UPB Corporate presentation

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No Image No Image No Image No Image This presentation contains “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, each as amended. These statements may be identified by words such as “aims,” “anticipates,” “believes,” “continue,” “could,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “predict,” “project,” “seeks,” “should,” “target,” “will” and variations of these words or similar expressions. Any statements in this presentation that are not statements of historical fact may be deemed to be forward-looking statements. These forward-looking statements include, without limitation, express or implied statements regarding: the clinical development of verekitug for the treatment of severe asthma, CRSwNP and COPD, including the timing, progress and results of ongoing and planned clinical trials; expectations regarding interactions with regulatory authorities and the potential of the endpoints of our clinical trials to produce data that could support submissions for product approval; our expectations regarding the differentiation, safety, efficacy, tolerability, or extended dosing interval of verekitug and the ability for verekitug to deliver best-in-class efficacy; expectations for the size and growth potential of the market for verekitugand our ability to serve that market; additional potential indications for verekitug; and our expected cash runway. Forward-looking statements are based on our current expectations and are described in “Risk Factors,” in our Annual Report on Form 10-K and most recent Quarterly Report on Form 10-Q, as well as discussions of potential risks, subject to risks, uncertainties and assumptions that could negatively affect our business, operating results, financial condition and stock value. Factors that could cause actual results to differ materially from those currently anticipated include: risks relating to our ability to advance verekitug through clinical development; the results of preclinical studies, or clinical studies not being predictive of future results in connection with future studies; the initiation, timing, progress and results of clinical trials; our ability to fund our development activities and achieve development goals; our research and development activities; our ability to execute on our strategy for verekitug including obtaining the requisite regulatory approvals on the expected timeline, if at all; uncertainties relating to preclinical and clinical development activities; our dependence on third parties to conduct clinical trials, manufacture verekitug and develop and commercialize our product candidates, if approved; our ability to attract, integrate and retain key personnel; risks related to the company’s financial condition and need for substantial additional funds in order to complete development activities and commercialize a product candidate, if approved; risks related to regulatory developments and approval processes of the U.S. Food and Drug Administration and comparable foreign regulatory authorities; risks related to establishing and maintaining our intellectual property protections; and risks related to the competitive landscape for verekitug; and other risks uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission. These risks are not exhaustive. New risk factors emerge from 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 combination 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. Any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in its expectations or any changes in events, conditions or circumstances on which any such statement is based, except as required by law, and claims the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995. Market data and industry information used throughout this presentation are based on management's knowledge of the industry and the 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, publications, 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 information 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. In addition, we have not conducted any head-to-head studies comparing our product candidates to any third-party drug products or candidates, whether investigated or approved. Information regarding other drug products in this presentation is meant to provide context for illustrative purposes only. Because there are no head-to-head studies, no conclusions should be made based on cross study comparisons. Recipients are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date such statements are made and should not be construed as statements of fact. Tradenames, trademarks and service marks of other companies appearing in this presentation are the property of their respective 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 © 2026 Upstream Bio, Inc. 2

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No Image No Image No Image No Image About Upstream Bio Clinical-stage immunology company focused on severe respiratory diseases © 2026 Upstream Bio, Inc. 3 Developing verekitug, the only known clinical- stage antagonist of the TSLP receptor → Verekitug’s pharmacology is unique and characterized by high-potency inhibition of TSLP signaling → Focused on multiple indications with high unmet need: • Completed Phase 2 trials in severe asthma and CRSwNP • Ongoing Phase 2 trial in COPD; Enrollment in VENTURE completed, with data expected in H2 2027 Addressing significant commercial opportunities → Severe asthma and COPD markets expected to drive a $35B+ global biologics market by 2033 TSLP, thymic stromal lymphopoietin; CRSwNP, chronic rhinosinusitis with nasal polyps; COPD, chronic obstructive pulmonary disease. Pursuing Phase 3 development strategy designed to deliver best-in-class efficacy with a single quarterly at-home injection in broad patient populations  Robust clinical data and comprehensive market research in severe asthma and CRSwNP provide a clear path to maximize the potential commercial value of verekitug  The Company plans to engage with FDA in mid-2026 and initiate Phase 3 trials in severe asthma and CRSwNP in Q1 2027 Existing capital is expected to fund planned operations through 2027

