Group 1 - Upstream Bio, Inc. is a clinical-stage biotechnology company focused on developing treatments for inflammatory diseases, particularly severe respiratory disorders [4] - The company is advancing verekitug, a monoclonal antibody targeting the receptor for thymic stromal lymphopoietin (TSLP), which is involved in inflammatory responses [4] - The Phase 2 VIBRANT trial is designed to evaluate the efficacy and safety of verekitug in adults with chronic rhinosinusitis with nasal polyps (CRSwNP) [2] Group 2 - The VIBRANT trial is a global, randomized, placebo-controlled study where participants receive either 100 mg of verekitug or a placebo every 12 weeks for 24 weeks [2] - The primary endpoint of the trial is the change in endoscopic nasal polyp score (NPS) at Week 24 [2] - Top-line data from the VIBRANT trial will be reported on September 2, 2025, during a conference call and webcast [1][3]

Core Insights - Upstream Bio reported significant clinical advancements and financial results for Q2 2025, with a focus on its lead drug candidate, verekitug, aimed at treating respiratory diseases [1][5][12] Financial Performance - Revenue for Q2 2025 was $0.9 million, exceeding the estimate of $0.69 million and showing an 80% increase from $0.5 million in Q2 2024 [2][8] - Research and development expenses surged to $37.9 million, up 168.8% from $14.1 million in Q2 2024, primarily due to increased clinical and manufacturing costs related to verekitug [2][7] - General and administrative expenses rose to $7.4 million, an 85% increase from $4.0 million in Q2 2024 [2][7] - The net loss widened to $40.0 million compared to $14.7 million in Q2 2024, reflecting the transition to more expensive Phase 2 trials [2][8] - Cash reserves stood at $393.6 million as of June 30, 2025, expected to sustain operations through 2027 [8][12] Clinical Development - Upstream Bio is advancing verekitug through multiple Phase 2 clinical trials, with significant milestones achieved in severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) [1][4] - Patient enrollment for the VALIANT Phase 2 trial for severe asthma was completed in June 2025, with top-line results anticipated in early 2026 [5][12] - The VIBRANT Phase 2 trial for CRSwNP completed patient enrollment by January 2025, with efficacy data expected in Q3 2025 [5][12] - The company initiated dosing in the VENTURE Phase 2 trial for chronic obstructive pulmonary disease (COPD) in July 2025 [6][12] Product Pipeline and Competitive Position - Verekitug is the only monoclonal antibody in human trials targeting the TSLP receptor, which may offer longer intervals between doses compared to existing biologics [10][11] - The competitive landscape remains uncertain as there are no approved products or recent head-to-head data against other biologics [11] - The regulatory strategy focuses on trial endpoints that could support future marketing applications if successful [11] Future Outlook - Management highlighted two key upcoming catalysts: top-line data from the VIBRANT CRSwNP Phase 2 trial in Q3 2025 and the VALIANT severe asthma Phase 2 readout in Q1 2026 [12][13] - Investors are expected to closely monitor the outcomes of these trials, as positive results could lead to regulatory submissions and potential partnerships [13]

[PART I. FINANCIAL INFORMATION](index=8&type=section&id=PART%20I.%20FINANCIAL%20INFORMATION) [Item 1. Financial Statements (Unaudited)](index=8&type=section&id=Item%201.%20Financial%20Statements%20(Unaudited)) Presents unaudited financial statements for a clinical-stage biopharmaceutical firm, showing an accumulated deficit of **$258.0 million** - Upstream Bio, Inc. is a clinical-stage biopharmaceutical company focused on developing treatments for inflammatory diseases, with its primary product candidate being verekitug, a monoclonal antibody targeting the Thymic Stromal Lymphopoietin receptor[32](index=32&type=chunk) Condensed Consolidated Balance Sheets (Amounts in thousands) | Item | June 30, 2025 | December 31, 2024 | | :-------------------------------- | :------------ | :---------------- | | Cash and cash equivalents | $45,458 | $325,892 | | Short-term investments | $348,123 | $144,559 | | Total current assets | $418,272 | $479,160 | | Total assets | $420,521 | $481,719 | | Total current liabilities | $10,929 | $10,737 | | Total liabilities | $11,778 | $11,867 | | Total stockholders' equity | $408,743 | $469,852 | | Accumulated deficit | $(258,016) | $(190,780) | Condensed Consolidated Statements of Operations and Comprehensive Loss (Amounts in thousands) | Item | Three Months Ended June 30, 2025 | Three Months Ended June 30, 2024 | Six Months Ended June 30, 2025 | Six Months Ended June 30, 2024 | | :------------------------------------------ | :------------------------------- | :------------------------------- | :----------------------------- | :----------------------------- | | Collaboration revenue | $937 | $510 | $1,503 | $1,150 | | Research and development expenses | $37,865 | $14,069 | $63,662 | $25,760 | | General and administrative expenses | $7,419 | $3,981 | $14,201 | $7,943 | | Net loss | $(39,966) | $(14,678) | $(67,236) | $(25,572) | | Net