by: Jason Chew
July 19, 2010
Pegylated interferon plus ribavirin is the current standard of care for HCV treatment. However, it is a 48-week treatment and is only effective in about 50% of patients. On top of that, patients must deal with the inconvenience of injections and side effects that include fatigue, depression, anemia and rash.
Now a new generation of so-called “direct acting” antivirals is expected to change the way HCV is treated, lead by the protease inhibitor teleprevir from Vertex (VRTX). In a Phase III trial, it was shown that a short 12-week treatment of teleprevir on top of Peg-interferon plus ribavirin resulted in a cure rate of 75% compared to just 44% with Peg-interferon plus ribavirin alone for 48 weeks. In the most likely scenario, teleprevir will reach the market toward the end of 2011, with a similar drug from Schering-Plough (SGP), boceprevir, following soon after.
The World Health Organization estimates 200 million people worldwide are infected with HCV, with an additional 3 to 4 million contracting the disease each year. The global market for HCV treatment is currently around $2 to $3 billion. With the advent of new available treatments, this market is expected to increase to more than $8 billion by 2016.
Teleprevir and boceprevir are only the first in a long list of novel HCV treatments moving through the pipeline. There are now four main classes of direct acting oral antivirals in clinical trials:
NS3/4A protease inhibitors- these are the most advanced agents; Teleprevir is among them
Non-nucleoside NS5B polymerase inhibitors- many are in development
Nucleoside NS5B polymerase inhibitors- these are showing a great deal of promise
NS5A inhibitors- most recently developed
The market for these novel medicines is still in its infancy, with no drugs so far approved by the FDA, yet there are no fewer than 14 companies working on these four classes of HCV treatments.
Companies with market caps ranging from less than $100 million to greater than $100 billion are involved in this work.
To divine the future of HCV drug development, it may be intuitive to look at the history of HIV drugs. Both HCV and HIV are RNA viruses, and some of the most effective early drugs to treat HIV were protease inhibitors. Over time, new classes of drugs were developed that were more potent and had fewer side effects. Scientists found that combinations of multiple drugs taken together worked the best; HIV became highly treatable even though no cure was found. Single pills containing a cocktail of antiviral drugs became the standard of care. Importantly, the current leader in the HIV market was not among the first entrants, it usurped the throne by developing a superior treatment.
Now as teleprevir heads towards market, drug makers are already at work on combinations of direct acting drugs. None of the compounds in development today work as monotherapies. The first generation of these combination drugs are protease inhibitor plus non-nucleoside NS5B polymerase inhibitor or protease inhibitor plus nucleoside NS5B polymerase inhibitor. The former of these is slightly more advanced in the clinic. The ultimate goal is to find a combination of oral drugs, which will eradicate the virus without the need for the addition of Peg-interferon plus ribavirin.
With four drug classes, the number of drug combinations is quite large. It is expected that similar to HIV treatment, these drug combos will consist of from two to four different compounds. Certain combinations of three drugs have now been shown to be synergistic together. It is not necessary that each of the drugs in the combo come from a different drug class. For instance, multiple polymerase inhibitors, each attacking different sites on the polymerase, can be used together, allowing for an even greater diversity of drug combinations.
In my opinion, it is almost a certainty that neither of the first two protease inhibitors will reign as standard of care in HCV treatment for very long. They have a significant head start on other compounds, but both have similar weaknesses. Neither can be taken once-daily, and resistant strains have already been identified for both compounds. Early stage protease inhibitors are now being developed that are more potent against the NS3/4A protease by greater than 100 fold, may have the potential for once-daily dosing, and have been shown to be active against HCV strains resistant to teleprevir and boceprevir. It is also thought that nucleoside polymerase inhibitors may have an advantage over other compound classes due to the high barrier it presents to the creation of resistant viral strains.
With the rapid advances in drug development, some predict treatment time may be reduced to as short as six weeks. The HCV space will be fascinating to watch in the coming years as new treatments become approved.