Upstream Bio presented translational pharmacology modeling data at the European Academy of Allergy & Clinical Immunology (EAACI) Congress that provides mechanistic insights into verekitug's greater potency compared to existing TSLP-targeting therapies. The data, presented June 13-16, 2025, in Glasgow, United Kingdom, supports the company's approach of targeting the TSLP receptor rather than the TSLP ligand itself.
Mechanism of Enhanced Potency
The modeling data utilized an in silico system pharmacology approach to compare verekitug with tezepelumab, an approved TSLP ligand-targeting therapy. Semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) models were built using identical biological and drug-specific parameters for both treatments, populated with observed clinical data for verekitug and published clinical data for tezepelumab.
Across a range of doses, PK/PD model simulations predicted complete and sustained inhibition of the TSLP/TSLPR complex with verekitug compared to tezepelumab. The dose-response model simulations indicated that this potent inhibition would result in a greater reduction in fractional exhaled nitric oxide (FeNO), a biomarker of lung inflammation.
The modeling data revealed that verekitug's superior predicted reduction of FeNO is potentially driven by lower expression levels of the TSLP receptor over time versus the ligand, as well as slower protein turnover time for the TSLP receptor versus the ligand.
Clinical Development Progress
Verekitug is currently the only monoclonal antibody in clinical development that targets and inhibits the TSLP receptor. The company is conducting Phase 2 clinical trials across multiple severe respiratory diseases, including the VALIANT trial in patients with severe asthma (NCT06196879) and the VIBRANT trial in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) (NCT06164704). Upstream Bio is also initiating a Phase 2 clinical trial (NCT06981078) in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).
"These data reinforce our belief in the differentiated profile of verekitug, as the model elucidates important biologic parameters that drive the differentiated rapid, substantial and sustained treatment effects observed through TSLP receptor inhibition with verekitug," said Aaron Deykin, MD, Chief Medical Officer and Head of Research & Development of Upstream Bio.
TSLP Pathway Targeting Strategy
Thymic Stromal Lymphopoietin (TSLP) is a cytokine that serves as a key driver of the inflammatory response in major allergic and inflammatory diseases. TSLP activation is one of the first events in the inflammatory cascade stimulated by allergens, viruses and other triggers, initiating the activation of downstream targets such as IL-4, IL-5, IL-13, IL-17 and IgE.
Because TSLP is positioned upstream in the inflammatory cascade, blocking the TSLP receptor presents an opportunity for a single treatment to impact the drivers of multiple pathological inflammatory processes across a broad set of diseases.
Preclinical and Early Clinical Data
In preclinical studies, verekitug demonstrated high occupancy of the TSLP receptor and potent inhibition of TSLP signaling. The antibody inhibited cytokine production from both CD4+ T cells and ILC2 cells and completely suppressed skin allergic reactions in a non-human primate model.
Three clinical trials have been completed for verekitug, including a Phase 1 single-ascending dose (SAD) clinical trial and a Phase 1b multiple-ascending dose (MAD) clinical trial. In these trials, verekitug was well tolerated, had no clinically meaningful immunogenicity, and showed a predictable and consistent pharmacokinetic profile and high subcutaneous bioavailability.
Upcoming Milestones
The company anticipates top-line Phase 2 clinical data in CRSwNP in the third quarter of 2025, followed by data in severe asthma in the first half of 2026. These results will provide crucial insights into whether the mechanistic advantages demonstrated in the modeling data translate into clinical benefits for patients with severe respiratory diseases.
