New drug targets raise hopes for hepatitis C cure

Article appearing in the online "news" section of the journal Nature, discussing how the best in HCV treatment - and prevention of resistance - may be yet to come with drugs currently in the development pipeline. Companies mentioned are Pharmasset, BMS and iTherX.



New drug targets raise hopes for hepatitis C cure

As the first targeted therapies edge towards regulatory approval, attention turns to the next drugs in line.

Heidi Ledford


A cocktail of tailored drugs will be needed to defeat the hepatitis C virus.
This week, a panel of advisers to the US Food and Drug Administration (FDA) will decide whether the regulator should approve the first therapies tailored to target the hepatitis C virus (HCV). The drugs, called protease inhibitors, are expected to win approval, but observers say that they are only the beginning of a revolution in HCV treatment.

The most exciting developments for patients, they say, may still be in the drug-development pipeline. Researchers are working on drugs that target many aspects of the virus's biology. Used in combination, these might thwart HCV's ability to evolve resistance.

About 3% of the world's population is infected with HCV, an RNA virus that can cause chronic liver disease. Current therapy — a year-long regimen of the antiviral compounds interferon-alpha and ribavirin — cures only about half of cases. Side effects of this treatment can be severe: interferon-alpha can cause flu-like symptoms, fatigue, anaemia and depression.

On 27 and 28 April, the FDA's Antiviral Drugs Advisory Committee will meet to discuss the first anti-HCV drugs to target HCV proteins. Both these drugs — boceprevir, made by pharmaceutical giant Merck, headquartered in Whitehouse Station, New Jersey, and telaprevir from Vertex Pharmaceuticals, based in Cambridge, Massachusetts — target a protein called the NS3-4A protease, which is required to make essential viral proteins.

Each drug, when combined with standard therapy, boosts the cure rate to about 75%.

"I am very excited," says Michael Houghton, a virologist at the University of Alberta in Edmonton, who was a member of the team that discovered the virus in 1989. "These drugs are great news for HCV patients."

The long road to a blockbuster
Nevertheless, these drugs are only the beginning. "These first-generation protease inhibitors will enjoy their day in the sun for maybe two or three years," says Raymond Chung, head of hepatology at the Massachusetts General Hospital in Boston. "But I don't see them having staying power once we have many more of these targeted drugs getting into the game."

The hope is to eventually use several drugs in combination, avoiding the need for interferon-alpha while staving off drug resistance. Houghton estimates, based on mathematical models and clinical studies, that it will take a cocktail of three targeted therapies to prevent drug resistance.

There are about 60 compounds in preclinical and clinical development as companies jostle to grab a slice of a multi-billion-dollar market.

In 2010, researchers at Bristol-Myers-Squibb's lab in Wallingford, Connecticut, reported their discovery of an HCV protein called NS5A that is essential for the assembly of infectious viral particles and the amplification of viral RNA1. In early clinical trials of an NS5A inhibitor, the level of HCV RNA in the blood dropped almost 2,000-fold after only one day of treatment. This drug is now in phase 2 clinical trials.

Combining the NS5A inhibitor with a protease inhibitor wiped out the virus in four of 11 patients whose infections had not responded to standard therapy. The virus remained undetectable for at least 24 weeks.

These latest results, presented at the International Liver Congress annual meeting in Berlin on 1 April, are exciting because they suggest that interferon may eventually be dispensable, says Chung. He anticipates a flurry of such combination studies in the next few years.

Access denied
Another approach is to stop HCV spreading inside patients by targeting its ability to enter cells. "To contain the virus in a subset of cells rather than allowing it to spread would be a huge boost for containing liver damage," says Michael Gale, a virologist at the University of Washington in Seattle.

In a study published in Nature Medicine on 24 April, a team led by virologist Thomas Baumert of the University of Strasbourg, France, reports that HCV relies on a cellular receptor protein, the epidermal growth factor receptor (EGFR), to enter human cells2. EGFR inhibitors are already on the market as cancer therapies and Baumert's team plans to begin clinical trials of the EGFR inhibitor erlotinib in HCV patients by the end of the year.

Another drug that blocks entry, ITX-5061, is being developed by iTherX, a pharmaceutical company based in San Diego, California, and is in phase 2 clinical trials.


Chung, meanwhile, believes that drugs called nucleoside polymerase inhibitors, which prevent the virus from copying its genome, will be a key ingredient of any future HCV drug cocktail. These compounds set a high barrier for the virus, he notes, and early tests suggest that resistance to them is rare.

Pharmasset, a pharmaceutical firm in Princeton, New Jersey, has several such drugs in development. One called RG7128 is in phase 2 clinical trials and is being developed by Pharmasset together with the Swiss drug giant Roche, based in Basel.

"We used to live in a monochromatic world," says Chung. "Now we realize there are several roads to the same destination."

References
1.Gao, M. et al. Nature 465, 96-100 (2010).
2.Lupberger, J. et al. Nature Med. doi:10.1038/nm.2341 (2011).