The Discovery of Velpatasvir (GS-5816): The Potent Pan-Genotypic Once-Daily Oral HCV NS5A Inhibitor in the Single-Tablet Regimens Epclusa® and Vosevi®

The initial approval of the single-tablet regimen (STR) Harvoni®, containing the hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitor ledipasvir and the nonstructural 5B protein (NS5B) nucleotide inhibitor sofosbuvir (SOF), provided a major advancement in the treatment of individuals with chronic genotype 1 (GT1) HCV infection. Herein is described the discovery of velpatasvir (VEL, GS-5816), a pan-genotypic NS5A inhibitor with low picomolar activity against GT1–6 HCV and a high resistance barrier. The combinations of SOF/VEL as Epclusa® and SOF/VEL/voxilaprevir (VOX, NS3/4a protease inhibitor) as Vosevi® are the only pan-genotypic STRs for the treatment and cure of HCV infection. Epclusa® is the first approved pan-genotypic STR and affords high cure rates with a single 12-week treatment duration regardless of genotype, cirrhosis status, or the presence of baseline resistance variants. Vosevi® provides high cure rates for GT1–6-infected individuals who have previously failed therapy (96% cure rates for GT1–6 patients who had failed regimens with an NS5A inhibitor or 98% for those who had failed regimens without an NS5A inhibitor). With pan-genotype activity, no need for on-treatment monitoring, and real-world effectiveness comparable to that observed in clinical trials, the safe, simple, and effective STR Epclusa® is an important agent for eradication of HCV infection worldwide.