loss per share, basic and diluted | $(0.74) | $(6.50) | $(1.25) | $(11.18) | Condensed Consolidated Statements of Cash Flows (Amounts in thousands) | Item | Six Months Ended June 30, 2025 | Six Months Ended June 30, 2024 | | :----------------------------------- | :----------------------------- | :----------------------------- | | Net cash used in operating activities | $(80,404) | $(25,598) | | Net cash used in investing activities | $(200,608) | $(102,802) | | Net cash provided by financing activities | $578 | $149,903 | | Net increase (decrease) in cash, cash equivalents and restricted cash | $(280,434) | $21,503 | | Cash, cash equivalents and restricted cash at end of period | $45,652 | $47,336 | [Condensed Consolidated Balance Sheets](index=8&type=section&id=Condensed%20Consolidated%20Balance%20Sheets) [Condensed Consolidated Statements of Operations and Comprehensive Loss](index=9&type=section&id=Condensed%20Consolidated%20Statements%20of%20Operations%20and%20Comprehensive%20Loss) [Condensed Consolidated Statement of Redeemable Convertible Preferred Stock and Stockholders' Deficit](index=10&type=section&id=Condensed%20Consolidated%20Statement%20of%20Redeemable%20Convertible%20Preferred%20Stock%20and%20Stockholders'%20Deficit) [Condensed Consolidated Statement of Stockholders' Equity](index=11&type=section&id=Condensed%20Consolidated%20Statement%20of%20Stockholders'%20Equity) [Condensed Consolidated Statements of Cash Flows](index=12&type=section&id=Condensed%20Consolidated%20Statements%20of%20Cash%20Flows) [Notes to Unaudited Condensed Consolidated Financial Statements](index=13&type=section&id=Notes%20to%20Unaudited%20Condensed%20Consolidated%20Financial%20Statements) Details business, accounting policies, and financial components, highlighting verekitug, operating losses, and external funding reliance - The company was incorporated in April 2021 and is focused on developing treatments for inflammatory diseases, with an initial focus on severe respiratory disorders, primarily advancing verekitug[32](index=32&type=chunk) - The company has incurred recurring losses and negative cash flows from operations since its inception, with net losses of **$67.2 million** and **$25.6 million** for the six months ended June 30, 2025 and 2024, respectively, and an accumulated deficit of **$258.0 million** as of June 30, 2025[36](index=36&type=chunk) - On October 4, 2024, the company effected a **1.049-for-one stock split** of its common stock and proportional adjustment to preferred stock conversion ratios[34](index=34&type=chunk) - The company expects its cash, cash equivalents, and short-term investments to be sufficient to fund operating expenses and capital expenditure requirements for at least the next twelve months from the issuance date of these financial statements[37](index=37&type=chunk) [1. Nature of the business and basis of presentation](index=13&type=section&id=1.%20Nature%20of%20the%20business%20and%20basis%20of%20presentation) [2. Summary of Significant Accounting Policies](index=15&type=section&id=2.%20Summary%20of%20Significant%20Accounting%20Policies) [3. Fair value measurements](index=16&type=section&id=3.%20Fair%20value%20measurements) [4. Prepaid expenses and other current assets](index=18&type=section&id=4.%20Prepaid%20expenses%20and%20other%20current%20assets) [5. Property and equipment, net](index=18&type=section&id=5.%20Property%20and%20equipment,%20net) [6. Accrued expenses and other current liabilities](index=18&type=section&id=6.%20Accrued%20expenses%20and%20other%20current%20liabilities) [7. Leases](index=18&type=section&id=7.%20Leases) [8. Redeemable convertible preferred stock](index=18&type=section&id=8.%20Redeemable%20convertible%20preferred%20stock) [9. Common stock](index=19&type=section&id=9.%20Common%20stock) [10. Stock-based compensation](index=20&type=section&id=10.%20Stock-based%20compensation) [11. Income Taxes](index=22&type=section&id=11.%20Income%20Taxes) [12. Net loss per share](index=22&type=section&id=12.%20Net%20loss%20per%20share) [13. Commitments and contingencies](index=23&type=section&id=13.%20Commitments%20and%20contingencies) [14. License agreements](index=23&type=section&id=14.%20License%20agreements) [15. Revenue](index=25&type=section&id=15.%20Revenue) [16. Related parties](index=25&type=section&id=16.%20Related%20parties) [17. Segment reporting](index=27&type=section&id=17.%20Segment%20reporting) [Item 2. Management's Discussion and Analysis of Financial Condition and Results of Operations](index=28&type=section&id=Item%202.