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]

Core Insights - Upstream Bio, Inc. has appointed Stacy Price as Chief Technology Officer to enhance its technical operations and product development for verekitug, a treatment for severe respiratory disorders [1][2] - The company is preparing to initiate a third clinical program for verekitug, which targets the receptor for thymic stromal lymphopoietin, a key driver of inflammatory responses [2][3] - Upstream Bio is committed to addressing unmet medical needs in severe respiratory diseases through the development of verekitug, which is currently in Phase 2 trials for severe asthma and chronic rhinosinusitis with nasal polyps [3] Company Overview - Upstream Bio is a clinical-stage biotechnology company focused on developing treatments for inflammatory diseases, particularly severe respiratory disorders [3] - The company is advancing verekitug, a monoclonal antibody that is the only known antagonist in clinical development targeting the receptor for thymic stromal lymphopoietin [3] - Upstream Bio aims to maximize the unique attributes of verekitug to meet the substantial unmet needs of patients underserved by current standard care [3]

[PART I. FINANCIAL INFORMATION](index=8&type=section&id=PART%20I.%2E%20FINANCIAL%20INFORMATION) [Item 1. Financial Statements (Unaudited)](index=8&type=section&id=Item%201.%20Financial%20Statements%20%28Unaudited%29) Presents the unaudited condensed consolidated financial statements for Upstream Bio, Inc., reporting a $27.3 million net loss and $431.4 million in cash and investments Condensed Consolidated Balance Sheet Data (in thousands) | | March 31, 2025 | December 31, 2024 | | :--- | :--- | :--- | | **Assets** | | | | Cash and cash equivalents | $71,312 | $325,892 | | Short-term investments | $360,068 | $144,559 | | Total current assets | $453,787 | $479,160 | | Total assets | $456,169 | $481,719 | | **Liabilities and Stockholders' Equity** | | | | Total current liabilities | $9,567 | $10,737 | | Total liabilities | $10,559 | $11,867 | | Total stockholders' equity | $445,610 | $469,852 | | Accumulated deficit | $(218,050) | $(190,780) | Condensed Consolidated Statements of Operations (in thousands) | | Three Months Ended March 31, 2025 | Three Months Ended March 31, 2024 | | :--- | :--- | :--- | | Collaboration revenue | $566 | $640 | | Research and development | $25,797 | $11,691 | | General and administrative | $6,782 | $3,962 | | Loss from operations | $(32,013) | $(15,013) | | Net loss | $(27,270) | $(10,894) | | Net loss per share, basic and diluted | $(0.51) | $(4.68) | Condensed Consolidated Statements of Cash Flows (in thousands) | | Three Months Ended March 31, 2025 | Three Months Ended March 31, 2024 | | :--- | :--- | :--- | | Net cash used in operating activities | $(41,165) | $(17,562) | | Net cash provided by (used in) investing activities | $(213,381) | $13,852 | | Net cash provided by (used in) financing activities | $(34) | $9,387 | [Management's Discussion and Analysis of Financial Condition and Results of Operations](index=31&type=section&id=Management%27s%20Discussion%20and%20Analysis%20of%20Financial%20Condition%20and%20Results%20of%20Operations) Discusses the company's financial condition, operational results, and future outlook, highlighting increased R&D expenses and sufficient funding through 2027 - The company is advancing its sole product candidate, verekitug, into Phase 2 trials for severe asthma, CRSwNP, and COPD. Top-line data for the CRSwNP trial is expected in **Q3 2025**, and for the severe asthma trial in the **first half of 2026**[113](index=113&type=chunk) - Based on the current operating plan, the company believes its existing cash, cash equivalents, and short-term investments of **$431.4 million** as of March 31, 2025, will be sufficient to fund operating expenses and capital expenditure requirements through **2027**[115](index=115&type=chunk)[165](index=165&type=chunk) Comparison of Results of Operations (in thousands) | | Three Months Ended March 31, 2025 | Three Months Ended March 31, 2024 | Change | | :--- | :--- | :--- | :--- | | Collaboration revenue | $566 | $640 | $(74) | | Research and development | $25,797 | $11,691 | $14,106 | | General and administrative | $6,782 | $3,962 | $2,820 | | Loss from operations | $(32,013) | $(15,013) | $(17,000) | | Net loss | $(27,270) | $(10,894) | $(16,376) | - R&D expenses increased by **$14.1 million** YoY, primarily due to a **$5.7 million** increase for the COPD indication planning, a **$3.9 million** increase for the