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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 future development and commercialization of SPR720 and SPR206; the potential number of patients who could be treated by SPR 720 and
tebipenem HBr and market demand for SPR720 and 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 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; 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 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
Developing Therapies for Rare and Multi-drug Resistant Infectious
Diseases Diversified clinical stage portfolio SPR720, positioned for near-term inflection Indications with high unmet need in addressable Potential novel, oral, first-line treatment for non- patient populations tuberculous mycobacterial pulmonary
disease (NTM-PD) Late-stage development pipeline Rare disease with ~245,000 diagnosed patients in 1 developed markets Focused on oral, small molecule drugs No first-line therapies approved Orphan drug and/or QIDP designations Proof-of-concept data
anticipated in 4Q 2024 Strong global intellectual property Supported by world class partnerships Partnership milestones, cash and cash equivalents are 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.
Maturing Pipeline with Differentiated Clinical Assets Asset Indication
Preclinical Phase 1 Phase 2 Phase 3 Anticipated Milestone Wholly Owned SPR720 First-line Preliminary Data NTM-PD (4Q 2024) Partnered Assets Tebipenem HBr Complete Enrollment cUTI (2H 2025) Worldwide Rights (ex. Asia) SPR206 1 HABP/VABP Initiate
Phase 2 China OUS, ex. 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.
SPR720 Oral Antibiotic for Non-Tuberculosis Mycobacterium Pulmonary
NTM-PD: Chronic Debilitating Disease with Significant Patient Burden
Patient with existing structural lung damage Exposure to NTM species Presentation of signs and symptoms of NTM-PD 1 2 3 and/or immunocompromised status Fatigue 83% Cough 78% Select pre-existing indications M. avium complex (80-85%)* include: Sputum
(phlegm) 67% Short of breath 65% Additional species, including M. abscessus Bronchiectasis Night sweats 54% Fever 44% COPD Hemoptysis 29% Cystic fibrosis Weight loss 3.7 5.2 kg Worsening of lung damage First-line treatment options include
6-12 4 5 High-Resolution CT Scans (HRCT) Confirms NTM-PD diagnosis and severity months (or more) on a combination of antibiotics, including a macrolide Drug-resistance &/or exacerbations 6 eventually leads to 5-yr all-cause 1,2 mortality rate of
~35% NTM: non-tuberculous mycobacteria; NTM-PD: NTM pulmonary disease; *SPR720 is being developed for MAC NTM-PD. 6 1. Marras TK, et al. Respir Med 2018; 145:80-88. 2. Kim RD, et al. Am J Respir Crit Care Med 2008; 178:1066-74; mortality rate
represents midpoint of published range.
High Unmet Need in First-Line Patients With Long Treatment Duration, and
Lack of Efficacy and Tolerability from Current Treatment Options Rare Disease with High Unmet Need ~245,000 diagnosed Chronic condition ~35% Five-year all- patients in developed requiring long- 2 cause mortality rate 1 markets term treatment Current
SOC Treatments Have Severe Limitations Poor outcomes driven Safety & tolerability ~50% of treated by emergence of concerns & high rate patients experience 3 resistance of treatment drop-offs infection recurrence No Approved First-Line
Treatment Off-label use of No other oral agent Inhaled amikacin in Azithromycin in clinical Ethambutol Phase 3 trial development Rifampin Inhaled amikacin approved for refractory (2L) patients; 1.Winthrop KL, et al. Ann Am
Thorac Soc 2020; 17:178-85 and Spero internal analysis. 2.Kim RD, et al. Am J Respir Crit Care Med 2008; 178:1066-74; 7 mortality rate represents midpoint of published range 3. Hamed KA and Tillotson G. Expert Rev Respir Med
SPR720, An Oral, Small Molecule Gyrase B Inhibitor in Development to
Address Unmet Patient Need in First-line Setting Oral Potency against multiple NTM pathogens, such as MAC absorption 1 (including macrolide-resistant MAC) and M. abscessus Novel mechanism of action for NTM-PD not exploited by current antibiotics 1
No evidence of cross resistance against marketed antibiotics 2 Low propensity for selection of resistance Data support potential for efficacy, lung macrophage penetration, and safety/tolerability May be administered with or without food Composition
of matter patent into 2032 Active moiety Phosphate ester prodrug 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 8 1. Brown-Elliott BA, et al. Antimicrob Agents Chemother. 2018; 62:e01503-18. 2. Aragaw WW, et al. Microbiol Spectr 2022;10:e0132121.
