2013: Sofosbuvir: Hepatitis C Cure (2013)

The FDA approval of sofosbuvir (Sovaldi) in December 2013 for chronic hepatitis C infection
transformed what had been a difficult, toxic, year-long treatment into a short, well-tolerated,
near-universally curative oral regimen. Sofosbuvir is a nucleotide analogue prodrug that, after
intracellular phosphorylation, inhibits the hepatitis C virus (HCV) NS5B RNA-dependent RNA
polymerase—an enzyme with no human homologue, making it an exquisitely selective target with a
favourable therapeutic index.

Before sofosbuvir, standard-of-care consisted of pegylated interferon-alpha plus ribavirin for
24–48 weeks. This regimen was poorly tolerated, with severe flu-like symptoms, depression, and
haematological toxicity, and achieved sustained virological response (SVR, effectively a cure) in
only 40–50 % of patients with genotype 1 infection, the most prevalent in the United States.
Earlier NS3/4A protease inhibitors (telaprevir, boceprevir, approved 2011) improved SVR rates but
retained the interferon backbone and added pill burden.

Sofosbuvir's pan-genotypic activity and high barrier to resistance—arising from the intrinsic
fidelity of nucleotide polymerase inhibitors—enabled a paradigm shift. Combinations of sofosbuvir
with NS5A inhibitors (ledipasvir, velpatasvir) and NS3/4A inhibitors achieved SVR rates of 95–99 %
across all genotypes in 8–12 weeks without interferon. The price—$84,000 for a 12-week course at
launch—triggered intense debate about pharmaceutical pricing, access, and value-based frameworks
that reshaped policy discussions globally.

Michael Sofia and colleagues at Pharmasset (later acquired by Gilead Sciences) designed the
ProTide phosphoramidate prodrug approach that gave sofosbuvir its intracellular activation
properties; Sofia was subsequently awarded the Lasker-DeBakey Clinical Medical Research Award
in 2016.