycobacteria; NTM-PD: NTM pulmonary disease; PK: pharmacokinetics

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SPR720 Well Positioned to Become the Foundation of First-line NTM-PD Therapy SPR720 Epatraborole Arikayce MNKD101 * Key Attribute SPRO ANTX INSM MNKD Novel MOA✓✓ X X 1 Low Propensity for Resistance✓ X✓ ? 2 3 MAC MIC ≤2 mg/L✓ X X✓ 90 Macrolide-Resistant MAC Activity✓ ?✓✓ Oral Administration✓✓ X X No Food Effect✓✓ N/A N/A * The above table describes features of different first-line, pre-commercial, NTM-PD therapies and is based on publicly available data. It does not represent the results of head-to-head comparison studies. MOA: mechanism of action; MAC: Mycobacterium avium complex; MIC: minimum inhibitory concentration; MIC : MIC at which 90% of isolates were inhibited; N/A: not applicable 90 19 1. O'Dwyer K. et al. Antimicrob Agents Chemother 2015; 59:289-98. 2.White TK et al. Open Forum Infect Dis 2023;10(Suppl 2):ofad500.1758. 3.Brown-Elliott BA, et al. Antimicrob Agents Chemother 2018; 62:e01503-18.

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Tebipenem HBr Oral Carbapenem

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cUTI Patients Often Cycle through Multiple Therapies Lack of effective oral treatment options has resulted in increased… • Outpatient visits st 1 line Oral • Emergency department visits • Unwarranted outpatient IV use • Unnecessary hospitalizations • Hospital days nd IV 2 line Oral • Home health and long-term care stays Carbapenem (Resistant/Failed) Piperacillin/ post-hospitalization tazobactam Tebipenem Focus: cUTI • Annual cUTI treatment episodes estimated IV Therapy/ nd 2 + line 1 to be 3.4M rd 3 line Oral Oral (Resistant/ (Resistant/Failed) Failed) IV: intravenous; tebipenem HBr: tebipenem pivoxil hydrobromide (formerly SPR994); UTI: urinary tract infection 21 1. GSK Epidemiology data - fy-2023-epidemiology-report.xlsx (live.com)

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Tebipenem HBr: Potentially Differentiated Oral Therapy for cUTI, if Approved Potential first-to-market Global commercial Phase 3 enrolling oral carbapenem partnership • Out-licensed global • PIVOT-PO trial protocol • Potential treatment of commercial rights (except approved under FDA Special complicated UTI in the Japan and certain other Asian Protocol Assessment (SPA) outpatient setting countries) to GSK • Enrollment began with “First • Broad prescriber base beyond • Robust financial terms Patient, First Dose” in Q4 2023 infectious disease specialists including potential • Robust IP through 2038 developmental, regulatory, and commercial milestones, • QIDP designation as well as tiered sales royalties IP: intellectual property; tebipenem HBr: tebipenem pivoxil hydrobromide (formerly SPR994); QIDP: qualified infectious disease product; SPA: Special Protocol Assessment (by FDA); UTI: urinary tract infection 22

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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 Two Treatment Arms Endpoints 1. TBP-PI-HBR (600 mg) orally and “dummy” Primary Endpoint: Patients with a diagnosis of cUTI or AP infusion IV, every 6 hours, days 1-10 (n=1324) 1. Overall response at TOC in micro-ITT population Approximately 2648 patients 2. Imipenem-cilastatin (500 mg) IV and matched Primary Analysis: (Stratified by age, baseline diagnosis, etc.) 7-10 Days of Dosing “dummy” tablets, orally every 6 hours, days 1-10, 1. Assessment of non-inferiority (NI) in micro-ITT (n=1324) population, based on a 10% NI margin Negotiated FDA Special Protocol Assessment Agreement (SPA): The FDA has indicated that positive and persuasive results from PIVOT-PO, along with previously completed studies, could be sufficient to support approval of tebipenem HBr as a treatment for cUTI, including pyelonephritis, for a limited use indication 23 AP: acute pyelonephritis; cUTI: complicated urinary tract infection; NI: non-inferiority; TBP-PI-HBr/tebipenem HBr: tebipenem pivoxil hydrobromide (formerly SPR994)