SPR720's Novel Mechanism of Action Not Exploited by Existing Antibiotics
for NTM-PD SPR720/719 targets DNA gyrase (GyrB subunit), Azithromycin (AZM) disrupts ribosomal Ethambutol (EMB) disrupts 1 2 3 a critical enzyme for DNA replication and RNA activity; AZM blocks passage of growing Arabinogalactan formation, a
critical 1 transcription peptide & RNA through ribosome cell wall component Arabinosyl DNA replication DNA gyrase transferase Peptide Ribosome mRNA transcription AZM ethambutol SPR720/719 Arabinose Arabinogalactan Cell wall production DNA
replication Translation 1 2 3 and integrity and transcription mRNA Ribosomes Arabinogalactan Critical component of mycobacterial cell walls Novel target and differentiated MOA potentially position SPR720 to improve current SOC regimen 1. Winthrop
KL, et al. Expert Rev Anti Infect Ther 2023; 21:1177-87. 9
SPR719 Inhibits Growth of MAC Isolates at Lower Concentrations (MICs)
than SOC Agents in vitro MIC 90% MAC organism (n) Agent ( g/mL) SPR719 2 Amikacin 64 Low MIC values for SPR719 M. avium (12) Clarithromycin 8 90 suggest consistent activity Linezolid 64 against most clinically Moxifloxacin 8 important NTM
species SPR719 2 Amikacin >64 Low variability in MIC values 90 M. intracellulare (19) Clarithromycin >64 across species support thesis Linezolid 64 that SPR719 has a novel mechanism with minimal Moxifloxacin 8 pre-existing drug resistance
SPR719 1 Amikacin 32 MAC-X (10) Clarithromycin 4 Linezolid 64 Moxifloxacin >8 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 10 Brown-Elliott BA, et al. Antimicrob Agents Chemother 2018; 62:e01503-18. SPR720, Investigator Brochure Edition 5; 07Apr2022, on file with Spero
In Vivo Murine Data Demonstrate Increased Potency When Combined with
SOC Agents SPR720 as monotherapy and in combination with SOC agents SPR720 active as monotherapy with evidence of dose response Demonstrates improved efficacy when used in combination with SOC agents BID: twice daily; CFU: colony
forming units; CLR: clarithromycin; EMB: ethambutol; SOC: standard of care; QD: once daily 11 Cotroneo N, et al. J Antimicrob Chemother 2024; doi: 10.1093/jac/dkae046. Online ahead of print.
Phase 1 SAD/MAD Study in 96 HV: Favorable Safety/Tolerability Profile
SAD (100 to 2000 mg) MAD evaluated over 7 days (500, 1000 and 1500 mg) and over 14 days (500 and 1000 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 12 Talley AK, et al. Antimicrob Agents Chemother 2021; 65:e0120821.
SPR720 Plasma Concentration Increases with Dose Escalation; No
Clinically Significant Food Effect Observed Phase 1 SAD/MAD study Mean plasma concentration-time curves following single ascending dosing (SAD) of SPR720 SAD: single ascending dose. N=6 per group 13 Talley AK, et al. Antimicrob Agents Chemother
SPR720 Aims to be the Foundation of First-line Combination Regimen for
NTM-PD Therapeutic Landscape Challenges SPR720 Differentiation No approved oral therapy for newly SPR720 is the only oral agent in clinical diagnosed symptomatic patients, the development for first-line treatment of NTM- majority
with MAC infections PD patients infected with MAC Regimen tolerability Dosing to date support a tolerable profile Emergence of resistance even with SPR720 in vitro data suggest low evidence combination therapy of
emergence of resistance when used in combination with current oral SOC agents Limited efficacy in current SOC 14
Areas of Ongoing Focus for SPR720 Clinical Development Question Study
Phase 2a PoC study intended to determine Does SPR720 reduce MAC bacterial burden and SPR720 monotherapy activity in st demonstrate tolerability in 1 line patients? MAC infected patients Does SPR719 (active moiety of SPR720) get to Phase 1
HV BAL study to understand exposure the site of infection? in lung Phase 1 HV and HFIM SOC combo studies to Does SPR720 exposure change when co- explore potential for therapeutic effectiveness administered with primary SOC agents?