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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 of the TSLP receptor  Fully-human IgG1 antibody, discovered by Astellas/Regeneron and acquired by Upstream Bio  Verekitug's potency is approximately 300-fold greater than that of tezepelumab, enabling both robust efficacy and extended interval dosing  Comprehensive dataset from ~500 participants treated with verekitug across Phase 1 & 2 trials  Demonstrated strong clinical benefit and favorable safety with every 12-week dosing in both severe asthma and CRWsNP About verekitug © 2026 Upstream Bio, Inc. 5 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 Developing verekitug in TSLP-driven severe respiratory diseases 6 DEVELOPMENT INDICATIONS PRECLINICAL PHASE 1 PHASE 2 PHASE 3 MILESTONES Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) Phase 3 Initiation Q1 2027* Severe Asthma Phase 3 Initiation Q1 2027* Data Expected H2 2027 † Chronic Obstructive Pulmonary Disease (COPD) Data Expected H2 2027* * Anticipated timing. Phase 3 preparations ongoing in CRSwNP and severe asthma. † VALOUR is a Phase 2 long-term safety and efficacy study of verekitug in eligible participants with severe asthma who completed the Phase 2 VALIANT study. © 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 Biologic eligible severe asthma patients in the US1 of biologic sales are in the US 2 Severe Asthma 2023: $7.5B2 2032e: $12.6B2 CRSwNP 2025: >$1.5B5,6 COPD 2033e: $23B2 1 Upstream Bio Analysis 2025. 2 Datamonitor. 3 IQVIA Claims Data (Unique Asthma Pts on Biologics FY ’24, Pt Growth Rate ‘20-’24). 4 Amgen Investor Presentation May 2024. 5 Symphony Claims Data (June ’24 – May ’25). 6 Manufacturer Sales and Pricing Disclosures. 7 Analyst projections. © 2026 Upstream Bio, Inc. 8 of eligible patients with severe asthma are currently estimated to receive biologic therapies 1,3 Projected global sales for all approved biologics in severe asthma by 2033 2 Tezspire is projected to reach global annual sales of over $3B for severe asthma alone in 20322 ~1.3M ~80% <25% >$12.5B >$3B Biologic eligible CRSwNP patients in the US1 ~300K Current global biologics sales in CRSwNP alone estimated to be $1.5B+ annually 5,6 >$1.5B Tezspire is projected to reach global annual sales of over $600M for CRSwNP by early 2030s7 >$600M COPD patients inadequately controlled on triple-therapy in the US 2 ~1.1M Projected COPD patients inadequately controlled on triple-therapy in the US by 2033 2 ~3.5M of 2033 COPD biologic sales are expected to be in the US 2 ~70% Tezspire is projected to reach global annual sales of over $5B for COPD alone in 2033 2, if approved in this indication >$5B

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No Image No Image No Image No Image Optimizing development strategy to address patient needs and maximize commercial value *Trinity Quantitative Research with N=100 HCPs and N=120 Patients; Trinity Qualitative Research with N=10 Payers Insights represent Trinity’s interpretation of market research findings These findings are consistent across multiple waves of qualitative and quantitative market research conducted with HCPs, patients, and payers Efficacy differentiation is the primary driver of clinical impact and commercial success Prioritizing verekitug development strategy to deliver best-in-class efficacy with quarterly dosing The majority of dosing convenience value is captured with quarterly administration © 2026 Upstream Bio, Inc. 9 Supported by market research* that shows:

