Business Society, January 16 — Hepatitis C virus (HCV) is the leading global cause of liver disease and, over the long term, is associated with extremely high morbidity and mortality. According to estimates by the World Health Organization (WHO), approximately 170 million people worldwide are living with chronic hepatitis C, representing about 3% of the global population, with 3 to 4 million new cases reported each year. According to data from the U.S. Centers for Disease Control and Prevention (CDC), the United States alone has nearly 3 million individuals with chronic hepatitis C, with about 300,000 new cases diagnosed annually across the country.

R&D pipeline: Small companies have achieved remarkable results.

Currently, the standard treatment for hepatitis C is combination therapy with pegylated interferon (PEG-IFN) and ribavirin. PEG-IFN products on the market include PEG-Intron from Schering-Plough and Pegasys from Roche, while ribavirin includes Rebetol from Schering-Plough, Copegus from Roche, and a wide range of generic formulations. However, in terms of sustained virological response (SVR), the current standard regimen delivers suboptimal outcomes, with a clinical cure rate of approximately 50%. Moreover, the treatment duration is relatively long—patients with HCV genotype 1, for example, require 48 weeks of therapy—and serious adverse reactions are common, including neuropsychiatric events, influenza-like symptoms, and hematologic toxicity. These issues significantly deter patients from adhering to treatment. Overall, it is estimated that the success rate of existing therapies for hepatitis C remains only about 10%.

Currently, at least 24 hepatitis C drugs under development are designed to complement or replace the existing PEG-IFN plus ribavirin combination therapy. The primary research focus in this field is antiviral treatment, with particular attention being paid to two classes of drugs: NS3–4A serine protease inhibitors and NS5B RNA-dependent RNA polymerase inhibitors.

Currently, many small biotechnology companies have established multi-faceted collaborations with large pharmaceutical firms, and HCV therapeutics are presenting small biotech companies with multiple, innovative opportunities. Notably, even many preclinical programs—though not yet representative Phase II clinical trials—have already secured funding from major pharmaceutical giants.

Protease Inhibitors: Unprecedented Antiviral Activity

The NS3–4A protease primarily inhibits hepatitis C virus replication, particularly in strains that can evade clearance by the host immune system. Consequently, protease inhibitors deliver a dual blow to the virus.

Telaprevir (VX-950), jointly developed by Vertex, Johnson & Johnson, and Mitsubishi Tanabe Pharma, is one of the most promising innovative protease inhibitors. To date, clinical studies have demonstrated that Telaprevir exhibits unprecedented antiviral activity, offering hope for improving the efficacy of existing hepatitis C therapies and shortening treatment duration—specifically, a 24-week regimen, half the length of the standard course. Moreover, Telaprevir is the first drug shown to remain effective in patients with prior treatment failure. An interim report from the Phase IIb PROVE3 trial revealed that, after 24 weeks of Telaprevir therapy, 52% of patients maintained undetectable HCV RNA levels at week 12 post-treatment. Recognizing that patients who previously failed standard therapy represent a critical unmet need in this field, Vertex is preparing to initiate a Phase III clinical trial in this population. However, Telaprevir is initially expected to be approved for the treatment of genotype 1 hepatitis C in treatment-naïve patients. A 24-week, placebo-controlled Phase III trial evaluating Telaprevir in treatment-naïve patients with genotype 1 hepatitis C is currently underway. If this trial is successful, Telaprevir is anticipated to receive approval for this indication by late 2010 or early 2011.

Although telaprevir has the potential to become the first hepatitis C treatment to be launched on the market, a large number of competing protease inhibitors are currently under development. Examples include Boceprevir from Schering-Plough, ITMN-191 from InterMune and Roche, and TMC435350 from Tibotec and Medivir. These agents are expected to offer better tolerability and greater convenience of use—for instance, requiring only once-daily dosing, whereas telaprevir requires three doses per day. Nevertheless, superior efficacy and shorter treatment duration will remain the primary drivers of market acceptance for new hepatitis C therapies.

Polymerase Inhibitors: Repeated Failures and Renewed Efforts in the Treatment of Hepatitis C

Polymerase inhibitors have been successfully used to treat viral diseases such as AIDS, hepatitis B, and herpesvirus infections. Unfortunately, however, polymerase inhibitors have failed to deliver in the case of hepatitis C virus. Many polymerase inhibitors in development have been discontinued due to efficacy or safety concerns. These include Valopicitabine from Idenix Pharmaceuticals and Novartis, R803 from Rigel Pharmaceuticals, XTL-2125 from XTL Pharmaceuticals, and HCV-796 from Viro and Wyeth.

