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No Image No Image Corporate Presentation January 2026 © 2026 Upstream Bio, Inc.
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No Image No Image No Image No Image This presentation contains forward-looking statements of Upstream Bio, Inc. (“Upstream,” “the Company,” “we,” “us,” or “our”) that involve substantial risks and uncertainties. All statements other than statements of historical facts contained in this presentation, including statements regarding our future financial condition, results of operations, business strategy and plans, and objectives of management for future operations, as well as statements regarding industry trends, are forward -looking statements. In some cases, you can identify forward-looking statements by terminology such as “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potentially” “predict,” “should,” “will” or the negative of these terms or other similar expressions. We have based these forward-looking statements largely on our current expectations and projections about future events and trends that we believe may affect our financial condition, results of operations, business strategy and financial needs. These forward-looking statements are subject to a number of risks, uncertainties and assumptions, including, among other things: the initiation, timing, progress, and results of our planned and future clinical trials for verekitug, including our clinical trials in severe asthma, chronic rhinosinusitis with nasal polyps, and chronic obstructive pulmonary disease; our ability to replicate positive results from earlier preclinical studies or clinical trials conducted by us or third parties in current or future clinical trials; our ability to demonstrate that verekitug and any potential future product candidates are safe and effective for their proposed indications and our expectations around their beneficial characteristics and therapeutic effects; our ability to advance verekitug and any potential future product candidates through applicable regulatory approval processes, including timing of Investigati onal New Drug applications and final U.S. Food and Drug Administration approval of verekitug or any future product candidate; our estimates of the number of patients that we will enroll and our ability to initiate, recruit and enroll patients in and conduct and successfully complete our clinical trials at the pace we project; the i mplementation of our business model and strategic plans; our ability to rely on third-party manufacturers and successfully manufacture verekitug for preclinical use, for clinical trials and on a larger scale for commercial use, if approved; our ability to commercialize verekitug, if approved, and obtain favorable pricing and reimbursement; the size and growth potential of the markets for verekitug and our ability to serve those markets; our ability to realize the benefits of collaborations for the development and commercialization of verekitug or any other potential future product candidates; our ability to maintain, expand and protect our intellectual property; developments relating to our competitors and our industry; existing regulations and regulatory developments in the United States and other jurisdictions; general economic, industry, and market conditions, including interest rates, tariffs and inflation; our ability to attract, hire, and retain our key personnel and additional qualified personnel; our anticipated use of our existing cash, cash equivalents and short-term investments; our estimates regarding expenses, future revenue, capital requirements, and needs for additional financing; and those risks and uncertainties identified in our filings with the Securities and Exchange Commission. These risks are not exhaustive. New risk factors emerge f rom time to time, and it is not possible for our management to predict all risk factors, nor can we assess the impact of all factors on our business or the extent to which any factor, or c ombination of factors, may cause actual results to differ materially from those contained in, or implied by, any forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements. Except as required by law, we undertake no obligation to update publicly any forward-looking statements for any reason after the date of this presentation. Market data and industry information used throughout this presentation are based on management's knowledge of the industry and t he good faith estimates of management. Certain information contained in this presentation and statements made orally during this presentation relate to or are based on studies, publica tions, surveys and other data obtained from third-party sources and our own internal estimates and research. While we believe these third-party studies, publications, surveys and other data to be reliable as of the date of this presentation, we have not independently verified, and make no representations as to the adequacy, fairness, accuracy or completeness of, any informatio n obtained from third-party sources. In addition, no independent source has evaluated the reasonableness or accuracy of our internal estimates or research, and no reliance should be made on any information or statements made in this presentation relating to or based on such internal estimates and research. Tradenames, trademarks and service marks of other companies appearing in this presentation are the property of their respecti ve owners. Solely for convenience, the trademarks and tradenames referred to in this presentation appear without the ® and symbols, but those references are not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable law, our rights, or the right of the applicable licensor, to these trademarks and tradenames. Disclaimer 2 © 2026 Upstream Bio, Inc.
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No Image No Image No Image No Image About Upstream Bio 3 © 2026 Upstream Bio, Inc. Clinical-stage immunology company focused on severe respiratory diseases Developing only known clinical-stage antagonist of the TSLP receptor → Verekitug’s pharmacology is unique and characterized by rapid, complete and sustained occupancy of the TSLP receptor, for up to 24 weeks after the last dose Studying verekitug across multiple indications with high unmet need → VIBRANT, our phase 2 trial in CRSwNP, now complete and reported top-line results in September 2025 → VALIANT, our phase 2 trial in severe asthma, on track to report top-line results in Q1 2026 VALOUR, our open-label extension study, is currently enrolling eligible participants who have completed VALIANT → VENTURE, our phase 2 trial in COPD, currently enrolling → All trials randomized and placebo-controlled, with registrational endpoints → TSLP biology supports expansion into other therapeutic areas, including dermatology and GI Addressing significant commercial opportunities → Asthma and COPD markets are expanding and expected to drive a $35B+ global biologics market by mid-2030s Existing capital expected to fund planned operations through 2027 TSLP - thymic stromal lymphopoietin; CRSwNP - chronic rhinosinusitis with nasal polyps; COPD - chronic obstructive pulmonary disease.