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No Image No Image No Image No Image Market research shows efficacy is the primary driver for decision- making among HCPs in both asthma and CRSwNP © 2026 Upstream Bio, Inc. 10 Importance of Product Attributes for Asthma and CRSwNP % HCPs ranking attribute as the top 3 most important when selecting biologics for asthma & CRSwNP patients Product Attributes Asthma i.e., AAER, FEV1, and symptomology CRSwNP i.e., reduction NPS and improvement in NCS Efficacy Safety Dosing frequency July 2025 Trinity Research; N=210 Quantitative Survey CRSwNP, chronic rhinosinusitis with nasal polyps; HCP, healthcare provider; NCS, nasal congestion score; NPS, nasal polyp score Insights represent Trinity’s interpretation of market research findings 100% 28% 14% 100% 21% 5% Market research shows HCPs are not willing to trade off safety or efficacy for extended dosing interval For instance, ~70% of HCPs reported that they would switch their asthma patients to another biologic if they observed waning efficacy of a q24w drug

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No Image © 2026 Upstream Bio, Inc. 12 Phase 3 strategy designed to maximize verekitug's commercial value by targeting best-in-class efficacy with at-home quarterly dosing Target product profile Deliver best-in-class efficacy with quarterly dosing in both severe asthma and CRSwNP Strategy supported by strong clinical data package and comprehensive market research in both indications Convenient quarterly dosing regimen High and low-eosinophil populations Parallel Phase 3 trials in severe asthma & CRSwNP Self-administration via autoinjector at launch Single high-dose injection, up to 400 mg* *Final dose and design pending FDA engagement

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No Image No Image No Image No Image © 2026 Upstream Bio, Inc. Verekitug’s profile supports potential for best-in-class efficacy & quarterly dosing in severe asthma and CRSwNP 13 Top-line results for Phase 2 VIBRANT study of verekitug in CRSwNP 5 clinical studies completed to date with ~500 participants dosed with verekitug Phase 2 trials delivered efficacy outcomes meeting or exceeding approved biologics in both severe asthma and CRSwNP with 100 mg dosed every 12 weeks Favorable safety profile, consistent across clinical development program Potential to deliver best-in-class efficacy in severe asthma and CRSwNP with a single high-dose quarterly injection Phase 2 trials demonstrate positive treatment effects in high and low eosinophil subgroups in severe asthma and CRSwNP Well-characterized immunogenicity profile has no meaningful impact on safety or efficacy 1 2 3 4 5

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No Image No Image No Image No Image Top-line results for Phase 2 VIBRANT study in CRSwNP Verekitug dosed every 12 weeks, treatment period 24 weeks © 2026 Upstream Bio, Inc. 14 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. Top-line data reported Sept 2025.

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No Image No Image No Image No Image Top-line results for Phase 2 VALIANT study in severe asthma © 2026 Upstream Bio, Inc. 15 56% reduction in AAER (p<0.0003) 122mL1 improvement in FEV1 20.4ppb1 reduction in FeNO 43.5%1 reduction vs baseline 0.21 point1,2 reduction in ACQ-6 Generally well tolerated, with a safety profile consistent with prior studies Statistically significant and clinically meaningful reductions in AAER for up to 60 weeks Clinically meaningful improvements in lung function (FEV1) and exhaled nitric oxide (FeNO) Phase 2 VALIANT 100 mg q12w vs placebo dataset 1 Placebo-corrected. 2 At 24 week AAER, annualized asthma exacerbation rates; FEV1, forced expiratory volume in 1 second; FeNO, fractional exhaled nitric oxide; ACQ-6, asthma control questionnaire. Top-line data reported Feb 2026. Verekitug dosed every 12 weeks, treatment period up to 60 weeks