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Exclusive License Agreement with GSK for Tebipenem HBr and Equity Investment Global Collaboration (ex-Asia) • GSK received exclusive license to obtain regulatory approval and commercialize tebipenem HBr in all territories, except Japan and certain other Asian countries (Meiji Seika Territories) • Spero is responsible for execution and costs of the tebipenem HBr Phase 3 in the United States • GSK is responsible for the execution and costs of commercial activities for tebipenem HBr in the United States, as well as all development and commercial activities in territories outside of United States (not including Meiji Seika Territories) • Transaction closed November 7, 2022 Financial Terms ü Received $66 Million upfront and $9 Million in common stock investment ü Received $30 Million upon SPA agreement with the FDA ü Upon FPFD, Spero qualified to receive $95 Million in development milestones payable in equal installments over two years • Spero eligible to receive up to $400 Million in additional potential regulatory, commercial and sales milestone payments • $25 Million to be paid upon GSK’s submission of tebipenem HBr’s New Drug Application (NDA) • Up to $150 million in potential commercial milestones based on first commercial sales (US/EU) • Up to $225 million in sales related milestone payments • Spero to receive tiered low-single digit to low-double digit (if sales exceed $1billion) tiered royalties on net product sales FPFD: first patient first dose. SPA: Special Protocol Assessment 24

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SPR206 Direct Acting IV Potentiator

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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 • 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 1 2 3 Studies Phase 1 Trial Lavage Phase 1 Trial Phase 1 Trial Supportive of renal dosing in Support increased efficacy beyond No evidence of Well-tolerated and achieved lung subsequent trials for patients impacted traditional antibiotics and potential nephrotoxicity at predicted exposures consistent with predicted by differences in renal function for single agent activity therapeutic dose levels therapeutic levels ✓✓ ✓ ✓ 4 Next Steps: Phase 2 HABP/VABP Proof of Concept Study SPR206 has Potential to Fulfill Unmet Need for a Well Tolerated, Efficacious Single-Agent 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; 26 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.

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Leadership Team Esther Rajavelu Sath Shukla Chief Financial Officer President and Chief Executive Officer Chief Business Officer • Prior CFO at Spero Therapeutics; Prior CFO at Ziopharm Oncology; VP • Over two decades of life science sector and Global Head of Corporate experience, combining equities Finance at Vertex research, investment banking, strategy • Over 20 years of financial consulting, and M&A. leadership, executing within • Prior CFO at Fulcrum Therapeutics. commercial and clinical companies Senior equity research analyst at UBS, Oppenheimer and Deutsche Bank. Healthcare Investment Banker at Bank of America. Timothy Keutzer James Brady Chief Operating Officer Chief Human Resource Officer • Previously, Spero’s Chief Development • Prior CHRO at uniQure Therapeutics; Officer Vice President, Human Resources at Intarcia Therapeutics • Prior VP Program and Portfolio Management, Cubist • Over 30 years of senior human resources leadership with over 17 • Extensive antibiotic development years in the life science space experience from pre-clinical to approval • Over 30 years in the pharmaceutical industry *Trademarks are properties of their respective owners 27

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Thank You

v3.24.2.u1

Document and Entity Information	Aug. 05, 2024
Cover [Abstract]
Amendment Flag	false
Entity Central Index Key	0001701108
Document Type	8-K
Document Period End Date	Aug. 05, 2024
Entity Registrant Name	SPERO THERAPEUTICS, INC.
Entity Incorporation State Country Code	DE
Entity File Number	001-38266
Entity Tax Identification Number	46-4590683
Entity Address, Address Line One	675 Massachusetts Avenue
Entity Address, Address Line Two	14th Floor
Entity Address, City or Town	Cambridge
Entity Address, State or Province	MA
Entity Address, Postal Zip Code	02139
City Area Code	(857)
Local Phone Number	242-1600
Written Communications	false
Soliciting Material	false
Pre Commencement Tender Offer	false
Pre Commencement Issuer Tender Offer	false
Security 12b Title	Common Stock, $0.001 par value
Trading Symbol	SPRO
Security Exchange Name	NASDAQ
Entity Emerging Growth Company	false

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