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No Image No Image No Image No Image Leadership team Deep experience and complementary areas of expertise 4 All trademarks are property of their respective owners EXECUTIVE TEAM Aaron Deykin, MD Chief Medical Officer & Head of R&D Rand Sutherland, MD Chief Executive Officer Mike Gray Chief Financial Officer & Chief Operating Officer Adam Houghton, PhD Chief Business Officer Allison Ambrose General Counsel Lisa Fiering SVP, People & Culture Stacy Price Chief Technology Officer © 2026 Upstream Bio, Inc.
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No Image No Image No Image No Image → Verekitug is the only known clinical-stage antagonist targeting the TSLP receptor – Fully-human IgG1 antibody, discovered by Astellas/Regeneron and acquired by Upstream Bio → Phase 1 clinical trials have demonstrated a differentiated profile – Complete and sustained occupancy of the TSLP receptor, for up to 24 weeks after last dose – High-potency antagonism of TSLP signaling as reflected by differentiated suppression of disease-associated biomarkers exhaled nitric oxide (FENO) and eosinophils in patients with asthma → Pharmacology enables: – Extended interval dosing with evaluation of every 12-week and every 24-week dosing in ongoing Phase 2 trials – Potential for enhanced efficacy relative to TSLP ligand-targeting approaches → Phase 2 trial of verekitug in CRSwNP delivered clinical activity meeting or exceeding that of other approved biologics at 24 weeks, with less-frequent Q12W dosing About verekitug © 2026 Upstream Bio, Inc. 5 FENO – fractional exhaled nitric oxide 1. Verstraete et al, Nat Commun, (2017). 2. Numazaki et al, J Pharmacol Exp Ther, (2022). 3. Chowdhury et al, ERS presentation, (2025). Mechanism of verekitug inhibition of TSLP signaling1,2,3
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No Image No Image No Image No Image FENO: Fractional Exhaled Nitric Oxide 1 100 mg dose data from MAD study; 2Astrazeneca AB, Tezspire (tezepelumab-ekko) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761224s003lbl.pdf; 3Regeneron Pharmaceuticals, Dupixent (dupilumab) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761055s059lbl.pdf; 4Multidisciplinary review of Dupixent in moderate-to-severe eosinophilic asthma. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/761055Orig1s007.pdf;5Glaxosmithkline LLC, Nucala (mepolizumab) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125526Orig1s021,761122Orig1s011Corrected_lbl.pdf;6Ramonelle. Ann Allergy Asthma Immunol. 2021 January ; 126(1): 102–104. © 2026 Upstream Bio, Inc. Asthma MAD data provide proof of concept, support differentiated profile 6 Attribute Verekitug Tezepelumab Dupilumab Mepolizumab Target TSLP Receptor TSLP Ligand IL-4/-13 Receptor IL-5 Ligand Dosing Interval 12, 24 weeks 4 weeks2 2 weeks3 4 weeks5 Injection Volume 0.5 mL (100 mg) 2.0 mL (400 mg) 1.91 mL2 2 mL3 1 mL5 Effect on FENO ↓54%1 ↓~25%2 ↓~27%4 No effect6 Effect on Eosinophils ↓54%1 ↓~45%2 ↑~30%4 ↓84%5 Biomarker – restricted population Not anticipated No2 Yes; eosinophilic phenotype or CS resistant asthma 3 Yes; eosinophilic phenotype 5 Information for approved products based on FDA-approved labeling and publicly available data; head-to-head clinical studies have not been conducted. Differences exist between trial designs and subject characteristics, and caution should be exercised when comparing data across studies.
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No Image No Image No Image No Image Top-line results for Phase 2 VIBRANT study of verekitug in CRSwNP Study drug dosed every 12 weeks, treatment period 24 weeks © 2026 Upstream Bio, Inc. 7 Generally well tolerated, no SAEs observed Observed clinical benefit at 12-week dosing interval supports potential utility in severe asthma and other Type 2 inflammatory diseases Met primary endpoint, with NPS reduction of -1.8 (p<0.0001) Met key secondary endpoints, including NCS reduction of -0.8 (p=0.0003*) and 76% reduction in need for surgery/steroids (p=0.03*) Phase 2 VIBRANT 100 mg Q12W vs placebo *Nominal p values NPS - Nasal Polyp Score; NCS - Nasal Congestion Score; Q12W - every 12 weeks; SAEs - serious adverse events.