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No Image No Image No Image No Image Consistent and favorable safety profile across both Phase 2 trials © 2025 Upstream Bio, Inc. 16 → Overall incidence of TEAEs was similar across treatment groups → Serious TEAEs were similar across treatment groups → Overall incidence of AEs was similar across treatment groups → TEAEs related to study treatment occurred more frequently in placebo → No SAEs reported → Most common TEAEs in study population (>5%) were consistent with CRSwNP symptoms, which occurred frequently in the placebo group *Safety follow-up is ongoing. AE, adverse event; q×w, every × weeks; TEAE, treatment-emergent adverse event. SAEs, serious adverse events. 1 Top-line data reported Sept 2025. 2 Data on file. 14.3.1.2. 3 Top-line data reported Feb 2026. 4 Data on File. Table 14.3.1.1. 5 Data on File. Table 14.3.1.2. 3. * 2 1 3 4 5

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No Image No Image No Image No Image © 2026 Upstream Bio, Inc. Verekitug’s profile supports potential for best-in-class efficacy & quarterly dosing in severe asthma and CRSwNP 17 Top-line results for Phase 2 VIBRANT study of verekitug in CRSwNP 5 clinical studies completed to date with ~500 participants dosed with verekitug Phase 2 trials delivered efficacy outcomes meeting or exceeding approved biologics in both severe asthma and CRSwNP with 100 mg dosed every 12 weeks Favorable safety profile, consistent across clinical development program Potential to deliver best-in-class efficacy in severe asthma and CRSwNP with a single high-dose quarterly injection Phase 2 trials demonstrate positive treatment effects in high and low eosinophil subgroups in severe asthma and CRSwNP Well-characterized immunogenicity profile has no meaningful impact on safety or efficacy 1 2 3 4 5

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No Image No Image No Image No Image Primary Endpoint Key Secondary Endpoints No Image 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† In CRSwNP, verekitug led to significant and clinically meaningful improvements in NPS and all key secondary endpoints © 2025 Upstream Bio, Inc. 18 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. Top-line data reported Sept 2025. Data on file: Tables 14.2.1.1.1, 14.2.2.1.1, 14.2.2.2.1, 14.2.2.3.1, 14.2.2.9.1, 14.2.2.4.1

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No Image No Image No Image No Image Timing Endpoint Verekitug 100 mg q12w Verekitug 400 mg q24w Verekitug 100 mg q24w Baseline through week 60 AAER* Rate ratio vs placebo (95% CI) P value N=121 0.44 (0.28, 0.69) 0.0003 N=118 0.61 (0.40, 0.93) 0.0227 N=120 0.51 (0.33, 0.79) 0.0028 Change from baseline to week 24* Pre-BD FEV1 LSM difference vs placebo mL (95% CI) P value N=106 112 (8, 216) 0.0350 N=107 133 (30, 237) 0.0119 N=103 -4 (-108, 100) 0.9419 ACQ-6 LSM difference vs placebo (95% CI) P value N=114 -0.21 (-0.43, 0.01) 0.0651 N=111 -0.34 (-0.57, -0.12) 0.0027 N=112 -0.23 (-0.45, -0.01) 0.0447 Change from baseline to week 60* Pre-BD FEV1 LSM difference vs placebo mL (95% CI) P value N=18 122 (-90, 335) 0.2589 N=18 139 (-76, 353) 0.2047 N=17 18 (-198, 235) 0.8678 ACQ-6 LSM difference vs placebo (95% CI) P value N=19 0.06 (-0.42, 0.55) 0.8000 N=19 -0.21 (-0.70, 0.28) 0.3928 N=17 -0.24 (-0.74, 0.26) 0.3541 In severe asthma, verekitug led to meaningful improvements in primary and secondary endpoints at week 24 that were generally sustained to week 60 © 2026 Upstream Bio, Inc. 19 *AAER, Rate Ratio, 95% confidence intervals, and p-values are from a negative binomial regression model with number of asthma exacerbations as the dependent variable and fixed effects for study treatment, region, baseline steroid use as randomized, and baseline eosinophil level as randomized. Top-line data reported Feb 2026. Data on File. Table 14.2.1.1.1; Table 14.2.2.2.1.3; Table 14.2.2.3.2; Table 14.2.2.4.2