Nevertheless, numerous novel polymerase inhibitors are currently under development for the treatment of hepatitis C. Roche has taken a leading position with two compounds—R1626 and R7128—where R7128 is licensed from Pharmasset. Experts believe that R7128 is more attractive, as it has thus far demonstrated a favorable safety profile, whereas R1626 is associated with significant hematologic toxicity, including neutropenia. In treatment-naïve patients with hepatitis C, when combined with the current standard-of-care regimen, R7128 achieves a faster virologic response compared with telaprevir; after four weeks of therapy, undetectable HCV RNA levels were observed in 85% of patients receiving R7128 and in 79% of those receiving telaprevir. For most protease inhibitors, it remains to be seen whether next-generation agents with antiviral activity will ultimately advance into clinical practice.

Other Targets: Tackling Drug Resistance

As with HIV, future therapeutic approaches for hepatitis C will inevitably involve combination regimens incorporating innovative agents with diverse mechanisms of action. In the short term, these agents will initially be used in combination with current interferon-based therapies. Over time, promising antiviral combination regimens are expected to replace interferon-based treatments. However, the epidemiological experience with HIV underscores that, due to the high genetic heterogeneity and mutation rate of HCV, resistance may emerge even as more highly specific protease inhibitors and polymerase inhibitors are introduced. Therefore, it is crucial to develop additional drugs targeting distinct HCV viral targets, particularly those that intervene at different stages of the viral life cycle.

Numerous cyclophilin inhibitors, including Debio-025 from Debiopharm, NIM811 from Novartis, and SCY-635 from Scynexis, have already advanced to Phase I or Phase II clinical trials. Cyclophilins have been shown to be a critical cofactor supporting HCV replication. Another promising therapeutic approach for treating HCV infection is to inhibit viral entry into host cells. Companies such as XTL BioPharmaceuticals, Replicor, Progenics Pharmaceuticals, Samaritan Pharmaceuticals, and Trimeris currently have HCV fusion and entry inhibitor programs in the preclinical development stage.

Over the next 5 to 10 years, innovative direct-acting antiviral agents for hepatitis C will usher in breakthroughs in this field, including higher cure rates, reduced dosing frequency and duration, improved patient adherence, enhanced safety profiles, and greater convenience of administration, such as oral formulations. More importantly, the growing number of patients with hepatitis C are placing high hopes on access to these innovative therapies, which will further drive advances in the development of anti-hepatitis C treatments.

Currently, a 48-week interferon-based treatment regimen costs US$35,000. The introduction of innovative direct-acting antiviral agents for hepatitis C is expected to at least triple this cost. Consequently, by 2017 the global market for hepatitis C therapeutics is projected to surge to between US$10 billion and US$15 billion, compared with just US$2 billion in 2002.

Currently, many small biotechnology companies have established multi-faceted collaborations with large pharmaceutical firms and secured funding from these industry giants. Hepatitis C therapeutics have already generated multiple, innovative revenue streams for small biotech firms.

Hepatitis C Drug Market Grows Fivefold in 10 Years

According to an analysis by Decision Resources, one of the world’s leading research and consulting firms specializing in pharmaceutical and healthcare issues, the hepatitis C virus treatment market is projected to grow nearly fivefold over the next decade, increasing from approximately US$2 billion in 2007 to more than US$10 billion in 2017, covering the United States, France, Germany, Italy, Spain, the United Kingdom, and Japan.

Although the number of people infected with hepatitis C is much lower than that of hepatitis A and hepatitis B, clinical studies have shown that approximately 80% of hepatitis C patients will progress to cirrhosis or hepatocellular carcinoma, making it far more dangerous than hepatitis A or hepatitis B. According to a newly released report by Pharmacor titled “Hepatitis C Virus,” pharmaceutical manufacturers have recognized that substantial unmet demand remains in the hepatitis C market and that considerable commercial potential exists; consequently, this market has been one of the most dynamic areas for the development of drugs to treat infectious diseases in recent years.

Dr. John Lebbos, a medical director at DecisionResources, stated: “Hepatitis C virus remains a sizable market with significant untapped potential. The disease exhibits a complex epidemiology, with most patients being older adults who have chronic infections. Over the next decade, this patient population is expected to increasingly develop advanced-stage complications, such as cirrhosis. Given that fewer than half of patients currently achieve cure following treatment with pegylated interferon-alpha and ribavirin—and that these regimens are associated with substantial adverse effects—pharmaceutical developers still have considerable room to introduce safer and more effective therapies.” (Article)