Sustained reduction of triglyceride and LDL cholesterol from single administration of the novel long-acting FGF21 analogue 0499

We studied the effects of OCA on HA, PV, and hepatic vein, HV, flow in porcine liver perfused ex vivo with a cardio-emulation pump, the CaVESWave® system to determine whether vascular effects could explain its efficacy in the treatment of NASH Method: Six fresh porcine livers (two controls) were continuously perfused with phosphate buffered saline (PBS).OCA dosing was delivered in solution with methyl cellulose as carrier, directly into the portal vein catheter.Perfusion was initiated with the HA settings at 120/80 mmHg, PV around 15 mmHg and temperature at 15°C.Flow rates in HA, PV and HV were measured throughout.Carrier only was injected at 30 min intervals in the controls.For the treatment group, 0 mg OCA/kg liver weight, followed by 0.14, 0.28, 0.56 and 1.12 mg/kg, injected at 30 min intervals.Results: The cardio-emulated waveforms showed little variability, either before or after drug treatment was started (figure 1).HA pressure varied between 117 and 122 mmHg (systolic) and 75-84 mmHg (diastolic); perfusate pH between 7.35 and 7.4; DO between 104 and 105 and temperature 15.8 and 17.5°C.Control livers (n = 2) showed minor changes in flow after treatments with vehicle (figure 2).The maximum percentage increase in HA flow was 3.3 ± 3.5 and HV flow, 4.8 ± 2.8.By contrast, PV flow was reduced by up to -9.1 ± 5.9.In OCA treated livers (n = 4), there was a clear dose-relationship between OCA and HA, HV and PV.Hepatic venous outflow and HA flow increased progressively to 11 ± 11.8 and 9.9 ± 8.9, respectively.Conversely, PV flow was reduced by up to -19 ± 16%.