Presidio Pharmaceuticals, Inc.

This letter describes the discovery of a fused benzofuran scaffold viable for preparing a series of novel potent HCV NS5B polymerase non-nucleoside inhibitors. Designed on the basis of the functionalized benzofuran derivative nesbuvir (HCV-796), these compounds presumably bind similarly to the allosteric binding site in the "palm" domain of HCV NS5B protein. SAR of each potential hydrogen-bonding interaction site of this novel scaffold is discussed along with some preliminary genotypic profile and PK data of several advanced compounds.

Although treatment of hepatitis C virus (HCV) and HCV-genotype-4 (GT4) has become very effective, it remains very expensive, and affordable options are needed, especially in limited resource countries. The aim of this study was to assess the efficacy and safety of the combination of ravidasvir (an NS5A inhibitor) and sofosbuvir to treat patients with chronic HCV-GT4 infection.

A total of 300 patients with HCV-GT4 infection were recruited in three groups: treatment-naïve patients with or without compensated Child-A cirrhosis (Group 1); interferon-experienced patients without cirrhosis (Group 2); and interferon-experienced patients with cirrhosis (Group 3). Groups 1 and 2 received ravidasvir 200 mg QD plus sofosbuvir 400 mg QD for 12 weeks and were randomized 1:1 to treatment with or without weight-based ribavirin. Group 3 patients received ravidasvir plus sofosbuvir with ribavirin and were randomized 1:1 to a treatment duration of 12 weeks or 16 weeks. The primary endpoint was sustained virologic response at 12 weeks post-treatment (SVR12).

A total of 298 patients were enrolled: 149 in Group 1, 79 in Group 2 and 70 in Group 3. SVR12 was achieved in 95.3% of all patients who started the study, including 98% of patients without cirrhosis and 91% of patients with cirrhosis, whether treatment-naïve or interferon-experienced. Ribavirin intake and history of previous interferon therapy did not affect SVR12 rates. No virologic breakthroughs were observed and the study treatment was well tolerated.

Treatment with ravidasvir plus sofosbuvir, with or without ribavirin, was well tolerated and associated with high sustained virologic response rate for HCV-GT4 infected patients with and without cirrhosis, regardless of previous interferon-based treatments.

ClinicalTrials.gov Identifier: NCT02371408.

This study evaluated efficacy and safety of the new oral hepatitis C drug ravidasvir in combination with the approved oral drug sofosbuvir in 298 patients infected with hepatitis C type 4. Our results showed that treatment with ravidasvir plus sofosbuvir, with or without ribavirin, was well tolerated and associated with high response rate in patients with and without cirrhosis.

This Letter describes the synthesis, representative structure activity relationship (SAR), activity and PK profiles of a series of functionalized benzimidazole-naphthylene-imidazole derivatives as HCV NS5A inhibitors. This effort successfully led to the discovery of ravidasvir (PPI-668), which has been well tolerated and shown high sustained viral response rates as a key component in all-oral combination regimens in multiple human clinical trials.