INHALATIONAL DELIVERY OF MRI-1867 (ZEVAQUENABANT) AS AN EFFECTIVE MULTI-TARGETED THERAPEUTIC MODALITY IN PULMONARY FIBROSIS

Authors

  • A Basu
  • M Arif
  • KM Wolf
  • M Behee
  • N Johnson
  • L Pommerolle
  • R Pineda
  • CN Zawatsky
  • S Dvorácskó
  • NJ Coffey
  • JK Park
  • G Godlewski
  • T Jourdan
  • J Harvey-White
  • M Königshoff
  • MR Iyer
  • R Cinar

Abstract

Background and aims: Pulmonary fibrosis (PF) is a life-threatening disease. Among different pathogenic mechanisms, overactivity of the endocannabinoids/cannabinoid receptor 1 (CB1R) system plays a central role in the development of PF, which makes CB1R a potential therapeutic target. Accordingly, we have developed MRI-1867 (zevaquenabant) as a peripherally restricted hybrid CB1R/iNOS inhibitor. Systemic administration of MRI-1867 mitigates experimental pulmonary fibrosis (PF) in mice, and it has completed a Phase 1 clinical trial. Since the PF microenvironment involves the cells around and between the alveolar space and these cells are accessible via the inhalational route, we hypothesized that pulmonary delivery of MRI-1867 may yield high exposure to critical target cells.
Methods: Myeloid cells and alveolar type 2 cells specific CB1R-KO mice (My-Cnr1-/- and AT2-Cnr1-/-) were generated and investigated in the murine bleomycin model. Then, the antifibrotic efficacy of MRI-1867 at 0.5 mg/kg via the oropharyngeal route was evaluated both in young and aged mice.
Results: Myeloid cells specific deletion of CB1R (My-Cnr1-/-) showed significant inhibition of pulmonary fibrosis development compared to AT2-Cnr1-/- mice and almost comparable to the global CB1R-KO (Cnr1-/-) mice. Pharmacological treatment with MRI-1867 showed improved pulmonary functions and reduced collagen deposition. MRI-1867 significantly reduced infiltrating AMs, particularly profibrotic macrophages, showing target engagement. Transcriptomics analyses revealed that MRI-1867 treatment attenuated the gene signatures involved in fibrosis initiation and modification pathways, fibroblast proliferation, and inflammatory pathways.
Conclusions: Pulmonary delivery of MRI-1867 is an effective and more targeted therapeutic modality that could reinforce safety by reducing the therapeutic dose range.

Scientific Focus Area: Molecular Pharmacology

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