Translational Data Reveal Mechanism Behind Verekitug’s Enhanced Potency as a Novel TSLP Receptor Antibody Antagonist

– Modeling data presented at the EAACI Congress points to verekitug’s enhanced potency compared to tezepelumab –

– Supports potential for verekitug’s differentiated profile across multiple inflammatory diseases, including severe asthma, COPD, and CRSwNP –

WALTHAM, Mass. – June 15, 2025 – Biotech firm Upstream Bio (Nasdaq: UPB), is making waves with promising data on its lead candidate, verekitug, aimed at treating a range of inflammatory respiratory conditions. The company announced today the presentation of compelling translational pharmacology modeling data at the European Academy of Allergy & Clinical Immunology (EAACI) Congress, held in Glasgow, UK, from June 13-16, 2025. The data suggests verekitug, which targets the Thymic Stromal Lymphopoietin (TSLP) receptor, may offer enhanced potency compared to treatments focused on the TSLP ligand itself.

TSLP, a key driver of inflammation in diseases like asthma, has already shown its clinical significance as a therapeutic target. By blocking the TSLP receptor, verekitug could potentially address the root of multiple inflammatory pathways across a spectrum of diseases. Upstream Bio is actively developing verekitug for severe asthma, chronic obstructive pulmonary disease (COPD), and chronic rhinosinusitis with nasal polyps (CRSwNP). Notably, verekitug stands out as the only monoclonal antibody currently in clinical development specifically designed to target the TSLP receptor and inhibit its function.

“These findings strengthen our confidence in verekitug’s distinct profile,” stated Dr. Aaron Deykin, Chief Medical Officer and Head of Research & Development at Upstream Bio. “The model illuminates the critical biological factors driving the swift, substantial, and enduring treatment effects observed through TSLP receptor inhibition with verekitug. We are eager to see if this unique mechanism translates into tangible clinical benefits for patients battling severe respiratory diseases, with top-line results from Phase 2 trials in CRSwNP expected in the third quarter of this year, followed by severe asthma data in the first half of 2026.”

The modeling approach, used for the presentation, employed an in silico system pharmacology method to explain verekitug’s observed potency. The key takeaways are:

• Semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) models were constructed, using identical biological and drug-specific parameters for verekitug and tezepelumab, and populated with existing clinical data for verekitug and published data for tezepelumab.
• Simulations of these PK/PD models suggest that, across various doses, verekitug provides complete and sustained inhibition of the TSLP/TSLPR complex, compared to tezepelumab.
• Dose-response model simulations predict that effective inhibition of the TSLP/TSLPR complex would lead to a greater reduction in fractional exhaled nitric oxide (FeNO), a biomarker of lung inflammation.
• The data indicates that verekitug’s predicted greater reduction in FeNO, compared with published data for tezepelumab, may stem from TSLP receptor’s lower expression levels over time relative to the ligand, along with slower protein turnover rates for the TSLP receptor versus the ligand.
• This data points to the potential for the differentiated mechanism of TSLP receptor targeting with verekitug to provide superior potency when compared to treatments that target the TSLP ligand directly.
• Upstream Bio is currently conducting Phase 2 clinical trials in severe asthma and CRSwNP, and plans to launch a trial in COPD to further assess the potential clinical advantages of verekitug’s unique targeting mechanism for patients.

A digital copy of the presentation is available on the Upstream Bio website.

Decoding TSLP and TSLPR Blockade
Thymic Stromal Lymphopoietin (TSLP) is a cytokine playing a pivotal role in driving the inflammatory response in common allergic and inflammatory conditions, like asthma, where disrupting TSLP signaling has already been validated as a successful treatment strategy.

TSLP activation sets off the initial steps in the inflammatory cascade, triggered by allergens, viruses, and other irritants, prompting the activation of downstream targets like IL-4, IL-5, IL-13, IL-17, and IgE. Given that TSLP’s role is further “upstream” in this inflammatory process, blocking the TSLP receptor (TSLPR) presents a chance for a single therapy to address the drivers of multiple pathological inflammatory processes across many diseases.