asthma indication's Phase 2 trial and LTE study planning, and a **$1.2 million** increase for the CRSwNP Phase 2 trial[148](index=148&type=chunk)[149](index=149&type=chunk) - General and administrative expenses increased by **$2.8 million** YoY, mainly due to a **$1.9 million** increase in personnel expenses from higher headcount and a **$0.6 million** increase in corporate insurance and occupancy costs[153](index=153&type=chunk) [Item 3. Quantitative and Qualitative Disclosures About Market Risk](index=48&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 the information for this item - The company is a smaller reporting company as defined in Rule 12b-2 under the Securities Exchange Act of 1934 and is not required to provide quantitative and qualitative disclosures about market risk[182](index=182&type=chunk) [Item 4. Controls and Procedures](index=48&type=section&id=Item%204.%20Controls%20and%20Procedures) Management, including the CEO and CFO, evaluated the company's disclosure controls and procedures and concluded they were effective as of March 31, 2025. There were no material changes in internal control over financial reporting during the quarter - Management concluded that the company's disclosure controls and procedures were effective at a reasonable assurance level as of the end of the period covered by the report[184](index=184&type=chunk) - No changes in internal control over financial reporting occurred during the quarter ended March 31, 2025, that have materially affected, or are reasonably likely to materially affect, internal controls[185](index=185&type=chunk) [PART II. OTHER INFORMATION](index=49&type=section&id=PART%20II.%20OTHER%20INFORMATION) [Item 1. Legal Proceedings](index=49&type=section&id=Item%201.%20Legal%20Proceedings) The company is not currently a party to any litigation or legal proceedings that are expected to have a material adverse effect on its business - As of the report date, the company is not involved in any legal proceedings that management believes would have a material adverse effect on the business[188](index=188&type=chunk) [Item 1A. Risk Factors](index=49&type=section&id=Item%201A.%20Risk%20Factors) Outlines significant risks including limited operating history, dependence on a single product, funding needs, regulatory uncertainties, and reliance on third-party manufacturing - The company is a clinical-stage biopharmaceutical company with a limited operating history and a history of significant financial losses, which are expected to continue for the foreseeable future[192](index=192&type=chunk) - The company's business is entirely dependent on its only product candidate, verekitug. Any failure or significant delay in its development, regulatory approval, or commercialization would materially harm the business[205](index=205&type=chunk)[207](index=207&type=chunk) - The company will require additional funding to finance operations. Failure to raise capital when needed could force delays, reductions, or elimination of product development programs[197](index=197&type=chunk) - The regulatory approval processes of the FDA and other authorities are lengthy, time-consuming, and unpredictable. There is no guarantee that verekitug will obtain regulatory approval[243](index=243&type=chunk) - The company relies on third parties, such as WuXi Biologics, for manufacturing. Potential U.S. legislation like the BIOSECURE Act could materially impact its agreement with key Chinese manufacturing partners[314](index=314&type=chunk)[459](index=459&type=chunk) - The company faces risks related to the adoption and use of artificial intelligence (AI), including security risks to confidential information and an uncertain regulatory environment, such as the EU's AI Act[239](index=239&type=chunk)[240](index=240&type=chunk) [Item 2. Unregistered Sales of Equity Securities and Use of Proceeds](index=146&type=section&id=Item%202.%20Unregistered%20Sales%20of%20Equity%20Securities%20and%20Use%20of%20Proceeds) There were no unregistered sales of equity securities during the period. There has been no material change in the planned use of proceeds from the company's Initial Public Offering (IPO) as described in the final prospectus - There has been no material change in the planned use of proceeds from the IPO declared effective on October 10, 2024[480](index=480&type=chunk) [Item 5. Other Information](index=146&type=section&id=Item%205.%20Other%20Information) During the quarter ended March 31, 2025, none of the company's directors or officers adopted, modified, or terminated a Rule 10b5-1 trading arrangement or a non-Rule 10b5-1 trading arrangement - No director or officer adopted, modified, or terminated a Rule 10b5-1 or non-Rule 10b5-1 trading arrangement in Q1 2025[484](index=484&type=chunk)

