Hepatitis C (HCV) has a high rate of replication, with approximately one trillion particles produced each day in an infected individual. Due to lack of proofreading by the HCV RNA polymerase, HCV also has an exceptionally high mutation rate, a factor that may help it elude the host's immune response and increase resistance to current therapies.
The past standard of care for patients with chronic HCV infection is treatment with a combination of long-acting, pegylated forms of interferon alpha (IFN-alpha) administered through weekly injections coupled with daily, oral doses of ribavirin. The duration of treatment for patients infected with non-genotype 1 virus is six months and results in undetectable viral load and normalization of liver function markers in up to 80% of patients receiving a full course of treatment. However, in individuals infected with the genotype 1 virus, the standard of care calls for 12 months of treatment and is successful in only approximately 50% of patients receiving a full course of treatment.
Limitations of Current Treatment
The current standard of care for HCV has significant limitations with less than half of patients receiving a full course of treatment.
Treatment with pegylated interferon and ribavirin is further complicated by significant adverse side effects, including flu-like symptoms, anemia, depression, fatigue, suicidal tendencies and abnormal fetal development. Since chronic hepatitis C infection, with the exception of late-stage disease, is generally asymptomatic, the nature and extent of the treatment-related adverse side effects make patients feel sicker than they were prior to treatment. As a result, nearly 40% of treated patients require dosage adjustments and many of these patients discontinue therapy altogether. In addition, current treatments are administered by injection, which is inconvenient and problematic for patients who are afraid of needles.
There is therefore a pressing need for new HCV therapies. Goals for new HCV therapies include:
- Improving efficacy against the genotype 1 virus,
- Offering a treatment response in patients who have failed an interferon and ribavirin-based treatment,
- Reducing the magnitude of treatment-related adverse side effects, and
- Offering a more convenient, orally available, treatment option.
As with HIV, a common approach to the discovery of new therapies to treat chronic HCV focuses on the inhibition of viral proteins essential to the completion of the HCV replication cycle. The two most common of these HCV drug targets are NS5B polymerase and NS3 protease. NS5B polymerase is essential for viral replication, as it is directly involved in creating new copies of the viral RNA genome. NS3 protease is essential for viral protein processing and completion of the viral lifecycle. All of the NS3 inhibitors of which Achillion is aware work by binding to the proteins active site, thus preventing protein processing. Both NS5B and NS3 inhibitors have demonstrated in clinical trials significant viral load reduction in infected patients. Many experts believe that these drugs, if approved, will need to be used in combination with other drugs in order to improve upon the efficacy obtained with the current standard of care.
Achillions HCV approach focuses on the discovery and development of product candidates specific inhibition of NS3 protease, a key component in viral replication, and NS5A, a protein involved in multiple steps of HCV replication.