%20Management's%20Discussion%20and%20Analysis%20of%20Financial%20Condition%20and%20Results%20of%20Operations) Management discusses financial performance, verekitug development, operating losses, R&D/G&A expenses, and funding needs through **2027** - Upstream Bio is a clinical-stage biotechnology company developing verekitug for inflammatory diseases, with Phase 2 trials for severe asthma, CRSwNP, and COPD. Enrollment for CRSwNP Phase 2 completed in January 2025 (top-line data expected Q3 2025), severe asthma Phase 2 completed in June 2025 (top-line data expected Q1 2026), and COPD Phase 2 initiated in July 2025[114](index=114&type=chunk) - The company has incurred significant net operating losses since inception, reporting net losses of **$40.0 million** and **$14.7 million** for the three months ended June 30, 2025 and 2024, respectively, and **$67.2 million** and **$25.6 million** for the six months ended June 30, 2025 and 2024, respectively[116](index=116&type=chunk)[147](index=147&type=chunk)[154](index=154&type=chunk) - As of June 30, 2025, the company had cash, cash equivalents, and short-term investments of **$393.6 million**, which are believed to be sufficient to fund operating expenses and capital expenditure requirements through **2027**[116](index=116&type=chunk)[163](index=163&type=chunk)[173](index=173&type=chunk) Key Financial Changes (Three Months Ended June 30, 2025 vs 2024, in thousands) | Item | 2025 | 2024 | Change | | :-------------------------- | :----- | :----- | :----- | | Collaboration revenue | $937 | $510 | $427 | | Research and development | $37,865 | $14,069 | $23,796 | | General and administrative | $7,419 | $3,981 | $3,438 | | Net loss | $(39,966) | $(14,678) | $(25,288) | Key Financial Changes (Six Months Ended June 30, 2025 vs 2024, in thousands) | Item | 2025 | 2024 | Change | | :-------------------------- | :----- | :----- | :----- | | Collaboration revenue | $1,503 | $1,150 | $353 | | Research and development | $63,662 | $25,760 | $37,902 | | General and administrative | $14,201 | $7,943 | $6,258 | | Net loss | $(67,236) | $(25,572) | $(41,664) | [Overview](index=28&type=section&id=Overview) [Asset purchase and license agreements](index=30&type=section&id=Asset%20purchase%20and%20license%20agreements) [Components of our results of operations](index=32&type=section&id=Components%20of%20our%20results%20of%20operations) [Results of operations](index=35&type=section&id=Results%20of%20operations) [Liquidity and capital resources](index=39&type=section&id=Liquidity%20and%20capital%20resources) [Contractual obligations and other commitments](index=43&type=section&id=Contractual%20obligations%20and%20other%20commitments) [Critical accounting estimates and significant judgments](index=43&type=section&id=Critical%20accounting%20estimates%20and%20significant%20judgments) [Recently issued and adopted accounting pronouncements](index=45&type=section&id=Recently%20issued%20and%20adopted%20accounting%20pronouncements) [Emerging growth company and smaller reporting company status](index=45&type=section&id=Emerging%20growth%20company%20and%20smaller%20reporting%20company%20status) [Item 3. Quantitative and Qualitative Disclosures About Market Risk](index=45&type=section&id=Item%203.%20Quantitative%20and%20Qualitative%20Disclosures%20About%20Market%20Risk) As a smaller reporting company, Upstream Bio, Inc. is not required to provide quantitative and qualitative disclosures about market risk - The company is a smaller reporting company and is not required to provide quantitative and qualitative disclosures about market risk[191](index=191&type=chunk) [Item 4. Controls and Procedures](index=45&type=section&id=Item%204.%20Controls%20and%20Procedures) Management evaluated disclosure controls and procedures as effective as of June 30, 2025, with no material changes in internal control over financial reporting during the quarter - The principal executive officer and principal financial officer concluded that the company's disclosure controls and procedures were effective as of June 30, 2025, at the reasonable assurance level[193](index=193&type=chunk) - There have been no material changes in the company's internal control over financial reporting during the quarter ended June 30, 2025[194](index=194&type=chunk) [Management's evaluation of disclosure controls and procedures](index=45&type=section&id=Management's%20evaluation%20of%20disclosure%20controls%20and%20procedures) [Changes in internal control over financial reporting](index=47&type=section&id=Changes%20in%20internal%20control%20over%20financial%20reporting) [PART II. OTHER INFORMATION](index=48&type=section&id=PART%20II.%20OTHER%20INFORMATION) [Item 1. Legal Proceedings](index=48&type=section&id=Item%201.%20Legal%20Proceedings) The company is not currently a party to any material litigation or legal proceedings probable to have a material adverse effect on its business - The company is not currently involved in any material legal proceedings or claims that are probable to have a material adverse effect on its business[95](index=95&type=chunk)[196](index=196&type=chunk) [Item 1A. Risk Factors](index=48&type=section&id=Item%201A.