[Upstream Bio First Quarter 2025 Report](index=1&type=section&id=Upstream%20Bio%20First%20Quarter%202025%20Report) [Clinical Program Highlights](index=1&type=section&id=Clinical%20Program%20Highlights) The company announced accelerated clinical timelines for verekitug, its TSLP receptor-targeting monoclonal antibody - **Verekitug is the only monoclonal antibody** in clinical development that targets and inhibits the thymic stromal lymphopoietin (TSLP) receptor[1](index=1&type=chunk)[2](index=2&type=chunk) - Top-line data from the Phase 2 clinical trial in patients with CRSwNP is now expected in the **third quarter of 2025**, accelerated from previous guidance[1](index=1&type=chunk)[2](index=2&type=chunk)[3](index=3&type=chunk) - Top-line data from the Phase 2 clinical trial in patients with severe asthma is now expected in the **first half of 2026**[1](index=1&type=chunk)[2](index=2&type=chunk)[4](index=4&type=chunk) - The first patient in the Phase 2 clinical trial for COPD is expected to be dosed in **mid-2025**[1](index=1&type=chunk)[2](index=2&type=chunk)[4](index=4&type=chunk) - The clinical trials for CRSwNP, severe asthma, and COPD are designed with endpoints that could **potentially support submissions for product approval**, pending regulatory discussions[3](index=3&type=chunk)[4](index=4&type=chunk) [First Quarter 2025 Financial Results](index=2&type=section&id=First%20Quarter%202025%20Financial%20Results) The company reported a higher net loss of $27.3 million driven by increased R&D expenses but maintains a strong cash position of $431.4 million - As of March 31, 2025, cash, cash equivalents, and short-term investments totaled **$431.4 million**, which is expected to fund planned operations through 2027[5](index=5&type=chunk) Q1 2025 vs. Q1 2024 Financial Highlights | Financial Metric | Q1 2025 (in millions) | Q1 2024 (in millions) | Change | | :--- | :--- | :--- | :--- | | Research and Development Expenses | $25.8 | $11.7 | +$14.1 | | General and Administrative Expenses | $6.8 | $4.0 | +$2.8 | | Net Loss | $27.3 | $10.9 | +$16.4 | - The increase in R&D expenses was primarily driven by **higher clinical and manufacturing costs** for the verekitug program[5](index=5&type=chunk) - The rise in G&A expenses was mainly due to **increased personnel-related costs**, including share-based compensation, and professional service fees[6](index=6&type=chunk) [Upcoming Events](index=2&type=section&id=Upcoming%20Events) The company will participate in two key healthcare and immunology conferences in June 2025 - The company will present at the **Goldman Sachs 46th Annual Global Healthcare Conference** on June 11, 2025[8](index=8&type=chunk) - The company will participate in the **European Academy of Allergy and Clinical Immunology (EAACI) Congress** in Glasgow, United Kingdom, from June 13-16, 2025[9](index=9&type=chunk) [Financial Statements](index=5&type=section&id=Financial%20Statements) This section presents the unaudited condensed consolidated balance sheet and statement of operations as of March 31, 2025 [Condensed Consolidated Balance Sheet](index=5&type=section&id=Condensed%20Consolidated%20Balance%20Sheet) Total assets decreased to $456.2 million as of March 31, 2025, primarily due to cash used in operations Balance Sheet Summary (in thousands) | Account | March 31, 2025 | December 31, 2024 | | :--- | :--- | :--- | | Cash and cash equivalents | $71,312 | $325,892 | | Short-term investments | $360,068 | $144,559 | | **Total Assets** | **$456,169** | **$481,719** | | Total Liabilities | $10,559 | $11,867 | | **Total Stockholders' Equity** | **$445,610** | **$469,852** | [Condensed Consolidated Statements of Operations](index=6&type=section&id=Condensed%20Consolidated%20Statements%20of%20Operations) The company reported a net loss of $27.3 million for the quarter, a significant increase from the prior-year period due to higher operating expenses Statement of Operations Summary (in thousands) | Account | Three Months Ended March 31, 2025 | Three Months Ended March 31, 2024 | | :--- | :--- | :--- | | Collaboration revenue | $566 | $640 | | Research and development | $25,797 | $11,691 | | General and administrative | $6,782 | $3,962 | | Loss from operations | $(32,013) | $(15,013) | | Interest income | $4,743 | $1,266 | | **Net loss** | **$(27,270)** | **$(10,894)** |