Upstream Bio has dosed the first patients in two Phase 2 clinical trials evaluating verekitug (UPB-101), a novel monoclonal antibody targeting the thymic stromal lymphopoietin receptor (TSLPR), for the treatment of severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). The advancement follows compelling Phase 1b results demonstrating sustained biomarker reductions and superior potency compared to existing therapies.
Phase 2 VALIANT Study in Severe Asthma
The VALIANT study represents a randomized, double-blind, placebo-controlled trial evaluating verekitug in doses of 100 mg every 24 weeks (Q24W), 400 mg Q24W, 100 mg every 12 weeks (Q12W), or placebo administered subcutaneously in a single injection. The study's primary endpoint focuses on the annual asthma exacerbation rate (AAER), a registrational endpoint for severe asthma treatments.
"We are thrilled to initiate the Phase 2 study in severe asthma after the findings from our multiple ascending dose (MAD) study in asthma patients demonstrated that verekitug produces a compelling reduction in disease-related biomarkers," said Aaron Deykin, Head of R&D and Chief Medical Officer.
The Phase 1b multiple ascending dose study showed that the 100 mg dose produced a 54% reduction from baseline in fractional exhaled nitric oxide (FeNO) and blood eosinophils (EOS) at week 12, which was sustained through week 32—24 weeks after the last dose. These results enabled the company to explore extended dosing regimens in Phase 2, including administration every 24 weeks.
Superior Potency Profile
According to company leadership, verekitug demonstrated higher potency compared to published data from tezepelumab, another TSLP pathway inhibitor. The sustained biomarker reductions observed in the Phase 1b study positioned verekitug as the first TSLP signaling inhibitor to demonstrate sustained target engagement and maintain maximal inhibition of disease-related biomarkers in asthma patients 24 weeks after the last study dose.
"Verekitug has the potential to be a best-in-class inhibitor of TSLP signaling based on its swift, substantial and sustained effect on clinically relevant biomarkers that are known to correlate with impact on AAER," said Sam Truex, Chief Executive Officer.
Phase 2 Study in CRSwNP
The CRSwNP Phase 2 study is evaluating a dose of 100 mg administered subcutaneously every 12 weeks in a randomized, double-blind, placebo-controlled design. The primary endpoint is reduction in nasal polyp score. Data from both Phase 2 studies will inform the dose regimen for Phase 3 trials in both indications.
Mechanism of Action and Clinical Significance
Verekitug is a recombinant fully human immunoglobulin G1 monoclonal antibody that binds to the human TSLP receptor to inhibit signaling. TSLP is a cytokine that serves as a key driver of inflammatory response in major allergic and inflammatory diseases. TSLP signaling represents one of the first events in the inflammatory cascade stimulated by allergens, viruses, and other triggers, activating downstream targets including IL-4, IL-5, IL-13, IL-17, and IgE.
In preclinical studies, verekitug demonstrated inhibition of cytokine production from both CD4+ T cells and ILC2, suggesting efficacy against multiple types of inflammation. Data from three Phase 1 studies conducted to date demonstrate that verekitug is safe and well-tolerated.
Market Opportunity
Asthma affects approximately 350 million people worldwide and is often underdiagnosed and under-treated. Of the more than 25 million people in the U.S. living with asthma, about 5-10% suffer from severe asthma. CRSwNP is a chronic disease of the upper airway that obstructs the sinuses and nasal passages, with up to 65% of CRSwNP patients also suffering from asthma.
Verekitug is currently the most advanced TSLP signaling inhibitor in global development and the only agent with clinical data extending to 32 weeks from a completed study in asthmatic patients. The company's approach of targeting TSLP upstream in the inflammatory cascade presents an opportunity to address disease at its root, prior to the influence of other disease-related cytokines.