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No Image No Image No Image No Image © 2026 Upstream Bio, Inc. Verekitug 100 mg q12w and 400 mg q24w doses led to numerical improvements in lung function and FeNO as early as week 2 and sustained over 60 weeks 20 -60 -40 -20 0 20 40 60 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 No. of participants Secondary endpoints were not powered for statistical significance. FeNO, fractionated exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; LSM, least squares mean; ppb, parts per billion; q×w, every × weeks. Top-line data reported Feb 2026. 1 Data on file. Table 14.2.2.2.1.3. 2 Data on file. Table 14.2.2.3.5. Verekitug 100 mg q12w 121 118 117 114 108 115 113 78 69 64 47 40 38 23 19 Verekitug 400 mg q24w 118 115 115 112 109 112 109 82 66 60 46 38 34 21 18 Verekitug 100 mg q24w 119 115 115 113 113 113 111 84 66 62 42 35 31 21 17 Placebo 119 109 110 113 110 108 108 83 67 60 43 40 32 23 19 -0.1 0.0 0.1 0.2 0.3 0.4 0.5 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 Verekitug 100 mg q12w 118 114 111 110 106 109 106 66 43 35 21 18 Verekitug 400 mg q24w 117 110 111 111 110 114 107 67 44 32 20 18 Verekitug 100 mg q24w 116 110 110 109 112 109 103 62 40 31 21 17 Placebo 119 113 110 110 109 105 106 64 43 32 22 18 LSM change from baseline in FEV1 (liters) LSM percent change from baseline in FeNO (ppb) No. of participants WeekWeek FEV1 over 60 weeks1 FeNO over 60 weeks2

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No Image No Image No Image No Image In both CRSwNP and severe asthma, patients with highest verekitug exposures experienced the greatest clinical benefit Data presented as mean NCS, Nasal Congestion Score; FEV1, Forced Expiratory Volume in 1 second; q12w, every 12 weeks. 1 Based on top-line data reported Sept 2025. 2 Based on top-line data reported Feb 2026. Placebo Verekitug (All) Verekitug (group1,low) Verekitug (group2,mid) Verekitug (group3,high) 21 0 2 4 6 8 10 12 14 16 18 20 22 24 0.000 0.125 0.250 0.375 0.500 Weeks FEV1 (Change from baseline) 0 2 4 6 8 10 12 14 16 18 20 22 24 -2.0 -1.5 -1.0 -0.5 0.0 Weeks NCS (Change from Baseline) VIBRANT 100 mg q12w NCS by Exposure Tertiles1 VALIANT 100 mg q12w FEV1 by Exposure Tertiles2 © 2025 Upstream Bio, Inc. ~ -0.5 pt ~150 mL © 2026 Upstream Bio, Inc.

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No Image No Image No Image Modeling of data through Phase 2 predicts that increasing quarterly dose above 100 mg will further increase exposure over the FENO EC90 Exposure over verekitug FENO EC90 predicted to be greater than that of tezepelumab’s approved dose over its FENO EC90 22 Phase 2 PK/PD model prediction LLOQ - lower limit of PK quantification *Illustrative model for 400 mg q12w. 10,000 virtual patient simulations run with baseline weight as a covariate on V and ADA titer as a covariate on Cl. Inclusive of Phase 1 data and top-line data from Phase 2 studies in CRSwNP and severe asthma reported Sept 2025 and Feb 2026, respectively. © 2025 Upstream Bio, Inc.© 2026 Upstream Bio, Inc. 400 mg q12w up to 72 weeks* Verekitug Phase 2 FENO EC90 = 0.06 µg/mL 0 12 24 36 48 60 72 0.001 0.01 0.1 1 10 100 Time (weeks) Verekitug Concentration (μg/mL) FENO EC90 LLOQ High exposure tertile from Phase 2 studies

