Inhalation Delivery of MRI-1867 (zevaquenabant) As A Novel and Effective Therapeutic Modality in Pulmonary Fibrosis

FARE Award Winner

Authors

• A Basu
• M Arif
• KM Wolf
• M Behee
• CN Zawatsky
• N Johnson
• L Pommerolle
• J Harvey-White
• MR Iyer
• R Cinar

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease and requires long-term treatment. Recent research has identified cannabinoid receptor 1 (CB1R) as a potential target for treating IPF. Following this line, we have developed MRI-1867 (zevaquenabant) as a dual CB1R/iNOS inhibitor that can be administered systemically to effectively reduce experimental pulmonary fibrosis in mice. Our research has shown that CB1R is expressed in alveolar macrophages (AMs) and epithelial cells in the fibrotic environment of the lungs, indicating that these cells may contribute to the progression of PF. We hypothesized that delivering MRI-1867 through inhalation could provide high exposure to these target cells and limit distribution to other tissues, improving safety. During trials, we found that MRI-1867 at a dose of 0.5 mg/kg b.w. in mice can achieve the same concentration in the lungs as the therapeutic intraperitoneal (I.P.) dose of 10 mg/kg b.w. Further studies showed that administering MRI-1867 through pulmonary delivery at the O.P. dose of 0.5 mg/kg b.w. had comparable antifibrotic efficacy to the established I.P. dose of 10 mg/kg b.w. in a murine PF model. MRI-1867 treatment reduced monocyte-derived AMs and inflammatory cytokines and chemokines in the lungs, and restored several pathways involved in fibrosis initiation and modification, fibroblast proliferation, and inflammation. Overall, inhalation delivery of MRI-1867 is a promising treatment for PF and offers a more targeted therapeutic modality that could potentially increase safety during prolonged therapy. At present, clinical trials are in progress to validate the inhalation-based formulation of MRI-1867 for humans.

Scientific Focus Area: Molecular Pharmacology

This page was last updated on Monday, September 25, 2023