when used with AZM and EMB Does SPR720 provide a better resistance In vitro studies to evaluate resistance profile profile when used with SOC agents? HV: Healthy volunteers; BAL: Bronchoalveolar lavage; HFIM: Hollow fiber infection model;
Phase 2a Designed to Achieve SPR720 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 patients with mycobacterium avium complex (MAC) pulmonary
disease Endpoints Treatment Population Treatment Groups Primary Endpoint: Placebo 1. The rate of change in log 10 Treatment-na ve/ SPR720 (500 mg) R Colony Forming Units per experienced (non- patients milliliter (CFU/ml) SPR720 (1000 mg)
refractory) patients with randomized 1:1:1 NTM due to M. avium Secondary Endpoints: (blinded) complex 1. The rate of change in time SPR720 (1000 mg) to positivity (TTP) 25 patients enrolled Intense PK SPR720 (500 mg BID) 2. Safety & tolerability
56 Days of Dosing sub-study (open label) 3. Plasma PK BID: twice daily; MAC: Mycobacterium avium complex; NTM-PD: non-tuberculous mycobacterial pulmonary disease; PK: pharmacokinetics 16
Phase 2a Focused on Non-refractory Patients Future indication SPR720 is
currently being developed for treatment-na ve and expansion possibility in treatment-experienced non-refractory patients with MAC infection refractory NTM-PD Treatment-experienced Treatment-na ve Refractory non-refractory Never
received SOC multidrug Received SOC multidrug Received multidrug SOC treatment for NTM-PD treatment for NTM-PD and treatment for NTM-PD, but successfully converted cultures after 6 months of therapy, to negative fail to convert cultures to negative
Culture conversion defined as: 3 consecutive lower respiratory cultures, obtained 1 month apart, negative for acid-fast bacilli (AFB) SOC: Standard-Of-Care 17 17
SPR720 Efficacy Will be Evaluated via CFU and TTP Assays 3-4 wk
incubation Decreasing values indicate lowering of NTM burden Diluted sputum inoculated Visually count colonies Time of sample collection on culture plate Sputum Increasing values indicate lowering Assay device incubates and of NTM burden detects
growth Time of sample collection Diluted sputum inoculated Assay device automatically in liquid medium records time to positive growth signal 18 Danho, Rabi et al., CHEST, Volume 161, Issue 2, 370 - 372 Time to positive signal # of
Spero Plans to Share a Comprehensive Dataset in the Fourth Quarter
Question Study We hope to see 1) Numerical difference in key Does SPR720 reduce NTM bacterial Phase 2a PoC study to determine quantitative bacterial burden metrics burden and demonstrate tolerability SPR720 monotherapy activity st
in 1 line patients? in MAC infected patients 2) A well tolerated dosing regimen Higher concentration of active drug in Does SPR719 (active moiety of Phase 1 HV BAL Study to understand epithelial lining fluid and alveolar SPR720) get
to the site of infection? exposure potential in lung macrophages compared to plasma Phase 1 HV and HFIM SOC combo Consistent SPR719 plasma PK when Does SPR720 exposure change when studies to explore potential for co-administered with primary SOC
SPR720 is administered as a monotherapy therapeutic effectiveness when agents? vs in combination with SOC agents used with AZM and EMB 1) Low SMF values for SPR719 Does SPR720 provide a better In vitro resistance study to
monotherapy resistance profile when used with demonstrate lack of resistance 2) Ability of SPR719 to suppress SOC agents? development resistance to SOC drugs SMF: spontaneous mutation frequency; HV: Healthy volunteers; BAL:
Bronchoalveolar lavage; HFIM: Hollow fiber infection model; 19
Tebipenem HBr Oral Carbapenem
cUTI Patients Often Cycle through Multiple Therapies Tebipenem, in
development to offer an Lack of effective oral treatment options has resulted in increased - oral alternative to cUTI patients nd Outpatient visits 2 line Oral (Resistant/ Emergency department visits Failed) Unwarranted