Bexotegrast Shows Dose-Dependent Integrin αvβ6 Receptor Occupancy in Lungs of Participants with Idiopathic Pulmonary Fibrosis: A Phase 2, Open-Label Clinical Trial

<b>Rationale:</b> Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by dyspnea and loss of lung function. Transforming growth factor-β (TGF-β) activation mediated by α_v integrins is central to the pathogenesis of IPF. Bexotegrast (PLN-74809) is an oral, once-daily, dual-selective inhibitor of α_vβ₆ and α_vβ₁ integrins under investigation for the treatment of IPF. Positron emission tomography (PET) using an α_vβ₆-specific PET tracer could confirm target engagement of bexotegrast in the lungs of participants with IPF. <b>Objectives:</b> This Phase 2 study evaluated α_vβ₆ receptor occupancy in the lung as assessed by changes from baseline in α_vβ₆ PET tracer uptake, after single-dose administration of bexotegrast to participants with IPF. <b>Methods:</b> In this open-label, single-center study, adults with IPF received up to two single doses of bexotegrast, ranging from 60 to 320 mg with or without background IPF therapy (pirfenidone or nintedanib). At baseline and approximately 4 hours after each orally administered bexotegrast dose, a 60-minute dynamic PET-computed tomography scan was conducted after administration of an α_vβ₆-specific PET probe ([¹⁸F]FP-R₀1-MG-F2). α_vβ₆ receptor occupancy by bexotegrast was estimated from the changes in PET tracer uptake after bexotegrast administration. Pharmacokinetics, safety, and tolerability of bexotegrast were also assessed. <b>Results:</b> Eight participants completed the study. Total and unbound plasma bexotegrast concentrations increased in a dose-dependent manner, and regional PET volume of distribution values decreased in a dose- and concentration-dependent manner. The data for volume of distribution fit a simple saturation model, producing an unbound bexotegrast half maximal effective concentration estimate of 3.32 ng/ml. Estimated maximum receptor occupancy was 35%, 53%, 71%, 88%, and 92% after single 60-, 80-, 120-, 240-, and 320-mg doses of bexotegrast, respectively. No treatment-emergent adverse events related to bexotegrast were reported. <b>Conclusions:</b> Dose and concentration-dependent α_vβ₆ receptor occupancy by bexotegrast was observed by PET imaging, supporting once-daily 160- to 320-mg dosing to evaluate efficacy in clinical trials of IPF. Clinical trial registered with www.clinicaltrials.gov (NCT04072315).