The NS5A protein of HCV exerts multiple functions at various stages of the HCV viral life cycle. Different forms of NS5A protein are involved in virion production, interact with host proteins, are implicated in interferon resistance, and in vitro, bind with zinc and HCV RNA. The mechanism of action of NS5A inhibition has been clinically validated at low doses. Importantly, NS5A inhibitors are additive to synergistic in combination with immunomodulatory therapy (IFN and ribavirin) as well as with directly acting antivirals (DAAs.)
Virology
ACH-2928: Activity Against Genotype 1a Replicon
ACH-2928: Activity Against Genotype 1b Replicon
Pharmacokinetics
ACH-2928 demonstrates good metabolic stability across species. It is highly soluble and highly permeable. ACH-2928 demonstrates little off-target activity, including minimal inhibition of the hERG channel, and no inhibition of mammalian receptors, ion-channels or enzymes. The ADME properties of ACH-2929 support once-daily dosing with good stability in human liver microsomes and hepatocytes, minimal inhibition of CYP P450 enzymes and high oral bioavailability in preclinical species.
Safety
The safety of ACH-2928 has been evaluated in a 5-day repeat dose studies in two preclinical species. High exposures with good safety results were obtained at doses of up to 250mg/kg. ACH-2928 was well-tolerated and there were no significant changes in food consumption and body weight gain, no significant changes in clinical chemistries and hematology parameters.
