Liposomal encapsulation of trans-crocetin enhances oxygenation in patients with COVID-19-related ARDS receiving mechanical ventilation

Mertes, Paul-Michel; Collange, Olivier; Coliat, Pierre; Banerjee, Mainak; Diringer, Marie-Charlotte; Roche, Anne; Delabranche, Xavier; Chaban, Vitaliy; Voegelin, Manon; Bernard, Alexandre; Sartori, Valérie; Laurent, Nina; Velten, Michel; Dhindsa, Navreet; Defuria, Jason; Kim, Gwangseong; Xu, Zhenghong Hannah; Theodorou, Marina; Huang, Zhaohua Richard; Khalifa, Kaniz; Geng, Bolin; Niyikiza, Clet; Moyo, Victor; Gizzi, Patrick; Villa, Pascal; Detappe, Alexandre; Pivot, Xavier

Current therapeutic treatments improving the impaired transportation of oxygen in acute respiratory distress syndrome (ARDS) have been found to be relevant and beneficial for the therapeutic treatment of COVID-19 patients suffering from severe respiratory complications. Hence, we report the preclinical and the preliminary results of the Phase I/II clinical trial of LEAF-4L6715, a liposomal nanocarrier encapsulating the kosmotropic agent trans-crocetin (TC), which, once injected, enhance the oxygenation of vascular tissue and therefore has the potential to improve the clinical outcomes of ARDS and COVID-19 in severely impacted patients. We demonstrated that the liposomal formulation enabled to increase from 30 min to 48 h the reoxygenation properties of free TCs in vitro in endothelial cells, but also to improve the half-life of TC by 6-fold in healthy mice. Furthermore, we identified 25 mg/kg as the maximum tolerated dose in mice. This determined concentration led to the validation of the therapeutic efficacy of LEAF-4 L6715 in a sepsis mouse model. Finally, we report the preliminary outcomes of an open-label multicenter Phase I/II clinical trial (EudraCT 2020–001393-30; NCT04378920), which was aimed to define the appropriate schedule and dosage of LEAF-4L6715 and to confirm its tolerability profile and preliminary clinical activity in COVID-19 patients treated in intensive care unit.