ContraVir Pharmaceuticals, Inc., a biopharmaceutical company focused on the development and commercialization of targeted antiviral therapies, announced that it has taken a major step forward in its pursuit of a potentially curative combination therapy for chronic hepatitis B (HBV). The company presented new preclinical data profiling the robust anti-HBV activity of its potentially best-in-class cyclophilin inhibitor CRV431, including evidence of synergy with CMX157, ContraVir's highly potent prodrug of tenofovir, when the two drugs are used together. CMX157 is currently in phase 2 clinical trials in Thailand.
The peer-reviewed findings were presented at a joint meeting sponsored by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) called HBV Treatment Endpoints Workshop: From Discovery to Regulatory Approval, in a poster titled, "CRV431: An Optimized Cyclophilin Inhibitor with Multiple Anti-HBV Activities, High Selectivity Index, and Synergy with CMX157."
Human liver cells (AD38) treated in vitro with multiple combinations of CRV431 and CMX157 showed synergistic inhibition of HBV replication, as measured by a reduction in HBV DNA. These data are the first to demonstrate synergistic activity of these drugs against HBV, confirming ContraVir's belief that a combination of CRV431 and CMX157 may be more effective at killing the virus by potently targeting multiple stages of the viral life cycle.
"This study validates our approach and the significant opportunity we have to leverage our two HBV assets to create a uniquely powerful combination therapy and potential functional cure for hepatitis B," said James Sapirstein, CEO of ContraVir. "On its own, CRV431 demonstrates the potential to address multiple key endpoints thought to be essential for curing HBV. As we have seen with other successfully cured viral diseases, combination with a proven backbone therapy like tenofovir/CMX157 may unlock the full potential of these drugs and bring us closer to an HBV cure."
Data from the study also describe the in vitro anti-HBV activity of CRV431, as well as other clinically relevant findings. Importantly, CRV431 was shown to have the widest selective index of any known cyclophilin inhibitor, calculated by CC50/IC50 ratio. This optimized selective index may correlate with a best-in-class therapeutic index, and therefore, enhanced clinical utility against HBV. Other key findings for CRV431 monotherapy in vitro include:
Cyclophilin-independent inhibition of viral uptake by liver cells through its common route, the sodium taurocholate co-transporting polypeptide (NTCP) receptor;
Significantly greater potency compared to a related cyclophilin inhibitor, alisporovir, as measured by inhibition of intracellular HBV DNA in AD38 cells; and
Inhibition of production and/or secretion of HBV antigens HBeAg and HBsAg by infected or transfected Huh7 cells. Reduction or elimination of these antigens is considered to be a key requirement for a curative HBV regimen.
In vivo studies in rats and mice highlighted additional characteristics of CRV431 that enhance its profile. Dosing studies showed that CRV431 is suitable for oral dosing, demonstrating a significantly improved oral pharmacokinetic profile compared to cyclosporine A, the parent molecule from which CRV431 is derived. Additionally, in a mouse model of liver fibrosis, orally-administered CRV431 was shown to reduce the area of fibrosis in a dose dependent manner. This activity is independent of viral inhibition and instead may be a result of CRV431's interaction with host cyclophilins, which are implicated in multiple pro-fibrotic mechanisms.
Sapirstein concluded, "We are highly encouraged by these findings, which clearly support further development of CRV431 into IND-enabling studies and ultimately into clinical development in human combination studies with CMX157. We expect to continue preclinical development of CRV431, with a potential IND filing in the last quarter of 2017."