The news gains special importance as individuals who have been infected for more than 20 years is increasing. The peak incidence of infection occurred in the mid-1980's. As complications from HCV take 20 to 30 years to develop, the number of people requiring treatment is predicted to dramatically increase. Hospitalisation and death rates are projected to triple over the next 10 to 15 years, mostly affecting people who are currently unaware of their status.
Scientists from InterMune and Array BioPharma's stable collaborated on the preclinical study. In vitro studies showed that the two compounds were stable on incubation with human liver cells and displayed a high degree of selectivity. Neither compounds showed significant inhibition of cytochrome P450 isoforms (liver enzymes that break down toxins and other substances processed in the liver) or hERG channel-blocking activity (a complication that can lead to abnormal cardiac rhythm).
"We were very encouraged to find that these two novel HCV NS3/4 protease inhibitors selectively targeted the liver, did not adversely impact the heart or liver and were well tolerated," said Dan Welch, president and CEO of InterMune.
"Based on these new data, we are moving these compounds into IND-enabling toxicology studies in order to select the most appropriate clinical candidate," he added.
In preclinical models, both compounds showed concentrations in the liver in orders of magnitude above the EC50 level (the concentration that leads to 50 per cent maximal response and a measure of the potency of a drug). The two compounds were well tolerated after seven days of dosing. No change in weight, abnormalities in clinical chemistries or hematology tests or mortality were observed.
"We are very pleased that data from these preclinical models support once- or twice-daily dosing in the clinical setting," said Lawrence Blatt, senior vice president of preclinical and applied research at InterMune.
He added: "Furthermore, these two compounds were highly concentrated in the liver and at levels in excess of the amounts required for HCV RNA decreases."
The progress of Intermune's HCV research program has made significant progress over the past three years and they are amongst a handful of companies with similar research interests. InterMune launched its drug discovery program with Array BioPharma in September 2002 to pursue small molecule therapeutics targeting HCV.
In November 2004, InterMune and Array announced an extension of their collaboration, under which Array will perform process development research and cGMP scale-up through Phase I clinical trials of drug candidates resulting from the program. In September 2004, InterMune entered into a nonexclusive licensing agreement with Chiron Corporation granting InterMune a license to discover, develop and commercialise small molecule therapeutic agents against certain HCV targets that Chiron currently holds under patent protection.
As reported last week, Vertex Pharmaceuticals announced the latest results of its investigational oral hepatitis C virus (HCV) protease inhibitor VX-950, which was found to be well tolerated, demonstrating potent antiviral activity in a Phase Ib clinical trial.
Likewise, in November last year, Pharmasset of the US received at least $168 million (€131.8m) in upfront and milestone payments after licensing its preclinical hepatitis C drug programme to Swiss drug giant Roche.
According to the Centres for Disease Control and Prevention (CDC), an estimated 3.9 million Americans (1.8 per cent) have been infected with HCV, of whom 2.7 million are chronically infected, and the prevalence of chronic HCV is increasing. Currently available therapies are insufficient, creating a need for the development of novel therapeutic approaches.
Protease inhibitors represent a promising class of drugs for HCV, and the HCV NS3/4 protease is an attractive drug target because of its involvement in viral replication and suppressive effects on host response to viral invasion.
The new data were presented Sunday at the Digestive Disease Week (DDW) meeting in Chicago as part of InterMune's protease inhibitor program.