%20Risk%20Factors) Details significant risks: limited operating history, financial losses, capital needs, verekitug development, competition, third-party reliance, and IP challenges - The company is a clinical-stage biopharmaceutical company with a limited operating history, has incurred significant financial losses since inception, and anticipates continued losses, making it difficult to evaluate future success[200](index=200&type=chunk)[201](index=201&type=chunk) - Verekitug is the company's only product candidate, making the business entirely dependent on its successful development, regulatory approval, and commercialization, which is a lengthy, expensive, and highly uncertain process[213](index=213&type=chunk)[215](index=215&type=chunk)[218](index=218&type=chunk) - The company relies on third parties for clinical trials and manufacturing, increasing risks related to supply, quality, regulatory compliance, and potential delays, especially with current manufacturing partner WuXi Biologics facing legislative scrutiny[305](index=305&type=chunk)[321](index=321&type=chunk)[322](index=322&type=chunk) - The company faces significant competition in the inflammatory disease market from major pharmaceutical and biotechnology companies with greater resources and established market presence[288](index=288&type=chunk)[291](index=291&type=chunk) - Protecting intellectual property is crucial but uncertain due to the complex patent application process, potential challenges to existing patents, and the risk of third-party infringement claims[396](index=396&type=chunk)[398](index=398&type=chunk)[403](index=403&type=chunk) [Risks related to our limited operating history, financial condition and need for additional capital](index=48&type=section&id=Risks%20related%20to%20our%20limited%20operating%20history,%20financial%20condition%20and%20need%20for%20additional%20capital) [Risks related to our business](index=53&type=section&id=Risks%20related%20to%20our%20business) [Risks related to the discovery and development of verekitug or any other potential future product candidates](index=66&type=section&id=Risks%20related%20to%20the%20discovery%20and%20development%20of%20verekitug%20or%20any%20other%20potential%20future%20product%20candidates) [Risks related to the commercialization of verekitug or any other potential future product candidates](index=77&type=section&id=Risks%20related%20to%20the%20commercialization%20of%20verekitug%20or%20any%20other%20potential%20future%20product%20candidates) [Risks related to government regulation](index=95&type=section&id=Risks%20related%20to%20government%20regulation) [Risks related to our intellectual property](index=111&type=section&id=Risks%20related%20to%20our%20intellectual%20property) [Risks related to ownership of our common stock](index=126&type=section&id=Risks%20related%20to%20ownership%20of%20our%20common%20stock) [Other general risks](index=133&type=section&id=Other%20general%20risks) [Item 2. Unregistered Sales of Equity Securities and Use of Proceeds](index=142&type=section&id=Item%202.%20Unregistered%20Sales%20of%20Equity%20Securities%20and%20Use%20of%20Proceeds) Confirms no unregistered equity sales and no material change in planned IPO proceeds use - No unregistered sales of equity securities occurred during the period[486](index=486&type=chunk) - There has been no material change in the planned use of proceeds from the IPO[487](index=487&type=chunk) [Item 3. Defaults Upon Senior Securities](index=142&type=section&id=Item%203.%20Defaults%20Upon%20Senior%20Securities) The company reported no defaults upon senior securities during the period - There were no defaults upon senior securities[489](index=489&type=chunk) [Item 4. Mine Safety Disclosures](index=142&type=section&id=Item%204.%20Mine%20Safety%20Disclosures) This item is not applicable to the company - This item is not applicable to the company[490](index=490&type=chunk) [Item 5. Other Information](index=142&type=section&id=Item%205.%20Other%20Information) No other information to report, and no Rule 10b5-1 trading arrangement changes by directors or officers - No directors or officers adopted, modified, or terminated a Rule 10b5-1 trading arrangement during the quarter ended June 30, 2025[491](index=491&type=chunk) [Item 6. Exhibits](index=143&type=section&id=Item%206.%20Exhibits) Lists Form 10-Q exhibits: corporate charter documents, stock certificates, and officer certifications - The exhibits include the Third Amended and Restated Certificate of Incorporation, Second Amended and Restated Bylaws, Specimen Common Stock Certificate, and certifications from the Principal Executive Officer and Principal Financial Officer[493](index=493&type=chunk) [Signatures](index=144&type=section&id=Signatures) The report is duly signed by E. Rand Sutherland (CEO) and Michael Paul Gray (CFO/COO) on August 6, 2025 - The report was signed by E. Rand Sutherland, Chief Executive Officer, and Michael Paul Gray, Chief Financial and Operating Officer, on August 6, 2025[499](index=499&type=chunk)