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No Image Targeting TSLP receptor with verekitug: Severe Asthma, CRSwNP and COPD © 2026 Upstream Bio, Inc.
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No Image No Image No Image No Image Verekitug blocks TSLP receptor assembly and potently reduces TSLP-driven inflammation → Inhibition of TSLP signaling reduces type 2 and non-type 2 inflammation, as well as fibrotic responses → Verekitug blocks the formation of the heterodimeric TSLP receptor and reduces key disease-associated biomarkers → Verekitug's potency is approximately 300-fold greater than that of tezepelumab → Upstream Bio's clinical programs are designed to evaluate the impact of verekitug's high potency on both dosing interval and efficacy in CRSwNP, severe asthma and COPD TSLP TSLP TSLP © 2026 Upstream Bio, Inc. 9
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No Image No Image No Image No Image 10 In Severe Asthma, TSLP is a key driver of exacerbations and decline in lung function → Severe asthma is a chronic inflammatory disease marked by persistent airflow obstruction, recurrent exacerbations, and symptoms that remain uncontrolled despite high-intensity treatment 1 → Uncontrolled asthma is associated with substantial morbidity and mortality 2,3 → TSLP is a key driver of asthma airway inflammation and a clinically validated therapeutic target in severe asthma 4,5 → Biologic treatment remains underutilized among eligible patients, highlighting meaningful growth potential → The global market for biologics in severe asthma is forecast to be >$12B by 2032 6 1 www.lung.org/lung-health-diseases/lung-disease-lookup/asthma/learn-about-asthma/types/severe-asthma. 2 Qin et al, J. Asthma (2021). 3 https://www.cdc.gov/asthma/most_recent_national_asthma_data.htm. 4 Roan et al J Leukoc Biol, (2012). 5 Panettieri J Asthma Allergy, (2024). 6 Datamonitor © 2026 Upstream Bio, Inc. FIGURE: https://www.britannica.com/science/asthma
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No Image No Image No Image No Image In CRSwNP, TSLP fuels chronic inflammation driving polyp growth and sinus obstruction → CRSwNP is a chronic inflammatory disease of the upper airway, marked by nasal and sinus inflammation and the presence of nasal polyps → Severe disease significantly impacts quality of life, often necessitating surgery and systemic steroid therapy 1 → TSLP is a key driver of inflammation in CRSwNP → Up to 70% of patients will have comorbid asthma2 → Current biologics sales in CRSwNP alone estimated to exceed $1.5B globally3,4 1. Bachert et al J Asthma Allergy, (2021). 2. Bachert et al J Allergy Clin Immunol Pract, (2023). 3. Symphony Claims Data (June ’24 – May ’25). 4. Manufacturer Sales and Pricing Disclosures. © 2026 Upstream Bio, Inc. 11 FIGURE: Mayo Clinic. (2025).
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No Image No Image → COPD is a progressive lung disease characterized by persistent airflow limitation and chronic inflammation of the airways → COPD, resulting in shortness of breath and frequent exacerbations, is the 4th leading cause of death worldwide 1 and affects over 391 million people2 → Translational and clinical data highlight TSLP as a key mediator of inflammation and exacerbations in COPD and suggest disrupting TSLP signaling may be a promising therapeutic approach 3,4,5 → No biologic targeting upstream mediators of inflammation approved for COPD treatment → The global market for biologics in COPD is forecast to be approximately $23B by 2033 6 In COPD, TSLP triggers airway inflammation, smooth muscle proliferation, and collagen deposition leading to airflow limitation and exacerbations 12 1 WHO https://www.who.int/news-room/fact-sheets/detail/chronic-obstructive-pulmonary-disease-(copd) 2 Adeloye et al, Lancet Resp, (2022). 3 Ying et al, J Immunol, (2008). 4 Yin et al, Front. Med, (2025). 5 Singh et al, Lancet Resp, (2025). 6 Datamonitor FIGURE: Wedzicha, et al, Lancet, (2007). © 2026 Upstream Bio, Inc. Triggers of COPD exacerbations and associated pathophysiological changes lead to increased symptoms
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No Image Clinical Data Overview © 2026 Upstream Bio, Inc.
