Preclinical Development History In preclinical studies, it has been demonstrated that Achillion's NS4A antagonists inhibit HCV replication in cell-based replicon assays that have developed resistance to other HCV protease and polymerase inhibitors. During 2005 and 2006, Achillion compared the potency of its NS4A antagonists, including ACH-806 and ACH-1095 as well as other compounds, with two other NS3 protease inhibitors currently in clinical development, VX-950, being developed by Vertex, and SCH-503034, being developed by Schering-Plough.
Results demonstrated that, in laboratory testing, ACH-1095 (one of a series of next-generation compounds to ACH-806), is approximately 10-fold more potent than SCH-503034, and approximately 14-fold more potent than VX-950. Potencies of ACH-1095, VX-950 and SCH-503034 are represented by the amount of inhibitor required (as measured in nanomoles, or nM) to inhibit 50% of HCV replication in in vitro laboratory tests. A lower nM number represents greater inhibition and potency. The following table describes these results:
NS4A Antagonists: Potent Inhibitor of HCV
In addition, this compound has demonstrated good oral bioavailability and a favorable safety profile in animals.
Clinical Development History - At the April 2007 meeting of the European Association for the Study of Liver Disease (EASL), Achillion presented data on its first NS4A antagonist, ACH-806, in a Phase 1 study in HCV genotype 1-infected individuals. The randomized, double-blind, placebo-controlled dose-escalation trial measured the antiviral activity, safety and pharmacokinetics of 300 mg of ACH-806 or placebo, dosed orally twice daily as a monotherapy over 5 days. The mean change in HCV RNA (log10) at day 5 was a decrease of 0.91 from baseline for treated subjects versus an increase of 0.05 for control subjects.
Phase 1b/2 study provides first clinical demonstration of efficacy for NS4A antagonists
Although this study provided the first demonstration of human antiviral activity of an NS4A antagonist for HCV, due to observed elevations in serum creatinine, Achillion and its partner Gilead Sciences have since discontinued development of ACH-806.
In addition to the Phase 1 data, a second presentation at EASL revealed that the NS4A antagonist did not show in vitro cross-resistance with agents from these other HCV therapeutic classes, and that NS4A antagonism appears to have a synergistic antiviral effect in combination in vitro with the HCV protease inhibitor VX-950 and the polymerase inhibitor NM 107.
Additionally, a third presentation described the novel mechanism of action of NS4A antagonists, demonstrating that these antagonists block the formation of functional viral replication complexes, thereby preventing HCV replication independent of protease or polymerase inhibition.
Achillion believes that candidates with the unique NS4A antagonism mechanism may be complementary to protease and polymerase inhibitors could be an important benefit in treating HCV infection.
Preclinical testing of ACH-1095 is completed. In 2009, Achillion and Gilead modified their collaboration to allow Achillion to advance ACH-1095 independently, subject to an opt-in right by Gilead. Achillion retains the right to develop ACH-1095 to clinical proof-of-concept, at which time Gilead retains certain rights to develop the compound in Phase II and beyond.
