Hepatitis C - merimepodib
Hepatitis C is a viral infection that causes inflammation of the liver. This can lead to fibrosis and cirrhosis, liver cancer and, ultimately, liver failure. Patients with chronic hepatitis C infection may be asymptomatic and the virus may go undetected for as long as 20 years before symptoms finally occur. Currently available treatments are effective in only maybe half of those with the most virulent genotype, type 1, which is also the most difficult to treat. If the patients do not respond to these existing treatments, then the options are limited, and only a very low proportion of these patients are able to achieve a sustained viral response with subsequent treatment regimens. As a result, alternative treatment approaches are very much needed.
Vertex Pharmaceuticals is developing merimepodib, formerly known as VX-497, as a potential therapy for hepatitis C (HCV) infection.1 The small molecule drug is orally active, and inhibits the enzyme inosine monophosphate dehydrogenase (IMDPH). Inhibiting this enzyme leads to a reduction in intracellular guanosine triphosphate (GTP), which is needed for the biosynthesis of both DNA and RNA. It is thought that IMDPH inhibitors may enhance the antiviral activity of ribavirin in vitro by depleting GTP, and hence could provide a strategy for increasing the sustained viral response rate to ribavirin in HCV patients.
In a double blind, placebo-controlled randomised Phase II study, 31 patients were given 25 or 50mg of merimepodib, or placebo, twice a day in combination with pegylated interferon and ribavirin for 24 weeks.2 The patients had been unresponsive to interferon-a and ribaviron. After the 24 weeks, those patients who were HCV-RNA negative continued treatment for a further 24 weeks. Six of seven given the higher dose had undetectable levels after the first period, compared with a third of the remainder.
Further analysis was carried out on the 11 patients who continued into the second phase of the study.3 Ten of these completed the 48 weeks, and the majority of side-effects reported were consistent with the known side-effect profile of peg-interferon and ribavirin.
One of the three patients in the placebo group and three of seven receiving merimepodib achieved a sustained viral response at week 72, 24 weeks after treatment had ceased. Trials continue, and merimepodib could well provide a useful additional therapy for hepatitis C sufferers.