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No Image No Image No Image No Image © 2026 Upstream Bio, Inc. Summary of verekitug development activity 14 Preclinical (Astellas) In vitro pharmacology Verekitug produced potent suppression of TSLP/TSLPR-mediated responses in cell assays with clear differences in potency demonstrated compared to tezepelumab In vivo pharmacology TSLPR mAb demonstrated superior biological effects to a TSLP mAb in preclinical mouse allergy models Toxicology No toxicology concerns observed Clinical Phase 1 SAD study in healthy volunteers (HV) (Astellas) Supported tolerability and potential for extended dosing intervals with subcutaneous (SC) administration Phase 1 MAD study in asthma patients Showed full receptor occupancy and substantial suppression of disease biomarkers (blood eos and FENO) for up to 24 weeks after last dose. PK/PD modeling indicated greater potency as compared to published data for tezepelumab Japanese bridging study Demonstrated comparable PK between Japanese and non-Japanese HV Phase 2 study in CRSwNP Top-line results met primary and key secondary endpoints and was generally well- tolerated at 100 mg administered Q12W CMC Novel formulation 200 mg/mL formulation developed – allows a Q24W dose in a single 2mL injection
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No Image No Image No Image No Image MAD study designed to evaluate PD effects in asthma patients and inform Phase 2 dose selection 15 Study results presented at American Thoracic Society International Conference in May 2024 Key eligibility criteria → Adults with asthma, aged 18-60 years → Blood eosinophils ≥200 cell/μL or ≥150 cell/μL with FENO >25 ppb → Participants on stable nonbiologic asthma medications with no dose adjustments, who experience no exacerbations, and with no new prescribed drugs within 8 weeks prior to screening Primary objective: To assess safety and tolerability of verekitug administered in MAD Secondary objective: → To assess PD effect of verekitug on F ENO and blood eosinophils → To assess the degree and duration of TSLPR occupancy in peripheral monoctyes → To assess immunogenicity and PK of verekitug 25 mg verekitug (n=6) or PBO (n=2) Week 0 onlyD 300 mg verekitug (n=6) or PBO (n=2) SC Q12W | Week 0, 12C 200 mg verekitug (n=6) or PBO (n=2) SC Q4W | Week 0, 4, 8B 100 mg verekitug (n=6) or PBO (n=2) SC Q4W | Week 0, 4, 8A © 2026 Upstream Bio, Inc.
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No Image No Image No Image No Image Most Common TEAE: Headache Several participants had mild, short-lived, and self-limited injection site reactions; none were reported as an adverse event No withdrawals from the trial or treatment discontinuation due to TEAEs 100 mg Q4W (N=6) 200 mg Q4W (N=6) 300 mg Q12W (N=6) 25 mg X 1 (N=6) Placebo (N=8) Overall (N=32) Number of TEAE 19 17 12 9 25 82 Number of Related TEAE 2 1 3 0 1 7 Subjects with any TEAE, n (%) 5 (83.3) 6 (100) 6 (100) 4 (66.7) 7 (87.5) 28 (87.5) Mild, n (%) 1 (16.7) 4 (66.7) 5 (83.3) 0 3 (37.5) 13 (40.6) Moderate, n (%) 4 (66.7) 2 (33.3) 1 (16.7) 4 (66.7) 4 (50.0) 15 (46.9) Severe, n (%) 0 0 0 0 0 0 Subjects with any Related TEAE, n (%) 1 (16.7) 1 (16.7) 2 (33.3) 0 1 (12.5) 5 (15.6) Subjects with any Serious TEAE, n 0 0 0 0 0 0 Subjects with any TEAE Leading to Withdrawal, n 0 0 0 0 0 0 Subjects with any TEAE Leading to Discontinuation of IMP, n 0 0 0 0 0 0 MAD study showed a generally favorable tolerability profile Treatment emergent adverse events were mild or moderate 16 TEAE - treatment emergent adverse event; Q4W - every 4 weeks. >90% of TEAEs were deemed unrelated to study drug © 2026 Upstream Bio, Inc.
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No Image No Image No Image No Image 32-week MAD data showed substantial PD effects for up to 24 weeks after last dose 0 4 8 12 16 20 24 28 32 -50 0 50 100 150 Receptor Occupancy (% cells) Elapsed Time (Weeks) % Free TSLP receptors (mean ± SEM) 100 mg Q4W 200 mg Q4W 300 mg Q12W Placebo 25 mg X1 Dosing Receptor Occupancy (% cells) -54% at W12 -51% at W12 -51% at W12 End of last dose cycle 0 4 8 12 16 20 24 28 32 -50 0 50 FeNO (% Change from BL) Elapsed Time (Weeks) % Change from baseline (mean ± SEM) *Note: Data from per protocol dosing shown - Dashed red line = Teze data with Q4W dosing up to 52-weeks. Corren et al Allergy, (2022). - Low titer ADA observed in 33-83% of subjects in each cohort without clinically meaningful impact on PK or PD. FENO (% Change from BL) End of last dose cycle -54% at W12 -65% at W12 -36% at W12 0 4 8 12 16 20 24 28 32 -50 0 50 Eosinophils (% Change from BL) Elapsed Time (Weeks) % Change from baseline (mean ± SEM) EOS (% Change from BL) © 2026 Upstream Bio, Inc. 17 Singh et al, Clin Pharm Ther, (2025).
