Research on the next generation of direct acting antiviral (DAA) therapies for hepatitis C (HCV) continues to excite scientists attending the 2013 International Liver Congress (ILC2013). One drug that is getting a lot of research attention at the conference is Janssen Pharmaceutical’s Simeprevir. Simeprevir, formerly known as TMC435, is a HCV NS3/4A protease inhibitor designed to be taken once a day. Currently working its way through phase III efficacy trials, it distinguishes itself from its competitors by being under investigation for use in patients with both genotype 1 and genotype 4 HCV. However, most of the research being presented at ILC2013 focuses on its use in genotype 1 infections.
Probably the most anticipated Simeprevir results to be presented at ILC2013 are the 12-week sustained viral response (SVR12) data from the QUEST-1 and QUEST-2 trials of Simeprevir in combination with peg-interferon-α / ribavirin (PR). (The difference between the two trials is that QUEST-1 used peginterferon α-2a while QUEST-2 looked at both peginterferon α-2a and peginterferon α-2b.) Overall, the addition of Simprevir to a PR regimen was found to be highly effective. In both trials, approximately 80 percent of patients achieved SVR12 in the combined treatment group compared to only half of the patients treated with PR alone. Furthermore, the combined treatment acted far more quickly than the standard of care. An impressive 80 percent of the patients using the combined treatment had a rapid virologic response (RVR) compared to only 13 percent of patients in the control group, where RVR was defined as having HCV blood levels < 25 IU/mL by week 4 and undetectable by week 12. Patients who achieved RVR were able to discontinue treatment at week 24, decreasing the expected duration of treatment by half.
Another interesting study, presented by Dr. Jane Scott and colleagues, examined how adding Simeprevir to PR treatment affected patient fatigue during and after treatment. The researchers found that while including Simeprevir in the treatment regimen increased treatment efficacy and improved the number of patients achieving SVR, it did not increase their level of fatigue while they were still taking the drugs. Instead, the addition of Simeprevir to the treatment regimen actually significantly decreased fatigue levels over the course of the study, since the higher efficacy of the combined treatment meant that most patients underwent shorter-duration treatment than those given PR alone. The reduction in average treatment length from 48 to 24 weeks meant that mean fatigue levels returned to baseline by 36 weeks in the combined treatment group, while patients in the PR-only group weren’t back to feeling like themselves until week 60.
One final study of Simeprevir that physicians should be paying attention to is Janssen’s research, presented by Dr. Sivi Ouwerkerk-Mahadevan, on how liver health affects the pharmacokinetics of the drug. The study compared drug metabolism in HCV-negative healthy controls with metabolism in HCV-negative individuals with varying degrees of hepatic impairment. As had been seen in an earlier study of HCV-positive patients, the extent of liver damage had a significant impact on drug availability. The maximum drug concentration (Cmax) seen in severely impaired (Child-Pugh C) patients was more than three times higher than that seen in patients with normal liver function and almost twice as high as seen in HCV-infected individuals with compensated liver disease who were receiving the same oral dose. Even moderate hepatic impairment (Child-Pugh B) patients had elevated Cmax when compared to controls, levels comparable seen to those in HCV-infected patients. Fortunately, Simeprevir was well tolerated in all the study groups, but the challenging pharmacokinetics will certainly affect the dosing recommendations for future use.
Looked at as a whole, the Simeprevir research presented at ILC2013 suggests that, over the next few years, this drug will likely become an important tool in the fight against HCV. It is certainly one of the promising candidates to emerge from the quest to develop the next generation of DAAs – a quest that has brought new hope to the many doctors and scientists who have long been searching for an HCV cure.