FDV

With the approval of telaprevir and boceprevir in 2011, hepatitis C NS3/4A protein of HCV was the target that oral HCV drugs were developed to inhibit. HCV protease is an essential viral function that is responsible for cleaving the HCV polyprotein, a step which is ennsential in HCV ribonucleic acid (RNA) replication and virion assembly. A number of investigational and approved HCV protease inhibitors have shown antiviral efficacy in HCV-infected patients. Faldaprevir (FDV) is a protease inhibitor which will be studied in a Phase 2a placebo-controlled, randomized, double-blind trial to investigate its safety and efficacy in combination with ribavirin and TD-6450 120 mg or TD 6450 240 mg for 12 Weeks in Treatment-Naive Patients Chronically Infected with Genotype 4 Hepatitis C Virus. FDV was acquired from Boehringer Ingelheim.

TD-6450

With the approval of daclatasvir in Europe in 2014, the hepatitis C non-structural 5A (NS5A) protein of HCV has emerged as an attractive drug target and inhibitors of NS5A have a central role in all-oral HCV therapy. The multi-functional NS5A protein is required for ribonucleic acid (RNA) replication and virion assembly, and a number of investigational and approved NS5A inhibitors have shown antiviral efficacy in HCV] infected patients. TD-6450 is a non-symmetrical NS5A inhibitor designed to have improved antiviral activity against GT-1 resistance-associated variants (RAV) resistant to first generation NS5A inhibitors. TD-6450’s heterodimeric structure permits an asymmetric binding mode to NS5A relative to structurally symmetric inhibitors. TD-6450 has demonstrated additive activity with other classes of anti-HCV agents in replicon assays, and no cross-resistance with RAVs that confer resistance to other anti-HCV agents
TD-6450 was previously evaluated in a single-ascending dose and a 14-day multiple-ascending dose study in healthy subjects (study 0094). This randomized, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacokinetics of TD-6450. Single doses (up to 500 mg) and multiple doses of TD-6450 (up to 240 mg daily for 14 days) were evaluated in healthy subjects. Following single and multiple doses, TD-6450 was generally well-tolerated and no subjects discontinued due to adverse events. Headache was the most commonly reported adverse event following multiple doses (n=4). TD-6450 pharmacokinetics were linear up to 240 mg following single and multiple doses and its long half-life supports once-daily dosing. TD-640 was acquired from Theravance.

VX-222 to be added