¹⁸F-FPP-RGD₂ PET Imaging for Interrogating Target Engagement and Antifibrotic Activity of an Integrin Antagonist in a...

Patient outcomes in metabolic dysfunction-associated steatohepatitis (MASH) are associated with the presence and stage of liver fibrosis. Activated hepatic stellate cells are a key mediator of MASH fibrogenesis and show increased expression of integrin α_vβ₃, making it a promising target for imaging and treatment of liver fibrosis. The ability to noninvasively measure target engagement of integrin inhibitors is key to understanding their chances of success in clinical development. Methods: Target engagement was assessed using PET imaging of an arginine-glycine-aspartic acid (RGD)-based integrin-binding tracer ¹⁸F-FPP-RGD₂ Mice were fed a choline-deficient, ʟ-amino acid-defined, high-fat diet (CDAHFD) or control diet for 2, 6, 10, or 14 wk to induce fibrosis (n = 6/time point). PET was conducted on subsequent days without and with an oral dose of integrin α_vβ₃ antagonist IDL-2965 (10 mg/kg). The antifibrotic activity was evaluated in mice fed CDAHFD for 12 wk and treated with daily oral IDL-2965 (10 mg/kg) or vehicle in weeks 5-12. Integrin β₃ expression was evaluated in liver biopsies from patients with varying degrees of fibrosis. Results: Significantly higher liver uptake of the integrin-binding PET tracer was found in MASH mice than in age-matched controls and increased with the duration of CDAHFD up to 10 wk. At each stage of fibrotic progression, a single oral dose of IDL-2965 significantly reduced hepatic ¹⁸F-FPP-RGD₂ uptake, consistent with strong IDL-2965 target engagement. In a separate study, therapeutic administration of IDL-2965 significantly reduced multiple measures of CDAHFD-induced liver fibrosis, including histologic fibrosis scores, Sirius Red-stained area, hydroxyproline content, Col1α1 messenger RNA expression, and plasma cytokeratin-18. In human liver biopsies, integrin β₃ expression increased with increasing fibrosis score. Conclusion: Increased expression of integrin α_vβ₃ and strong target engagement by IDL-2965 in the CDAHFD-induced MASH model can be detected in vivo using the integrin-binding PET tracer ¹⁸F-FPP-RGD₂ Consistent with strong target engagement, therapeutic administration of IDL-2965 significantly reduced multiple measures of CDAHFD-induced hepatic fibrosis.