Executive Summary & Company Overview Upstream Bio is a clinical-stage biotech developing verekitug for inflammatory diseases, with ongoing Phase 2 trials and upcoming data readouts [Company Profile and Strategic Focus](index=1&type=section&id=Company%20Profile%20and%20Strategic%20Focus) Upstream Bio is a clinical-stage biotechnology company focused on developing treatments for inflammatory diseases, particularly severe respiratory disorders - Upstream Bio is a clinical-stage company developing **verekitug**, the only monoclonal antibody currently in clinical development that targets and inhibits the thymic stromal lymphopoietin (TSLP) receptor[1](index=1&type=chunk) - The company's initial focus is on severe respiratory disorders, including chronic rhinosinusitis with nasal polyps (CRSwNP), severe asthma, and chronic obstructive pulmonary disease (COPD)[1](index=1&type=chunk) - Verekitug's unique pharmacology is believed to offer differentiated efficacy and an extended dosing interval compared to current standard of care biologics[1](index=1&type=chunk)[2](index=2&type=chunk) [Key Clinical Development Highlights](index=1&type=section&id=Key%20Clinical%20Development%20Highlights) Upstream Bio reported significant progress in its clinical development programs for verekitug, including completing enrollment for the severe asthma trial and initiating the COPD trial, while remaining on track for key data readouts - Completed enrollment in Phase 2 trial in severe asthma (VALIANT) in **June 2025**; top-line data expected in the **first quarter of 2026**[1](index=1&type=chunk)[2](index=2&type=chunk) - First patient dosed in Phase 2 trial in chronic obstructive pulmonary disease (COPD) (VENTURE) in **July 2025**, marking entry into a third major respiratory indication[1](index=1&type=chunk)[2](index=2&type=chunk) - On track to report top-line data from Phase 2 trial in chronic rhinosinusitis with nasal polyps (CRSwNP) (VIBRANT) in the **third quarter of 2025**[1](index=1&type=chunk)[2](index=2&type=chunk) Clinical Development Programs Upstream Bio is advancing verekitug through multiple Phase 2 clinical trials for severe respiratory disorders, with several key data readouts anticipated [Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) Program](index=1&type=section&id=Chronic%20Rhinosinusitis%20with%20Nasal%20Polyps%20(CRSwNP)%20Program) The VIBRANT Phase 2 trial for CRSwNP completed patient enrollment in January 2025, with top-line data anticipated in the third quarter of 2025 - Top-line data from the VIBRANT Phase 2 trial in CRSwNP expected in **Q3 2025**[3](index=3&type=chunk) - VIBRANT is a global, randomized, double-blind, placebo-controlled, parallel group clinical trial assessing verekitug efficacy and safety, dosed every **12 weeks**[3](index=3&type=chunk) - Patient enrollment for VIBRANT was completed in **January 2025**[3](index=3&type=chunk) [Severe Asthma Program](index=2&type=section&id=Severe%20Asthma%20Program) The VALIANT Phase 2 trial for severe asthma completed enrollment in June 2025, with top-line data expected in Q1 2026 - Top-line data from the VALIANT Phase 2 trial in severe asthma expected in **Q1 2026**[4](index=4&type=chunk) - VALIANT is a global, randomized, double-blind, placebo-controlled trial assessing verekitug efficacy and safety with extended dosing intervals of **12 and 24 weeks**[4](index=4&type=chunk) - Initiated long term extension study (VALOUR) in severe asthma in **May 2025** for eligible participants who completed the VALIANT trial[9](index=9&type=chunk) [Chronic Obstructive Pulmonary Disease (COPD) Program](index=2&type=section&id=Chronic%20Obstructive%20Pulmonary%20Disease%20(COPD)%20Program) Upstream Bio entered a third major respiratory indication with the initiation of the VENTURE Phase 2 clinical trial for moderate-to-severe COPD in July 2025 - First patient dosed in the VENTURE Phase 2 clinical trial in patients with COPD in **July 2025**, marking entry into a third major respiratory indication[9](index=9&type=chunk) - VENTURE is a global, randomized, double-blind, placebo-controlled trial designed to assess verekitug efficacy and safety in moderate-to-severe COPD with extended dosing intervals of **12 and 24 weeks**[9](index=9&type=chunk) Second Quarter 2025 Financial Results Upstream Bio reported a strong cash position expected to fund operations through 2027, despite increased operating expenses and a larger net loss in Q2 2025 [Cash Position and Runway](index=2&type=section&id=Cash%20Position%20and%20Runway) As of June 30, 2025, Upstream Bio maintained a strong cash position, which is projected to fund its planned operations through 2027 Cash, Cash Equivalents and Short-Term Investments | Metric | Amount (Millions) | | :-------------------------------- | :------------------ | | Cash, cash equivalents and short-term investments (June 30, 2025) | $393.6 | - The current cash position is expected to fund planned operations through **2027**[6](index=6&type=chunk) [Operating Expenses](index=2&type=section&id=Operating%20Expenses) Operating expenses significantly increased in Q2 2025 compared to Q2 2024, driven primarily by higher clinical and manufacturing costs for verekitug programs and increased personnel-related expenses Operating Expenses (Three Months Ended June 30) | Expense Category | Q2 2025 (Millions) | Q2 2024 (Millions) | Change (Millions) | Change (%) | | :----------------------- | :----------------- | :----------------- | :---------------- | :--------- | | Research and development | $37.9 | $14.1 | +$23.8 | +168.8% | | General and administrative | $7.4 | $4.0 | +$3.4 | +85.0% | - Increase in R&D expenses was primarily due to increased clinical and manufacturing expenses related to verekitug programs[6](index=6&type=chunk) - Increase in G&A expenses was primarily driven by higher personnel-related