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No Image No Image No Image No Image Verekitug has shown high potency in asthma patients Modeled effect of verekitug on FENO is substantially greater than that published for tezepelumab © 2026 Upstream Bio, Inc. 18 Verekitug FENO PK/PD Model Parameters with Tezepelumab 1Ly et al, J Clin Pharm, (2021). Verekitug Tezepelumab1 EMAX (reduction from BL) EC50 (µg/ml) EC90 (µg/ml) EMAX (reduction from BL) EC50 (µg/ml) EC90 (µg/ml) 43.4 %; 95% CI (36.6-50.4) 0.008 0.07 27.8 %; 95% CI (23.1-32.2) 2.5 22.5 → ~1.5 times greater maximal reduction in PD (FENO) → >300-fold lower EC50 /EC90 compared to tezepelumab No head-to-head clinical studies have been conducted. Differences exist between modeled data and trial design, and caution should be exercised when comparing data across studies.
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No Image No Image No Image Phase 1 PK/PD model used to select Phase 2 doses predicted to maintain verekitug concentrations ≥FENO EC90 for 12 or 24 weeks Exposure also predicted to be greater than that of approved tezepelumabdose 19 Solid line: median LLOQ: Lower Limit of PK Quantification 100 mg Q12W 100 mg Q12W 400 mg Q24W Tezepelumab values modeled from parameters in Ly et al J Clin Pharm, (2021). Approved dose for severe asthma FENO Emax= 43.4% FENO Emax= 27.8% Median of Population Phase 1 PK/PD model prediction © 2026 Upstream Bio, Inc. Solid line: median LLOQ - lower limit of PK quantification
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No Image No Image No Image No Image VIBRANT Phase 2 trial design Enrolled 81 patients with CRSwNP in the US and Europe © 2026 Upstream Bio, Inc. 20 Randomized, double-blind, placebo-controlled Phase 2 study with a 24-week treatment period (NCT06164704) Key inclusion criteria: → History of nasal polyp (NP) surgery OR NP exacerbation requiring systemic steroids in past 24 months → Endoscopic nasal polyp score (NPS) ≥5 → Nasal congestion score (NCS) ≥2 over 14 days → CRSwNP symptoms for ≥8 weeks → Stable standard of care treatment for CRSwNP for ≥30 days Primary endpoint: Change in NPS (from baseline to week 24) Key secondary endpoints: Change from baseline to week 24 → NCS → Sinus opacification (Lund-Mackay score) → Total Symptom Score (TSS) → Difficulty with sense of smell (DSS score) Proportion of patients requiring surgery or systemic corticosteroids over 24 weeks Follow-up Verekitug + SoC* 100 mg SC Q12W Placebo + SoC* SC Q12W 1:1N=81 Randomized 0 12 24 28 Week *SoC issued is an inhaled corticosteroid; SC - subcutaneous; SoC - standard of care.
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No Image No Image No Image No Image Baseline characteristics were balanced across treatment groups Slightly higher blood eosinophils observed in placebo group © 2026 Upstream Bio, Inc. 21 Verekitug Placebo *Includes participants with AERD. AERD - aspirin-exacerbated respiratory disease; SD - standard deviation. Age (years), mean (SD) 49.8 (13.26) 49.6 (13.42) CRSwNP duration (years), mean (SD) 13.7 (9.92) 11.7 (6.78) Patients with systemic corticosteroid use in the preceding 2 years, n (%) 17 (41.5) 15 (37.5) Patients with ≥1 prior NP surgery, n (%) 26 (63.4) 26 (65.0) Patients with comorbid asthma, n (%)* 24 (58.5) 23 (57.5) Bilateral endoscopic NPS (mean) 5.9 (1.6) 6.1 (1.32) Baseline NCS (mean) 2.6 (0.43) 2.6 (0.44) Baseline DSS (mean) 2.85 (0.33) 2.75 (0.57) Baseline LMK (mean) 17.1 (4.84) 16.9 (4.92) Blood eosinophil count (mean, cells/μL) 404 (260) 496 (378) % < 150 cells/μL 7.3 7.5 % ≥ 150 cells/μL 92.7 90.0 % < 300 cells/μL 36.6 32.5 % ≥ 300 cells/μL 63.4 65.0