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No Image No Image No Image No Image © 2026 Upstream Bio, Inc. Verekitug’s profile supports potential for best-in-class efficacy & quarterly dosing in severe asthma and CRSwNP 23 Top-line results for Phase 2 VIBRANT study of verekitug in CRSwNP 5 clinical studies completed to date with ~500 participants dosed with verekitug Phase 2 trials delivered efficacy outcomes meeting or exceeding approved biologics in both severe asthma and CRSwNP with 100 mg dosed every 12 weeks Favorable safety profile, consistent across clinical development program Potential to deliver best-in-class efficacy in severe asthma and CRSwNP with a single high-dose quarterly injection Phase 2 trials demonstrate positive treatment effects in high and low eosinophil subgroups in severe asthma and CRSwNP Well-characterized immunogenicity profile has no meaningful impact on safety or efficacy 1 2 3 4 5

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No Image No Image No Image No Image  Positive treatment responses in both high and low eosinophil subgroups in severe asthma and CRSwNP reinforce verekitug’s continued development in a broad population of patients in both indications, as observed in: – NPS subgroup analyses in CRSwNP – FEV1 subgroup analyses in severe asthma • In VALIANT, a very low placebo AAER of 0.73 in the low eosinophil group limited ability to detect therapeutic effect of verekitug in that subgroup  Preclinical and clinical studies of TSLP biology have identified effects that extend beyond Type 2 inflammation alone, with strong evidence of clinical efficacy in patients independent of eosinophilic phenotype Verekitug Phase 2 data support efficacy in broad populations in both severe asthma and CRSwNP © 2025 Upstream Bio, Inc. 24

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No Image No Image No Image No Image No Image Verekitug demonstrated clinical effect in NPS across all subgroups in the VIBRANT study Favors PlaceboFavors Verekitug 25 CI, confidence interval Top-line data reported Sept 2025. Data on file: UPB-CP-03, Table 14.2.1.1.4 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 © 2025 Upstream Bio, Inc.

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No Image No Image No Image No Image Verekitug Placebo LSM difference vs placebo (95% CI)Subgroups n LSM n LSM Overall 106 0.253 106 0.145 0.108 (0.004–0.213) Age, years < 65 80 0.302 80 0.135 0.168 (0.042–0.293) ≥ 65 26 0.090 26 0.178 -0.088 (-0.249 to 0.073) Sex Male 43 0.216 31 0.018 0.197 (-0.005 to 0.400) Female 63 0.273 75 0.196 0.077 (-0.044 to 0.198) Region North America 27 0.242 31 0.191 0.052 (-0.169 to 0.272) Western Europe 14 0.220 18 0.122 0.098 (-0.120 to 0.317) Central/Eastern Europe 30 0.162 31 0.223 -0.061 (-0.235 to 0.113) Rest of World 35 0.379 26 0.043 0.336 (0.122–0.550) Steroid use and dose Medium ICS without OCS 56 0.282 55 0.166 0.116 (-0.040 to 0.272) High ICS and/or OCS 50 0.232 51 0.129 0.103 (-0.038 to 0.243) Blood eosinophil level, cells/μL < 300 52 0.163 59 0.084 0.078 (-0.058 to 0.215) ≥ 300 54 0.344 47 0.223 0.121 (-0.045 to 0.287) FeNO at baseline, ppb < 25 40 0.150 56 0.172 -0.022 (-0.152 to 0.108) ≥ 25 66 0.299 50 0.104 0.195 (0.034–0.356) Verekitug Placebo Rate ratio (95% CI)Subgroups n AAER n AAER Overall 121 0.66 119 1.52 0.44 (0.28, 0.69) Age, years < 65 91 0.58 91 1.45 0.40 (0.23, 0.68) ≥ 65 30 0.87 28 1.67 0.52 (0.22, 1.22) Sex Male 48 0.47 38 2.09 0.23 (0.09, 0.57) Female 73 0.80 81 1.24 0.65 (0.39, 1.07) Region North America 32 0.51 38 0.73 0.70 (0.30, 1.62) Western Europe 17 0.63 19 1.17 0.54 (0.20, 1.47) Central/Eastern Europe 35 0.93 33 1.58 0.59 (0.28, 1.25) Rest of World 37 0.44 29 3.16 0.14 (0.05, 0.37) Steroid use and dose Medium ICS without OCS 63 0.63 61 0.99 0.64 (0.34, 1.20) High ICS and/or OCS 58 0.55 58 1.99 0.28 (0.15, 0.53) Blood eosinophil level, cells/μL < 300 62 0.98 68 0.73 1.35 (0.76, 2.42) ≥ 300 59 0.31 51 2.49 0.13 (0.06, 0.26) FeNO at baseline, ppb < 25 48 0.99 63 0.97 1.03 (0.56, 1.90) ≥ 25 73 0.45 56 2.18 0.21 (0.11, 0.40) 0.01 0.1 1 No Image Analysis of VALIANT data supports evaluation in broad populations in Phase 3, driven by FEV1 data and very low placebo AAER Favors placeboFavors verekitug 26 © 2026 Upstream Bio, Inc. AAER, annualized asthma exacerbation rate; FEV1, forced expiratory volume in 1 second; FeNO, fractional exhaled nitric oxide; ICS, inhaled corticosteroid; OCS, oral corticosteroid; ppb, parts per billion; LSM, least square mean. Top-line data reported Feb 2026. 1. Data on File. Figure 14.2.1.1.4.2. 2. At 60 weeks 3. Figure 14.2.2.2.1.7. 4. At 24 weeks AAER by subgroup1,2 FEV1 by subgroup3,4 -0.5 0.0 0.5 1.0 Favors verekitugFavors placebo