expenses, including share-based compensation, and professional service fees[7](index=7&type=chunk) [Net Loss](index=2&type=section&id=Net%20Loss) Upstream Bio reported a substantially larger net loss in Q2 2025 compared to the same period in 2024, mainly attributable to the increased research and development and general and administrative expenses Net Loss (Three Months Ended June 30) | Metric | Q2 2025 (Millions) | Q2 2024 (Millions) | Change (Millions) | Change (%) | | :------- | :----------------- | :----------------- | :---------------- | :--------- | | Net loss | $(40.0) | $(14.7) | $(25.3) | +172.1% | - The increase in net loss was largely due to increased research and development and general and administrative expenses, partially offset by increased interest income[8](index=8&type=chunk) Corporate Information This section provides an overview of Upstream Bio's mission, upcoming investor events, and important disclosures regarding forward-looking statements [About Upstream Bio](index=3&type=section&id=About%20Upstream%20Bio) Upstream Bio is dedicated to developing verekitug, a highly potent TSLP receptor antagonist, to address significant unmet needs in inflammatory diseases, particularly severe respiratory disorders, leveraging its unique mechanism of action - Upstream Bio is a clinical-stage biotechnology company developing treatments for inflammatory diseases, with an initial focus on severe respiratory disorders[11](index=11&type=chunk) - Verekitug is the only known antagonist currently in clinical development that targets the receptor for thymic stromal lymphopoietin (TSLP), a clinically validated driver of inflammatory response[11](index=11&type=chunk) - The company is committed to maximizing verekitug's unique attributes to address substantial unmet needs for patients underserved by today's standard of care[11](index=11&type=chunk) [Upcoming Events & Investor Relations](index=2&type=section&id=Upcoming%20Events%20%26%20Investor%20Relations) Upstream Bio plans to participate in several investor conferences and medical congresses in Q3 and Q4 2025 and utilizes its investor relations website as a primary channel for disclosing material nonpublic information - Upstream Bio expects to participate in the Stifel Virtual Immunology and Inflammation Forum (**September 15–16, 2025**), European Respiratory Society (**September 27–October 1, 2025**), and 2025 Truist Securities Biopharma Symposium (**November 6, 2025**)[10](index=10&type=chunk) - The company intends to use the investor relations page on its website (www.upstreambio.com) for disclosing material nonpublic information and complying with Regulation FD[12](index=12&type=chunk) [Forward-Looking Statements](index=3&type=section&id=Forward-Looking%20Statements) This section contains standard forward-looking statements, highlighting risks and uncertainties related to the clinical development, regulatory approval, funding, and commercialization of verekitug, as well as other business risks - Statements regarding the timing, progress, and results of ongoing and planned clinical trials for verekitug are forward-looking[13](index=13&type=chunk) - Risks include Upstream Bio's ability to advance verekitug through clinical development, obtain regulatory approval, fund development activities, and its dependence on third parties[13](index=13&type=chunk) - Readers are cautioned that actual results could differ materially due to various risks and uncertainties detailed in the company's SEC filings[13](index=13&type=chunk)[14](index=14&type=chunk) Condensed Consolidated Financial Statements This section presents Upstream Bio's condensed consolidated financial statements, including the balance sheet and statements of operations, for the periods ended June 30, 2025 [Condensed Consolidated Balance Sheet](index=5&type=section&id=Condensed%20Consolidated%20Balance%20Sheet) The balance sheet provides a snapshot of Upstream Bio's financial position, showing a decrease in total assets and stockholders' equity from December 31, 2024, to June 30, 202

Core Insights - Upstream Bio, Inc. is advancing its clinical development programs for verekitug, a monoclonal antibody targeting the TSLP receptor, focusing on severe respiratory diseases such as chronic rhinosinusitis with nasal polyps (CRSwNP), severe asthma, and chronic obstructive pulmonary disease (COPD) [1][2] Clinical Development Progress - The company is on track to report top-line data from the Phase 2 trial in CRSwNP in the third quarter of 2025 [1][5] - Enrollment in the Phase 2 trial for severe asthma was completed in June 2025, with top-line data expected in the first quarter of 2026 [1][5] - The first patient was dosed in the Phase 2 trial for COPD in July 2025, marking the entry into a third major respiratory indication [1][5] Financial Performance - As of June 30, 2025, Upstream Bio had cash, cash equivalents, and short-term investments totaling $393.6 million, which is projected to fund operations through 2027 [6] - Research and development expenses for the second quarter of 2025 were $37.9 million, a significant increase from $14.1 million in the same period of 2024, primarily due to clinical and manufacturing costs related to verekitug [6] - General and administrative expenses rose to $7.4 million for the quarter ended June 30, 2025, compared to $4.0 million for the same period in 2024, driven by personnel-related expenses and professional service fees [7] Net Loss - The net loss for the quarter ended June 30, 2025, was $40.0 million, compared to a net loss of $14.7 million for the same period in 2024, largely due to increased operating expenses [8][16]