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No Image No Image No Image No Image Most Common TEAEs consistent with disease symptoms: Upper respiratory tract infections, sinusitis, nasopharyngitis, nasal polyps, headache © 2026 Upstream Bio, Inc. Verekitug was generally well tolerated 22 Adverse Event Category, n, subjects (%) Any treatment-emergent adverse events (TEAE) 27 (67.5) 26 (65.0) Any TEAEs related to study treatment 1 (2.5) 3 (7.5) Any serious TEAEs 0 0 Any serious TEAEs related to study treatment 0 0 Any TEAEs with outcome of death 0 0 Any TEAEs leading to study drug discontinuation 0 (0.0) 1 (2.5) → Overall, incidence of AEs was similar across treatment groups → TEAEs related to study treatment occurred more frequently in placebo → No serious adverse events reported Placebo (n=40)Verekitug (n=40)
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No Image No Image No Image No Image Primary Endpoint Key Secondary Endpoints No Image © 2026 Upstream Bio, Inc. Verekitug led to significant and clinically meaningful improvements in NPS and key secondary endpoints, including reduction in need for surgery or systemic corticosteroids 23 PlaceboVerekitug Treatment difference *Change from baseline is least square (LS) mean (standard error) and treatment difference is LS mean difference vs placebo (95% confidence interval) **Risk reduction vs placebo †p values for secondary endpoints are nominal and not adjusted for multiple comparisons. LMK - Lund-Mackay; TSS - total symptom score; DSS - difficulty with smell score; SCS - systemic corticosteroids. NPS range: 0–8; NCS range: 0–3 over 2 weeks; LMK CT score (0-24); TSS range: 0–24; 8 symptoms over 2 weeks; DSS range: 0–3 over 2 weeks. NPS change from baseline* -2.1 (0.26) -0.3 (0.27) -1.8 (-2.51, -1.03) p<0.0001 NCS change from baseline* -1.5 (0.14) -0.8 (0.14) -0.8 (-1.17, -0.37) p=0.0003† LMK change from baseline* -9.0 (0.8) -1.0 (0.8) -8.0 (-10.2, -5.9) p<0.0001† TSS change from baseline* -10.1 (0.94) -5.8 (0.95) -4.3 (-6.94, -1.65) p=0.0018† DSS change from baseline* -1.5 (0.15) -0.6 (0.16) -0.9 (-1.29, -0.42) p=0.0002† % requiring sinus surgery and/or SCS 7.3% 25.0% 76% reduction** p=0.03†
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No Image No Image No Image No Image Endoscopic NPS change NCS change* © 2026 Upstream Bio, Inc. Verekitug dosed every 12 weeks led to significant reductions in NPS and NCS over 24 weeks 24 Week Week *NCS was calculated as the 14-day average of the daily scores. †Nominal p-value. Changes are shown as least-squares means. I bars indicate 95% confidence intervals (CI). -1.8 (-2.51, -1.03), p <0.0001 1st dose 2nd dose 1st dose 2nd dose Significant reduction in NCS observed at week 2 (p<0.01)† -0.8 (-1.17,-0.37) p=0.0003 NPS change from baseline (LS mean ±95% CI) NCS change from baseline (LS mean ±95% CI)
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No Image No Image No Image No Image No Image © 2026 Upstream Bio, Inc. Verekitug demonstrated clinical effect in NPS across all subgroups 25 Favors PlaceboFavors Verekitug CI - confidence interval Subgroups Verekitug Placebo n n Least Squares Mean Difference (95% CI) Overall 41 40 -1.8 (-2.51 to -1.03) Age (years) <65 36 34 -1.8 (-2.68 to -0.98) ≥65 5 6 -0.7 (-2.91 to 1.44) Sex Male 26 26 -2.1 (-3.08 to -1.19) Female 15 14 -0.9 (-2.36 to 0.59) Region USA and Western Europe 23 24 -1.9 (-2.81 to -0.99) Eastern Europe 18 16 -1.6 (-2.84 to -0.32) Weight <90 kg 22 27 -1.7 (-2.63 to -0.84) ≥90 kg 19 13 -1.8 (-3.33 to -0.27) Blood eosinophil level (cells/μL) <300 15 13 -1.3 (-2.65 to -0.01) ≥300 26 26 -2.1 (-3.00 to -1.12) Comorbid asthma Yes 24 23 -1.9 (-2.80 to -0.92) No 17 17 -1.7 (-2.93 to -0.39) Prior Nasal Polyp surgery Yes 26 26 -1.7 (-2.63 to -0.73) No 15 14 -2.0 (-3.28 to -0.80) Prior systemic corticosteroids Yes 17 15 -1.1 (-2.43 to 0.21) No 24 25 -2.1 (-3.05 to -1.13) -4.0 -2.0 .0 2.0
