Despite being preventable by vaccination, hepatitis B virus (HBV) infection still claims thousands of lives each year worldwide. It is estimated that in the US alone 5,000 HBV patients die annually from liver failure. Although no drug can provide a complete cure, treatment for the disease has been improving rapidly over the years, with new drugs entering the market and many promising compounds undergoing clinical trials.
A decade ago, hepatitis B patients and their physicians had no treatment options. Currently, four nucleoside/nucleotide analogues and two immunomodulators (interferons) are available in the US. Nucleoside analogues are oral therapies that interfere with the viral DNA polymerase enzyme used for HBV reproduction. GlaxoSmithKline's Zeffix/Epivir-HBV (lamivudine) was the first to be approved by the FDA in 1998. Since then, Gilead's Hepsera (adefovir dipovoxil), approved in 2002, Bristol-Myers Squibb's Baraclude (entecavir), approved in 2005, and Novartis/Idenix's Tyzeka/Sebivo (telbivudine), approved in 2006, entered the global market. Immunomodulators, which mimic infection-fighting immune substances produced by the body, have been around for longer. The interferon brands approved for HBV include Schering-Plough's Intron-A (interferon alpha-2b), available since 1991, and the pegylated version PEG-Intron, and Roche's Pegasys (peginterferon alpha-2a), launched in 2005.
The World Health Organization (WHO) estimates that more than two billion people worldwide have been infected with HBV, and of those, 360 million are chronically infected and at risk of serious illness and death from cirrhosis and liver cancer. The HBV market, however, is relatively modest in size. As a majority of infected patients are in undeveloped countries that do not have complete access to modern medical care, analysts at Cowen & Co estimate the market to be worth $750 million. Universal HBV vaccination in the US and Europe has also significantly reduced the incidence of infection in these regions.
Nevertheless, unmet needs in HBV persist for several reasons. First of all, the majority of the 1.25 million infected Americans and three million infected Europeans do not receive any therapy, in part due to under-diagnosis and also because guidelines simply recommend observation during early stage of disease. New treatment options and raised awareness of the disease and new therapies could increase the number of treated patients over the next few years, hence expanding the market.
Looking East for newer markets
A second reason why the pharmaceutical industry sees a good opportunity in new compounds targeting HBV is the Asian market. It is estimated that more than 70% of chronic carriers of the virus are in Asia. The continent accounts for more than half of the global mortality due to hepatitis B. China is by far the largest market, representing 34% of the world's chronic hepatitis B patients. With a booming economy, a fast rate populational growth, and an improving healthcare system, China's pharmaceutical market is projected by IMS to grow 14.1% (compound annual grwoth rate) until 2011, amplifying the demand for HBV drugs.
Above all, drug efficacy is obviously the most important factor driving the HBV global market. Like HIV drugs, oral HBV antivirals are prone to the development of resistance, especially lamivudine. The development of new compounds and different modes of action therefore appears very important for the treatment of the infection. Many companies have been studying mechanisms to overcome drug resistance and several promising agents are currently in late-stage development. The next one to enter the market will probably be Gilead's tenofovir, a nucleotide analogue, already approved and marketed for the treatment of HIV infection under the trade name Viread. Gilead has submitted tenofovir for regulatory approval in HBV in the US and the EU and expects marketing authorisation in 2008. Data from clinical trials in hepatitis B suggested that tenofovir may prove more effective than Hepsera for this indication. Some industry analysts estimate that tenofovir will eventually take over the market from Hepsera ($230 million in sales in 2006).
Bukwang, Eisai and Pharmasset's clevudine, another oral nucleoside analogue, has also demonstrated potent antiviral efficacy in clinical results. Bukwang received approval for the drug in HBV infection in South Korea in 2006 and Eisai is starting Phase III trials in China. Meanwhile, Idenix and Novartis are working on valtorcitabine, a once-daily nucleoside analogue, for use in combination with Tyzeka in difficult-to-treat HBV patients. Phase II trials are ongoing and a regulatory submission is planned for 2009.
Novartis expects combination therapy to play an increasingly prominent role in the treatment of HBV. If the history of drug development for HIV infection is any indication, this idea is a good bet. Combination therapy may prove to be more effective than monotherapy in suppressing viral replication and may decrease or delay the incidence of drug resistance. Several large studies are under way exploring the use of two nucleoside/nucleotide antivirals or an antiviral plus peginterferon.
Looking back, the treatment of hepatitis B has taken a quantum leap in the last 10 years, as patients' chances of keeping the disease under control increased significantly. Looking forward, the future looks bright for those chronically infected with HBV. With all of the exciting new drugs in research and potentially a drug cocktail to beat the virus, there is great hope that a complete cure will be on the horizon soon.