Core Insights - Upstream Bio has initiated a Phase 2 clinical trial, VENTURE, to evaluate the efficacy and safety of verekitug in patients with moderate-to-severe COPD, marking the expansion of its global development program into a third indication [1][3] - Verekitug is a novel antibody antagonist targeting the TSLP receptor, which plays a significant role in the inflammatory response associated with allergic and inflammatory diseases [2][6] - The trial aims to assess the annualized rate of moderate or severe COPD exacerbations as the primary endpoint, with secondary endpoints including changes in symptoms and lung function [4] Company Overview - Upstream Bio is a clinical-stage biotechnology company focused on developing treatments for inflammatory diseases, particularly severe respiratory disorders [17] - The company is advancing verekitug, the only known monoclonal antibody in clinical development targeting the TSLP receptor, through multiple Phase 2 trials for CRSwNP, severe asthma, and COPD [9][17] - The company aims to address unmet needs in patient populations underserved by current standard treatments [18] Clinical Trial Details - The VENTURE trial is a randomized, double-blind, placebo-controlled study involving approximately 670 adults with moderate-to-severe COPD, with treatment periods ranging from 60 to 108 weeks [3][4] - Participants will receive either verekitug at doses of 100 mg every 12 weeks, 400 mg every 24 weeks, or a placebo [3] - The trial is designed to potentially support regulatory submissions based on the data collected [4] Current Research and Development - Upstream Bio has completed enrollment in separate Phase 2 trials for CRSwNP and severe asthma, with top-line data expected in the third quarter of 2025 and the first quarter of 2026, respectively [5] - Preclinical studies have shown that verekitug effectively inhibits TSLP signaling and demonstrates potential efficacy against various types of inflammation [10][11] Disease Context - COPD is a chronic inflammatory disease that significantly impacts airflow and is associated with high morbidity and mortality, being the fourth leading cause of death globally [12][14] - The prevalence of COPD is projected to increase due to ongoing exposure to risk factors and an aging population [14] - Current treatments for COPD include inhaled steroids and bronchodilators, with biologics emerging as new treatment options [16]

Core Insights - Upstream Bio, Inc. presented pharmacology modeling data at the EAACI Congress, highlighting the greater potency of verekitug compared to tezepelumab in treating inflammatory diseases [1][3] - Verekitug targets the TSLP receptor, offering a potentially differentiated profile across severe asthma, COPD, and CRSwNP [1][2] Company Overview - Upstream Bio is a clinical-stage biotechnology company focused on developing treatments for inflammatory diseases, particularly severe respiratory disorders [11] - Verekitug is the only monoclonal antibody in clinical development that targets and inhibits the TSLP receptor, which is a key driver of inflammatory responses [2][11] Mechanism of Action - TSLP is a cytokine that initiates the inflammatory cascade, and blocking its receptor can impact multiple inflammatory processes [2][5] - The pharmacokinetic/pharmacodynamic (PK/PD) modeling indicates that verekitug provides complete and sustained inhibition of the TSLP/TSLPR complex, leading to a greater reduction in fractional exhaled nitric oxide (FeNO) compared to tezepelumab [6][8] Clinical Development - Verekitug is currently being evaluated in two Phase 2 clinical trials: the VALIANT trial for severe asthma and the VIBRANT trial for CRSwNP, with plans for a trial in COPD [8][10] - The company anticipates top-line Phase 2 clinical data for CRSwNP in Q3 2025 and for severe asthma in the first half of 2026 [3][8] Preclinical and Clinical Data - Preclinical studies demonstrated that verekitug has high occupancy of the TSLP receptor and effectively inhibits TSLP signaling [9] - Previous clinical trials showed that verekitug was well tolerated and exhibited a predictable pharmacokinetic profile [10]

