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

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by dyspnea and loss of lung function. Transforming growth factor-beta (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. Objectives: This Phase 2 study (NCT04072315) evaluated α_vβ₆ receptor occupancy in the lung, as assessed by changes from baseline in α_vβ₆ PET tracer uptake, following single dose administration of bexotegrast to participants with IPF. Methods: In this open-label, single-center, single-arm study, adults with IPF received up to 2 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/CT scan was conducted following 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 following bexotegrast. Pharmacokinetics, safety, and tolerability of bexotegrast were also assessed. Results: Eight participants completed the study. Total and unbound plasma bexotegrast concentrations increased in a dose-dependent manner, and regional PET volume of distribution (V_T) values decreased in a dose- and concentration-dependent manner. The V_T data fit a simple saturation model, producing an unbound bexotegrast EC₅₀ estimate of 3.32 ng/mL. Estimated maximum receptor occupancy was 35%, 53%, 71%, 88%, and 92% following single 60, 80, 120, 240, and 320-mg doses of bexotegrast, respectively. No treatment-emergent adverse events related to bexotegrast were reported. Conclusions: 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. Trial registration number: NCT04072315 Primary source of funding: Pliant Therapeutics, Inc. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).