1/2 Precision Tapering of Biologic Therapy in Asthma: Identifying Predictors of Successful Dupilumab Interval Extension - Project Summary / Abstract Severe asthma affects 10–15% of the 28 million Americans with asthma and drives disproportionate morbidity, mortality, and cost. Biologics like dupilumab, an anti-IL-4/IL-13 monoclonal antibody, reduce exacerbations, improve lung function, and can induce remission, but are typically continued indefinitely at a cost of ~$40,000/patient/year without evidence-based guidance for dose reduction. This proposal, “Precision Tapering of Biologic Therapy in Asthma: Identifying Predictors of Optimized Dupilumab Dosing,” will determine whether adults with well-controlled asthma on dupilumab can safely extend dosing intervals and will define clinical and molecular predictors of tapering success to enable precision, value-based care. In Specific Aim 1 we will conduct a pragmatic, two-period, randomized non-inferiority clinical trial in which 248 adults with asthma well controlled on dupilumab plus controller therapy will be assigned to continue every-2-week (Q2W) dosing or taper to every- 4-week (Q4W) dosing for 48 weeks. At week 48, those still controlled on Q2W will be re-randomized to Q2W or Q4W; those controlled on Q4W will explore Q6W→Q8W tapering. The primary endpoint is treatment failure (exacerbation, loss of control, or ≥20% FEV₁ decline). This design tests both safety and durability of interval extension while reducing injection burden and cost. In Specific Aim 2, we will identify phenotypic, biomarker, and molecular predictors of successful dupilumab tapering. By evaluating and integrating predefined clinical characteristics, biomarkers, novel immune and epigenetic predictors, as well as airway transcriptomic and microbiome signatures from nasal and sputum RNA-seq with treatment failure associated with dupilumab dose interval increase, we will create a precision-medicine model to predict who can safely taper biologic therapy while elucidating pathways of sustained asthma control. In Specific Aim 3, we will quantify the pharmacoeconomic impact of increased dupilumab dosing intervals and estimate cost savings, cost-effectiveness, and budget impact from patient, payer, and health-system perspectives. We hypothesize that extended-interval dosing will maintain control while reducing biologic expenditures by ~50%, enabling substantial U.S. health-system savings and improving access. With deep expertise in severe asthma trials, phenotyping, biomarker discovery, and pharmacoeconomic analysis, this UG3/UH3 proposal leverages an established partnership between our experienced Clinical Coordinating Center and our consortium of severe asthma research centers and translational scientists with the infrastructure of our Data Coordinating Center. Our long history of collaboration in prior NHLBI networks will lead us to execute this trial and mechanistic analyses with scientific rigor, operational efficiency, and the capacity to generate transformative insights into severe asthma management. These results will inform asthma guidelines, shape payer policy, and transform clinical decision-making, directly advancing the NHLBI’s strategic vision by establishing a precision-guided model to optimize therapy intensity, reduce burden, and promote sustainability in asthma care.