Financial Data and Key Metrics Changes - The company reported $430 million in cash at the end of the last quarter, which is expected to sustain operations through 2027, covering key milestones such as nasal polyps and severe asthma readouts [73][74]. Business Line Data and Key Metrics Changes - The company is developing Virecitug, a monoclonal antibody targeting the receptor for TSLP, which is unique in the market as it is the only drug in development targeting the receptor rather than the ligand [3][13]. - Clinical trials indicate that Virecitug can be dosed every 12 or 24 weeks, potentially offering a differentiated dosing schedule compared to competitors [4][19]. Market Data and Key Metrics Changes - The competitive landscape includes established products like tezepelumab, which targets the TSLP ligand, and the company believes that targeting the receptor may provide superior efficacy and broader patient eligibility [9][12][36]. Company Strategy and Development Direction - The company aims to differentiate itself through the unique pharmacology of Virecitug, which shows significant effects on disease-driving biomarkers like exhaled nitric oxide and blood eosinophils [13][25]. - The strategic focus includes exploring the potential for Virecitug in chronic rhinosinusitis and COPD, with plans to design trials that could demonstrate efficacy in these areas [71][72]. Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the safety profile of TSLP signaling, drawing parallels with the clean label of tezepelumab, and anticipates a similar profile for Virecitug [23][38]. - The company is actively preparing for commercial considerations and market access strategies as it progresses through clinical development [75][76]. Other Important Information - The company has completed enrollment in its nasal polyp study and expects to release data in Q3 of this year, with a robust trial design aimed at regulatory approval [49][50]. - The company is considering both in-office and at-home administration options for Virecitug, aligning with patient visit schedules [45][46]. Q&A Session Summary Question: Can you clarify the dosing intervals and their implications? - The company explained that the receptor is expressed at a low level compared to the circulating ligand, allowing for extended dosing intervals without significant risks [20][21]. Question: How does the company view the competitive landscape with other agents? - Management noted that while there are various agents in development, the efficacy and breadth of eligibility will drive prescribing behaviors, with a focus on the convenience of dosing intervals [33][37]. Question: What is the company's cash runway and future funding plans? - The company confirmed a strong cash position that supports its current and future clinical programs, although additional funds will be needed over time [73][74].

Core Insights - Upstream Bio, Inc. is focused on developing treatments for inflammatory diseases, particularly severe respiratory disorders, and will present new data on June 15, 2025, at the EAACI Congress 2025 in Glasgow, UK [1][2] Group 1: Presentation Details - The presentation will discuss translational pharmacology modeling data that supports the targeting of the TSLP receptor with verekitug, showing greater potency compared to treatments targeting the TSLP ligand [1][2] - The presenting author is Ashish Kalra, PhD, Vice President of Translational Research at Upstream Bio, and the poster number is D3.113 [2] Group 2: TSLP and TSLPR Blockade - Thymic Stromal Lymphopoietin (TSLP) is a key cytokine in the inflammatory response for diseases like asthma, and blocking TSLP signaling is a validated therapeutic strategy [3] - TSLP activation initiates a cascade of inflammatory responses, making TSLPR blockade a potential single treatment for multiple inflammatory diseases [4] Group 3: About Verekitug - Verekitug is a novel fully human IgG1 monoclonal antibody that inhibits TSLP receptor signaling and is currently the only mAb in clinical development targeting this receptor [5][8] - It is being evaluated in two Phase 2 clinical trials: the VALIANT trial for severe asthma and the VIBRANT trial for chronic rhinosinusitis with nasal polyps, with an additional trial for COPD being initiated [5][9] - Preclinical studies indicate verekitug has high receptor occupancy and effectively inhibits TSLP signaling, suggesting potential efficacy against various inflammatory conditions [6] Group 4: Clinical Trials and Development - Three clinical trials for verekitug have been completed, showing it was well tolerated with no significant immunogenicity and a consistent pharmacokinetic profile [7] - The company aims to address unmet needs in patients with severe respiratory disorders through the development of verekitug [9]

Company Overview - Upstream Bio, Inc. is a clinical-stage biotechnology company focused on developing treatments for inflammatory diseases, particularly severe respiratory disorders [3] - The company is advancing a monoclonal antibody named verekitug, which targets the receptor for thymic stromal lymphopoietin, a key cytokine involved in inflammatory responses [3] - Verekitug is currently in separate Phase 2 trials for severe asthma and chronic rhinosinusitis with nasal polyps, with plans to initiate development for chronic obstructive pulmonary disease [3] Upcoming Events - Rand Sutherland, MD, CEO of Upstream Bio, will participate in a fireside chat at the Goldman Sachs 46th Annual Global Healthcare Conference on June 11, 2025, at 9:20 a.m. ET [1] - A live webcast of the event will be available on the company's website, with a replay posted afterward [2]