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No Image No Image No Image No Image -2.1 -2.0 -1.9 -0.5-0.3 -0.4 -0.3 0.0 -2.5 -2.0 -1.5 -1.0 -0.5 0.0 0.5 © 2026 Upstream Bio, Inc. Verekitug dosed every 12 weeks delivered clinical activity at week 24 similar to tezepelumab dosed every 4 weeks 26 NPS change from baseline Injections per year NOTE: For illustrative purposes only. Efficacy data are derived from different clinical trials conducted at different times with differences in trial design and patient populations. As a result, cross-trial comparisons cannot be made, and no head-to-head clinical trials have been conducted. All efficacy data shown based on statistical treatments of intercurrent events and missing data that varied across studies shown. Comparison to Phase 2 data2 where possible. No Phase 2 studies were conducted for tezepelumab or depemokimab; *Data estimated from the Phase 3 trial1. †Integrated data, estimated. Only Dupilumab is FDA-approved for use in CRSwNP. TE - placebo-adjusted treatment effect. 1. Lipworth et al N Engl J Med, (2025). 2. Bachert et al JAMA, (2016). 3. Gevaert et al Lancet, (2025). 4 13 26 2 TE = -1.7TE = -1.8 TE = -1.6 TE = -0.5 n=81 Verekitug Phase 2 VIBRANT 24 weeks n=602 Dupilumab Phase 2 16 weeks n=5283 Depemokimab Phase 3 ANCHOR 1/2† 26 weeks n=4081 Tezepelumab Phase 3 WAYPOINT 24 weeks (est*) Verekitug Tezepelumab Dupilumab Depemokimab
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No Image No Image No Image No Image No Image CRSwNP and Severe Asthma Biological, Epidemiological and Clinical Overlap © 2026 Upstream Bio, Inc. 27 Shared biology with central role of TSLP driving activation of common cytokine pathways1-4 Shared Epidemiology 1 Common biologic therapies and magnitude of response 5 In patients with CRSwNP Up to 70% have comorbid asthma In patients with asthma Over 40% have comorbid CRSwNP Nasal polyps Asthma AER Reduction in T2 High Population Anti-IL4Rα Anti-TSLP Anti-IgE 1. Bachert et al J Allergy Clin Immunol Pract, (2023); 2. Castagnoli et al Exp Rev Respir Med, (2020); 3. Giombi et al Int J Mol Sci, (2024); 4. Pelaia C, et al J Clin Med, (2023); 5. Data derived: Dupilumab AER reduction based on BEC ≥300 (QUEST only); NPS based on SINUS-24 (Week 24) & SINUS-52 at (Week 52), Mepolizumab AER reduction based on USPI, 100 mg SC in MENSA trial only; NPS based on SYNAPSE at Week 52, Benralizumab AER reduction based on SIROCCO trial only in USPI, CALIMA was 37% reduction; NPS based on OSTRO at Week 40, Omalizumab AER reduction based on Normansell R, et al Cochrane Database Syst Rev, (2014); NPS based on POLYP1/2 at Week 24, Depemokimab AER reduction based on Pooled SWIFT-1/2; NPS based on ANCHOR-1/2 at Week 52, Tezepelumab AER reduction based on Pooled Analysis of the PATHWAY and NAVIGATOR Clinical Trials, BEC≥300; NPS based on WAYPOINT at Week 52. For illustrative purposes only. Efficacy data are derived from different clinical trials conducted at different times with differences in trial design and patient populations. As a result, cross-trial comparisons cannot be made, and no head-to-head clinical trials have been conducted. All efficacy data shown based on statistical treatments of intercurrent events and missing data that varied across studies shown. No trials simultaneously evaluating NPS/AER in same population have been conducted. AER - annualized exacerbation rate; BEC - blood eosinophil count; CRSwNP - chronic rhinosinusitis with nasal polyps; NPS - nasal polyp score; TSLP - thymic stromal lymphopoietin.
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No Image Phase 2 Clinical Trials © 2026 Upstream Bio, Inc.
