Therapy with pegylated interferon and ribavirin is currently the cornerstone of treatment for hepatitis C virus (HCV) infection. Despite its ability to cure the infection in many patients, there remains significant room for improvement. Indeed, major drawbacks of the current standard therapy include limited efficacy in HCV genotype 1, high incidence of adverse events, long duration of treatment and, consequently, suboptimal patient compliance.
The large market potential for HCV drugs, combined with the need for improved therapies compared to the current standard of care, has drawn drug developers into the HCV market and resulted in a highly active pipeline, comprising drugs with various mechanisms of action. Given the success of small molecule antivirals such as viral protease or polymerase inhibitors in the treatment of other viral infections (such as hepatitis B and HIV), this class of drugs currently dominates the HCV pipeline. Several strategies are being explored in clinical trials, including add-on therapy to the current standard of care and combinations of different oral direct acting antiviral agents without interferon/ribavirin.
At this years' European Association of the Study of the Liver meeting (EASL 2010), the use of novel agents and classes for the treatment of HCV - particularly small molecule antiviral agents - was a key focus of discussion. Delegates presented safety and efficacy data for various compounds in difficult-to-treat patients, such as those infected with HCV genotype 1 and those that have failed to respond to a prior course of pegylated interferon and ribavirin therapy.
Study 107 confirms efficacy of telaprevir
Tibotec/Johnson & Johnson's and Vertex's NS3/4a protease inhibitor telaprevir and Merck & Co's NS3/4a protease inhibitor boceprevir are the most advanced candidates among the small molecule antiviral HCV agents. Both compounds are currently being investigated in Phase III studies.
Data from study 107, investigating telaprevir in 117 patients that had failed to respond to a previous course of pegylated interferon and ribavirin therapy, were presented at a parallel session in the EASL meeting. Patients in this open-label study were null-responders, partial responders, relapsers or had viral breakthrough in the control arms of the PROVE1/2/3 studies. They were treated with 12 weeks of telaprevir (750mg) combined with current standard of care, followed by either 12 or 36 weeks of pegylated interferon and ribavirin alone depending on HCV RNA levels at week four and week 12.
Of the 81 patients who received 24 weeks of treatment, 60% achieved a sustained viral response, including 96% of prior relapsers and 86% of those with prior viral breakthrough. Of the 34 patients who received 48 weeks of treatment, 53% achieved a sustained viral response, including 56% of prior null-responders and 100% of prior relapsers.
Alongside the PROVE 3 results recently published in the New England Journal of Medicine, these data serve to further highlight the efficacy of telaprevir in this difficult-to-treat population. The compound is undergoing further evaluation in treatment-experienced patients in the REALIZE study. Pending the successful outcome of this Phase III trial, triple therapy with telaprevir could form an attractive alternative option for patients that do not respond to current standard of care.
Encouraging data for Bristol-Myers Squibb's novel Phase II NS5A inhibitor
Among the new HCV drug classes in development, the non-structural protein 5A (NS5A) inhibitors generated the most attention at the EASL meeting. The virus-encoded NS5A is a multifunctional protein essential for HCV replication. NS5A represents a relatively new target and inhibitors are expected to have a broad genotypic coverage. Currently, Bristol-Myers Squibb's candidate BMS-790052 is the most advanced in terms of development.
Results from a placebo-controlled Phase II study assessing the safety and efficacy of three different doses of BMS-790052 (3mg, 10mg and 60mg) in combination with current standard of care were presented at a late-breaker session at the EASL meeting. Impressive efficacy rates were observed, with 83% of patients in the BMS-790052 10mg arm achieving an extended rapid virologic response compared to only 8% in the placebo arm. The rate of adverse events was comparable across BMS-790052 dosing arms and placebo. Although larger studies investigating the efficacy of BMS-790052 over a longer timeframe are required to confirm these results, Datamonitor believes that, on the basis of the presented data, BMS-790052 seems a promising new agent for the treatment of chronic HCV. The company is also investigating BMS-790052 in combination with its NS3/4a protease inhibitor BMS-650032 in a Phase II study in null responders.
Additionally, encouraging results were observed for early-stage developmental agents including Boehringer Ingelheim's NS3/4A protease inhibitor BI201335, Idenix's nucleotide HCV polymerase inhibitor IDX184 and Anadys Pharmaceuticals' non-nucleoside polymerase inhibitor ANA598. These compounds were tested in various different populations, primarily genotype 1-infected patients as well as individuals failing on current standard of care.
Ritonavir boosting enables potent antiviral activity for danoprevir at low doses
Danoprevir (RG7227) is an NS3/4a protease inhibitor developed by Roche and Intermune. Preliminary results from two cohorts of the Phase Ib multiple-ascending-dose study for danoprevir were presented at EASL 2010. Doses of 100mg twice daily, 200mg once daily and 200mg twice daily were administered for 15 days in combination with 100mg ritonavir, and with standard-dose Pegasys (peginterferon alfa-2a) and Copegus (ribavirin).
The combination of 100mg danoprevir and 100mg ritonavir administered twice daily resulted in 78% of patients achieving a level of HCV RNA below the lower limit of quantification, and 67% of patients having HCV RNA levels below the lower limit of detection by day 15.
Ritonavir, a pharmacokinetic enhancer, is already widely used in HIV therapy to boost the plasma levels of protease inhibitors and facilitate the administration of lower drug doses. Given the recent discontinuation of the 900mg arm of danoprevir in a Phase II study over safety concerns, ritonavir boosting represents an attractive approach for the further development of danoprevir, enabling potent efficacy at lower doses.
Efficacy of novel agents suggests a possible paradigm shift in HCV therapy
The encouraging data observed for the small molecule antiviral classes to date has sparked interest in the possibility of using regimens consisting of oral agents alone. Several companies are exploring such strategies, the first of which is Roche in its INFORM studies. Others such as Bristol-Myers Squibb and Vertex have followed suit and are investigating regimens consisting or their oral HCV candidates.
While these studies are likely to give an indication of the feasibility of this approach, greater insight into issues such as resistance and safety is required in order to progress towards combination therapy with oral small molecule antivirals such as that used in HIV therapy. Ultimately, Datamonitor believes that in the short- to mid-term pegylated/interferon and ribavirin will remain standard of care. However, the most advanced novel agents such as telaprevir and boceprevir will add significant value as add-ons for difficult to treat populations.