Drug delivery formulation impacts cyclosporine efficacy in a humanised mouse model of acute graft versus host disease

Acute graft versus host disease (aGvHD) is an allogeneic T cell mediated disease which manifests as a severe inflammatory disease affecting multiple organs including the liver, skin, lungs and gastrointestinal tract. Existing prophylactic and therapeutic approaches in aGvHD include the use of cyclosporine A (CyA), however the currently approved CyA formulations which were designed to optimise systemic CyA bioavailability can have a number of side effects including nephrotoxicity as well as the potential to attenuate the beneficial Graft-versus Leukemia (GvL) effect. An added complication with CyA is that it has a narrow therapeutic window, and following oral administration is absorbed only from the small intestine, with variable cytochrome P450 metabolism contributing to intra-and inter-patient variability. This study sought to investigate the efficacy of a novel CyA oral formulation enabled by the integrated SmPill? oral drug delivery platform in a humanised mouse model of aGvHD. The study compared the approved optimised CyA (Neoral?) with SmPill?-enabled CyA and a systemic intravenous CyA formulation. Our findings clearly demonstrate superior efficacy of the novel SmPill? CyA in prolonging survival in a clinically relevant humanised aGvHD model. SmPill? CyA significantly reduced pathological score in the small intestine, colon, liver and lung of aGvHD mice. In addition, SmPill? CyA significantly reduced the levels of pro-inflammatory cytokines in all the GvHD target tissues examined. Notably, SmPill? CyA was significantly more potent in reducing GvHD associated pathology and inflammatory cytokine production compared to the optimised approved oral CyA formulation, Neoral?.