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).

Bristol Myers Squibb's BMS-790052 and BMS-650032 combo opens up new possibilites at EASL...

Wow. And I said it couldn't be done, that the possibilities were remote at best for an interferon-free DAA combination to cure HCV. Well, I'll gladly step up and dig in to my slice of Humble Pie, because this really is terrific news that quite possibly will open up a brand new treatment paradigm that sheds the side effect-laden burden of interferon, at least in some patients. BMS unleashed their Phase II data at EASL on the combination of their NS5A inhibitor BMS-790052 protease NS3 inhibitor BMS-650032 in patients that had been previously treated with the current standard of care therapy, peglyated-interferon plus ribavirin for 48 weeks. Out of the 11 patients who took took the drug combo without the inteferon component, five cleared virus at the end of treatment, and four of those remained undetectable 24 weeks after 24 weeks. In a similar patient population that received the drug combo plus peg and riba, 9 out 10 patients were cured. That's some potency right there. From a business perspective, it looks like the company is being extremely proactive in looking at partners to help fill the void between the pending launch of the first generation of DAA agents and BMS-790052 + BMS-650032. Pharmasset, which just announced positive two week data on their own interferon-free two drug combo PSI-938 and PSI-7977, might be looking mighty sexy to BMS at this point.


Bristol-Myers Squibb Co. (BMY)’s cocktail of two experimental drugs cured four hepatitis C patients in the first success for a therapy that excludes often-toxic existing drugs.

The combination had a higher rate of success when paired with the current standard treatment in the 21-person trial, curing nine of 10 patients, researchers said today at the Berlin meeting of the European Association for the Study of the Liver. The study points to the next generation of drugs for the evasive virus, said Mark Thursz, a professor of hepatology at Imperial College London and vice-secretary of EASL.

Bristol-Myers, based in New York, is among about a dozen companies trying to make better drug combinations that either include interferon, a decades-old shot that causes flu-like symptoms and only works in half of patients, or that replace interferon entirely. At stake is leadership in a market that Jefferies International Ltd. estimates may total $15 billion a year by 2019.

“This is perhaps one of the most exciting developments this year,” Thursz said in an interview. “For some patients who are not going to tolerate interferon, this is the light at the end of the tunnel.”

Bristol-Myers plans to begin the last trials required for regulatory approval this year, Douglas Manion, the drugmaker’s head of neuroscience and virology research, said in an interview.

Toughest-to-Treat

Today’s trial studied the Bristol-Myers drugs, BMS-790052 and BMS-650032, in patients for whom existing therapies hadn’t been successful, “the toughest-to-treat population,” Manion said.

Ten patients got the two drugs together with interferon and generic ribavirin. All showed no sign of the virus 12 weeks after the treatment was over. One patient had signs of virus at 24 weeks and was again virus-free in another follow-up test 35 days later.

Of 11 patients who took the Bristol-Myers combination alone, five had cleared the virus from their bodies at the end of treatment. Four remained virus-free after 24 weeks.

Patients may start treatment earlier if they aren’t faced with the toxic side effects of traditional hepatitis C drugs, said Howard Liang, a Boston-based analyst for Leerink Swann & Co., in an interview.

“If you have an interferon-free regimen, the market expands fairly dramatically,” Liang said.

Side Effects

Side effects of the existing interferon regimen are often severe enough to force patients to take time off work, said Charles Gore, president of the Geneva-based patient advocacy group World Hepatitis Alliance.

Roche Holding AG (ROG) of Basel, Switzerland, sells a version of interferon under the brand name Pegasys, while Merck & Co. of Whitehouse Station, New Jersey markets a form called PegIntron.

Merck, Vertex Pharmaceuticals Inc. (VRTX) and Johnson & Johnson are expected to bring the first new hepatitis C drugs in a decade to the market this year. About 90 percent of patients who responded quickly to treatment with Johnson & Johnson (JNJ) and Vertex’s telaprevir were cured, Cambridge, Massachusetts-based Vertex said in two studies last year. Three-quarters of all patients were cured. Patients who responded quickly to Merck’s boceprevir showed similarly high cure rates in studies last year, with about two-thirds of all patients being cured.

The Vertex and Merck trials included people who hadn’t yet been treated, an easier-to-cure group than those in today’s smaller study. By comparison, about 30 percent of those who hadn’t responded to previous treatment were cured after trying telaprevir plus standard therapy, researchers said.

Seeking Partners

Merck is seeking partnerships to gain its own hepatitis C drug combinations, Patrick Bergstedt, general manager of the infectious diseases franchise, said in an interview.

“We’re behind the others,” Bergstedt said. “We need to partner to fill the gap.”

Bristol-Myers expects an “element of consolidation” as companies use acquisitions, partnerships and research and development collaborations to gain their own hepatitis C drug combinations, Manion said. After signing a development deal with Princeton, New Jersey-based Pharmasset Inc. (VRUS) in January, Bristol- Myers is “talking to pretty much every company out there,” he said.

“This is like trying to redesign a car as you’re rolling down the road at 100 miles per hour, because the data are coming so fast,” he said. “What an exciting time.”

To contact the reporter on this story: Naomi Kresge in Frankfurt at nkresge@bloomberg.net

To contact the editor responsible for this story: Phil Serafino at pserafino@bloomberg.net