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No Image No Image No Image No Image Summary of ongoing verekitug Phase 2 Clinical Trials 29 VALIANT Severe Asthma Phase 2 Study* VENTURE Moderate-to-Severe COPD Phase 2 Study Design Duration Doses • 4 arm, randomized (1:1:1:1), parallel group • 24 week minimum 60 week maximum treatment • PBO, 100 mg Q24W, 400 mg Q24W, 100 mg Q12W • 3 arm, randomized (1:1:1), parallel group • 60 week minimum 108 week maximum treatment • PBO, 400 mg Q24W, 100 mg Q12W Target Population • Age range: 18-80 years • Age range: 40-85 years Primary Endpoint • Annualized Asthma Exacerbation Rate (AAER) • Annualized rate of moderate or severe COPD exacerbation events Secondary Endpoints • Change from baseline: • Pre–bronchodilator FEV 1 • FENO • ACQ-6 • Safety • Change from baseline: • Pre–bronchodilator FEV1 • FENO • SGRQ • Safety Sample Size 479 (actual) 666 (planned) *A long-term safety and efficacy study (LTE) of verekitug in eligible participants who completed the Phase 2 study was initiated in May 2025. NPS – Nasal Polyp Score; FEV1 – forced expiratory volume in first second; ACQ-6 – six element asthma control questionnaire; NCS – Nasal Congestion Score; SGRQ – St. George’s Respiratory Questionnaire; FeNO – Fractional Exhaled Nitric Oxide; CT – computed tomography, PBO – placebo © 2026 Upstream Bio, Inc.
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No Image Commercial Opportunity © 2026 Upstream Bio, Inc.
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No Image No Image No Image No Image Large and growing commercial opportunity in core indications, with asthma and COPD alone expected to be a $35B+ global biologics market in 2033 → Currently, ~1.3M biologic eligible severe asthma patients in the US1; ~80% of biologic sales are in the US2 → 5 of 6 asthma biologics have each achieved or are projected to achieve greater than $1.0 billion in global annual sales by 20252 → Tezspire is projected to reach peak global annual sales of over $3B for severe asthma alone in 2032,2 and achieved more than 20% of new to brand share of prescriptions in the US in its first commercial year3 Asthma 2023: $7.5B2 2032e: $12.6B2 CRSwNP 2025: >$1.5B4,5* COPD 2033e: $23B2 → Biologics to treat CRSwNP have been available for only ~6 years, now with 4 approved treatment options → Use of biologics is growing rapidly, with >20% increases in number of claims, prescribing HCPs, and patients receiving biologics to manage CRSwNP4 → Current global biologics sales in CRSwNP alone estimated to be $1.5B+ annually4,5* → Significant potential for growth as the proportion of eligible patients taking a biologic increases and novel biologics enter the market → Currently ~1.1M severe COPD patients in the US, expected to be ~3.5M globally by 20332; ~70% of 2033 biologic sales are expected to be in the US2 → Currently only 2 biologics are approved for the treatment of COPD → If approved in this indication, Tezspire is projected to reach global annual sales of over $5B for COPD alone in 20332 1 Amgen Business Review Program Feb 2022 2 Datamonitor 3 Amgen Investor Presentation May 2024 4 Symphony Claims Data (June ’24 – May ’25) 5 Manufacturer Sales and Pricing Disclosures * As of October 2025 © 2026 Upstream Bio, Inc. 31
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No Image No Image No Image No Image TSLP signaling is linked to a variety of indications Verekitug TSLP receptor inhibitor potentially has broad applicability 32 – Severe Asthma* – CRSwNP* – COPD* – Bronchiectasis – Idiopathic Pulmonary Fibrosis (IPF) – Systemic sclerosis (ILD) – Sarcoidosis Nephrology – Atopic Dermatitis – Bullous Pemphigoid – Prurigo Nodularis – Eczema Herpeticum – Dermatitis Herpetiform – Job’s syndrome – Eosinophilic Esophagitis – Eosinophilic Gastritis/Gastroenteritis – Ulcerative Colitis – Urticaria – Mastocytosis – Hypereosinophilic syndrome – Churg-Strauss Syndrome Respiratory Dermatology Gastroenterology Allergy/Immunology * Target indications for verekitug based on our current development strategy – IgA Nephropathy © 2026 Upstream Bio, Inc.
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No Image No Image No Image No Image About Upstream Bio 33 © 2026 Upstream Bio, Inc. Clinical-stage immunology company focused on severe respiratory diseases Developing only known clinical-stage antagonist of the TSLP receptor → Verekitug’s pharmacology is unique and characterized by rapid, complete and sustained occupancy of the TSLP receptor, for up to 24 weeks after the last dose Studying verekitug across multiple indications with high unmet need → VIBRANT, our phase 2 trial in CRSwNP, now complete and reported top-line results in September 2025 → VALIANT, our phase 2 trial in severe asthma, on track to report top-line results in Q1 2026 VALOUR, our open-label extension study, is currently enrolling eligible participants who have completed VALIANT → VENTURE, our phase 2 trial in COPD, currently enrolling → All trials randomized and placebo-controlled, with registrational endpoints → TSLP biology supports expansion into other therapeutic areas, including dermatology and GI Addressing significant commercial opportunities → Asthma and COPD markets are expanding and expected to drive a $35B+ global biologics market by mid-2030s Existing capital expected to fund planned operations through 2027