New hepatitis C therapies in clinical development

Abstract

With the current standard of care for the treatment of chronic hepatitis C, a combination of pegylated interferon alfa and ribavirin, sustained virologic response rates can be achieved in approximately 50% of patients only. - Improved understanding of the viral life cycle has led to the identification of numerous potential targets for novel, direct-acting antiviral compounds. Inhibitors of the NS3/4A protease are currently the most advanced in clinical development. Recently completed phase 3 studies of the two protease inhibitors telaprevir and boceprevir, each given in combination with standard of care, yielded sustained virologic response rates in the range of 66-75% in treatment-naive patients and 59-66% in treatment-experienced patients with HCV genotype 1 infection. Studies of second-generation protease inhibitors, with the potential advantage of improved potency, drug metabolism and pharmacokinetics profile, are already underway. - Inhibitors of the HCV NS5A protein and NS5B polymerase are potentially active across different HCV genotypes and have shown promising antiviral efficacy in early clinical studies. Other emerging mechanisms include silymarin components and inhibitors of cell proteins required for HCV replication. - While improved formulations of current HCV therapies are also being developed, future hopes lie on the combination of direct-acting antivirals with the eventual possibility of interferon-free treatment regimens.

Figure 1

A) ADVANCE and ILLUMINATE were conducted in treatment-naïve patients with HCV genotype 1. The ADVANCE treatment arms were as follows: (i) 12 weeks of telaprevir (T) plus PEG-IFN alfa-2a and ribavirin (PR) followed by PR for 12 or 36 weeks, based on treatment response at week 4 and 12, (ii) 8 weeks of T plus PR followed by PR for 16 or 40 weeks, based on treatment response at week 4 and 12; (iii) PR alone for 48 weeks. In the ILLUMINATE trial, patients who achieved an eRVR were randomized to receive 12 weeks of T plus PR followed by PR for (i) 12 weeks or (ii) 24 weeks. B) Treatment-experienced patients with HCV genotype 1 (REALIZE) received (i) 12 weeks of T plus PR followed by PR for 36 weeks, (ii) 4 weeks PR lead-in followed by TPR for 12 weeks followed by PR alone for 32 weeks (iii) PR alone for 48 weeks. In the REALIZE study, relapsers and non-responder (null-responders and partial non-responders) patients were enrolled. *eRVR defined as HCV RNA negativity at week 4 and 12.

Figure 2

A) SPRINT-2 treatment arms in treatment-naïve patients with HCV genotype 1 were as follows: (i) 4-week lead-in with PEG-IFN alfa-2b plus ribavirin (PR) followed by 44 weeks of PR plus boceprevir (B); (ii) 4-week lead-in with PR followed by PR plus B for 24 weeks or followed by PR plus B for 24 weeks and PR for additional 20 weeks, based on treatment response at week 8 and 12; (iii) PR alone for 48 weeks. B) The RESPOND-2 treatment schedule, conducted in treatment-experienced patients with HCV genotype 1 was as follows: (i) 4-week lead-in with PR followed by PR plus B for 44 weeks, (ii) 4-week lead in with PR followed by PR plus B for 32 weeks or followed by PR plus B for 32 weeks and PR for additional 12 weeks, based on treatment response at week 8 and 12; (iii) PR alone for 48 weeks. **eRVR defined as HCV RNA negativity at week 8 through 24; ***in the SRINT-2 control arm, only standard RVR data (negative HCV RNA at week 8) are shown. ERVR results were not available at the time of submission of this manuscript.