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No Image No Image No Image No Image © 2026 Upstream Bio, Inc. Verekitug’s profile supports potential for best-in-class efficacy & quarterly dosing in severe asthma and CRSwNP 27 Top-line results for Phase 2 VIBRANT study of verekitug in CRSwNP 5 clinical studies completed to date with ~500 participants dosed with verekitug Phase 2 trials delivered efficacy outcomes meeting or exceeding approved biologics in both severe asthma and CRSwNP with 100 mg dosed every 12 weeks Favorable safety profile, consistent across clinical development program Potential to deliver best-in-class efficacy in severe asthma and CRSwNP with a single high-dose quarterly injection Phase 2 trials demonstrate positive treatment effects in high and low eosinophil subgroups in severe asthma and CRSwNP Well-characterized immunogenicity profile has no meaningful impact on safety or efficacy 1 2 3 4 5

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No Image No Image No Image No Image No meaningful impact of immunogenicity on AAER or FEV1 in VALIANT Based on top-line data reported Feb 2026. Data on file: Table 14.2.1.1.5 AAER © 2025 Upstream Bio, Inc. 28 FEV1 100 mg q12w 0 12 24 36 48 60 0.0 0.1 0.2 0.3 0.4 0.5 Weeks FEV1 (Change from baseline) Placebo Verekitug (All) Verekitug (ADA-) Verekitug (ADA+) ADA+ ADA- OverallADA+ADA-OverallADA+ADA-OverallADA+ADA- 0.0 0.5 1.0 1.5 2.0 0.78 0.94 0.53 0.92 0.84 0.90 0.66 0.45 0.97 Annualized Asthma Exacerbation Rate 100 mg Q24W 100 mg Q12W 400 mg Q24W

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No Image No Image No Image No Image © 2026 Upstream Bio, Inc. Focused on disciplined execution 30 Q1 2027 – Initiate dosing in Phase 3 trials in severe asthma and CRSwNP – Engage with FDA in mid-2026 – Continue accelerated operational planning for Phase 3 start in severe asthma and CRSwNP – Continue ongoing Phase 2 trial in COPD; begin Phase 3 preparations – Ongoing investments in CMC and device development 2026 – Data from Phase 2 trial in COPD expected H2 2027 2027 – Data from severe asthma LTE expected

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