1144 - Belumosudil Attenuates Chronic Lung Allograft Dysfunction in a Rat Orthotopic Lung Transplant Model

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Author Block: X. Wang¹, S. El-Chemaly², K. Liu¹, M. Wang³, H. Wesseling², C. Wang³, A. Bauchet⁴, J. Liu⁴, H. Goulaouic⁵, R. Wang², ¹Sanofi, Suzhou, China, ²Sanofi, Cambridge, MA, ³Sanofi, Shanghai, China, ⁴Sanofi, Vitry-Sur-Seine, France, ⁵Sanofi, Gentilly, France
*Purpose: Chronic lung allograft dysfunction (CLAD) is a significant challenge in lung transplantation with limited therapeutic options. In this study, we aimed to validate the efficacy of belumosudil, a selective ROCK2 kinase inhibitor, in a technically challenging orthotopic lung transplantation rat model of CLAD using Fischer 344 (F344) to Lewis (LEW) rat strains.
*Methods: Left lung transplantation was performed from F344 to LEW rats (allogeneic) or from LEW to LEW (syngeneic control) rats. Allogeneic transplant recipients (n=40) were randomized to receive a control vehicle or belumosudil at 30, 60, or 100 mg/kg daily from day 8 to 92 post transplantation. Disease histopathology, compound blood exposure, and biomarkers were evaluated to understand correlations between efficacy, pharmacokinetics, and target engagement.
*Results: Ninety-two days post transplantation, the model exhibited pathological lesions resembling those in human CLAD. Belumosudil treatment demonstrated disease attenuation at dose levels covering the expected therapeutic exposure in humans, which was confirmed via pharmacokinetic analysis. Biomarker analyses using flow cytometry and transcriptomics revealed target engagement and attenuation of fibrosis and inflammation signals.
*Conclusions: This study successfully demonstrated the therapeutic potential of belumosudil. This model provides valuable insights into disease pathophysiology and treatment effects, potentially aiding the interpretation of future clinical results. Accordingly, these findings recommend further investigation of belumosudil as a promising therapeutic option for CLAD.