Influence of PAI-1 gene polymorphism on the effectiveness of tezepelumab in individuals with severe asthma: a study protocol for a prospective, non-randomized, interventional, comparative trial.

BACKGROUND

Severe uncontrolled asthma remains a major clinical challenge despite recent advances in biological therapies. Tezepelumab, a monoclonal antibody targeting thymic stromal lymphopoietin (TSLP), has shown broad efficacy across asthma phenotypes, yet predictive biomarkers of response remain uncertain. Plasminogen activator inhibitor type 1 (PAI-1) is implicated in airway inflammation and remodeling, can enhance virus/allergen-driven TSLP production, and its promoter polymorphism (-675 4G/5G) influences circulating PAI-1 levels.

METHODS

This multicenter, prospective, non-randomized, interventional, comparative trial is a hypothesis-generating pharmacogenetic study. Adults with severe asthma initiating tezepelumab (210 mg subcutaneously every 4 weeks) will be enrolled and followed for 52 weeks. Participants will be genotyped for the SERPINE1 (PAI-1) -675 4G/5G polymorphism (rs1799768; also reported as rs1799889) and analyzed by genotype groups. The primary endpoint is the annualized asthma exacerbation rate (AAER) over 52 weeks. Secondary endpoints include early (0-3 months) exacerbation frequency, Asthma-Control-Questionnaire-6 (ACQ-6) score, lung function [forced expiratory volume in 1 second (FEV1), peak expiratory flow (PEF)], fractional exhaled nitric oxide (FeNO), peripheral blood eosinophils, and total immunoglobulin E (IgE). Negative binomial regression will assess AAER; linear models will assess secondary outcomes with baseline covariates.

DISCUSSION: We hypothesize that high PAI-1-producing genotypes (4G/4G) may reflect heightened TSLP-driven inflammation and thus derive greater benefit from tezepelumab. If confirmed, PAI-1 genotyping could support precision selection of tezepelumab in severe asthma.

TRIAL REGISTRATION: UMIN000052531 (UMIN Clinical Trials Registry). Registered on October 18, 2023.