Verekitug: The Novel Approach
Verekitug is a cutting-edge recombinant, fully human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to the TSLP receptor, subsequently inhibiting pro-inflammatory signaling initiated by TSLP. As mentioned before, it is the only such antibody currently in clinical development that directly targets and inhibits the TSLP receptor. Verekitug is being evaluated in two separate multi-national, placebo-controlled, randomized Phase 2 clinical trials: The VALIANT trial for those with severe asthma (NCT06196879) and the VIBRANT trial in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) (NCT06164704). Upstream Bio is also launching a Phase 2 clinical trial (NCT06981078) of verekitug in individuals with moderate-to-severe chronic obstructive pulmonary disease (COPD).

In preclinical studies, verekitug demonstrated strong binding to the TSLP receptor and potent inhibition of TSLP signaling. Moreover, verekitug inhibited cytokine production from both CD4+ T cells and ILC2 cells and completely suppressed skin allergic reactions in a non-human primate model, indicating its potential effectiveness against various forms of inflammation.

Prior clinical trials of verekitug have been completed, including a Phase 1 single-ascending dose (SAD) study and a Phase 1b multiple-ascending dose (MAD) study. Verekitug was well tolerated in these trials, showed no clinically significant immunogenicity, and displayed predictable and consistent pharmacokinetic profiles with high subcutaneous bioavailability.

About Upstream Bio
Upstream Bio is a clinical-stage biotechnology firm focused on developing treatments for inflammatory diseases, particularly severe respiratory disorders. The company is developing verekitug, which is the only known antagonist currently in clinical development aimed at the receptor for thymic stromal lymphopoietin (TSLP). TSLP is a clinically validated driver of inflammatory responses and is positioned upstream of multiple signaling cascades that impact a variety of immune-mediated diseases. The company has advanced this highly potent monoclonal antibody into Phase 2 trials for the treatment of severe asthma and chronic rhinosinusitis with nasal polyps and is starting development in chronic obstructive pulmonary disease. The team at Upstream Bio is committed to maximizing verekitug’s unique properties to help patients who are underserved by current standards of care. To learn more, visit www.upstreambio.com.

Forward-Looking Statements
This press release 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 press release 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 initiation, timing, progress and results of ongoing and planned clinical trials; expectations for future discussions with regulatory authorities and the potential of the endpoints of the Company’s clinical trials to produce data that could support submissions for product approval; expectations regarding the differentiation, safety, efficacy or tolerability of verekitug; expectations regarding the translation of pharmacology modeling data of verekitug to clinical effects; and assessments comparing non-head-to-head clinical data of verekitug to published data for tezepelumab. Any forward-looking statements in this press release are based on the Company’s current expectations, estimates and projections only as of the date of this release and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. Readers are cautioned that actual results, levels of activity, safety, efficacy, performance or events and circumstances could differ materially from those expressed or implied in the Company’s forward-looking statements due to a variety of risks and uncertainties, which include, without limitation, risks and uncertainties related to: Upstream Bio’s ability to advance verekitug through clinical development, and to obtain regulatory approval of and ultimately commercialize verekitug on the expected timeline, if at all; the initiation, timing, progress and results of clinical trials; Upstream Bio’s ability to fund its development activities and achieve development goals; Upstream Bio’s dependence on third parties to conduct clinical trials and manufacture verekitug, and commercialize verekitug, if approved; Upstream Bio’s ability to attract, hire and retain key personnel, and protect its intellectual property; Upstream Bio’s financial condition and need for substantial additional funds in order to complete development activities and commercialize verekitug, if approved; regulatory developments and approval processes of the U.S. Food and Drug Administration and comparable foreign regulatory authorities; Upstream Bio’s competitors and industry; and other risks and uncertainties described in greater detail under the caption “Risk Factors” in Upstream Bio’s most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q, as well as any subsequent filings with the SEC. Any forward-looking statements represent Upstream Bio’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Upstream Bio explicitly disclaims any obligation or undertaking to update 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 to the extent 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.