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CURRENT NEWS-June 1, 2005
A New Hope for Hepatitis Therapy
June 1, 2005
After years of disappointing news, the outlook for hepatitis C drug therapy may be brightening under a deceptively simple premise: Attacking the virus head-on is the best way to improve both the low response rate and high side-effect burden of existing therapies.
Although relief may yet be years away, the pipeline is quickly filling with drugs designed to block key proteins involved in viral reproduction and subversion of a patient's immune response. The story behind one of these drugs, developed by Cambridge, Mass.-based Vertex Pharmaceuticals, says much about the emerging optimism in a field plagued by frequent failure.
"From where we sit, we're not on the doorstep of new treatments that are going to be in the marketplace this year," says Joshua Boger, chairman and chief executive of Vertex. "But we are on the doorstep of mid-stage clinical trials that are going to usher in a paradigm shift for clinical treatment."
By the end of the decade, he predicts, research and clinical tests could well lead to a treatment that has at its core a drug that directly hits a viral target. Boger is betting the target will be hepatitis C protease, and that a drug now called VX-950 will be the one to block it.
Existing therapies - alpha-interferon in particular - have unquestionably helped hundreds of thousands of patients, and reformulations are making the most of their anti-viral properties. In February, for example, the Food and Drug Administration approved a combination of ribavirin and pegylated alpha-interferon (marketed by Roche as Pegasys) for treating chronic hepatitis C infections in patients whose treatment has been complicated by HIV co-infection.
Even so, hepatitis C experts concede that for many patients, available treatment options are of no benefit. A big reason is that the most common variety of the virus in the United States - known as genotype 1 - also is the most difficult to treat, with a documented response rate ranging from 40 to 56 percent. Last year, researchers at Duke University Medical Center found that response rates among infected African-American patients are even lower.
Relapse is common
A significant portion of patients may relapse after the course of treatment ends, and for up to 15 percent of hepatitis C patients, the side effects of injected interferon therapy force a premature end to treatment, regardless of the response.
The relatively broad immune-boosting activity of interferon is often accompanied by flu-like symptoms, while more problematic side effects may range from hair loss, rashes and fatigue to severe depression and aggravated liver disease. In addition, ribavirin can cause severe anemia, or a low red blood cell count.
Understandably, the biomedical industry and patient advocates have a vested interest in pursuing alternative therapies. A "whole flock of companies" are doing just that, says Dr. Douglas Dieterich, a hepatitis C expert at Mount Sinai School of Medicine in Manhattan. In large part, their drugs are designed to hit the virus where it counts: undermining its ability to replicate or to outmaneuver the body's defenses.
In a study published this month in the journal Nature, researchers at Rockefeller University in Manhattan worked out the structure of a pivotal protein domain within the viral RNA replication machinery, offering a potential target for a drug that blocks the ability of the virus to copy its own RNA.
But another class of drugs known as protease inhibitors, including VX-950, are generating much of the current buzz. As in HIV, researchers say the protease enzyme of hepatitis C is absolutely essential for viral replication to occur. It's also relatively specific.
"There isn't any protease similar in the human body," Boger says.
But to be effective, a drug blocking the enzyme's activity must bind to its business end, and nowhere else - a tough assignment as researchers found.
"The so-called active site of that protein wasn't a nice deep groove or tunnel, just a shallow cleft, an indentation," Boger notes. "This was a little bit akin to climbing a rock face with your bare hands. There wasn't much to hang on to."
Less than two years ago, however, drug company Boehringer Ingelheim provided a critical proof-of-principle experiment, when a molecule under development dramatically lowered the hepatitis C viral load in infected volunteers within two days. The drug, named BILN 2061, proved remarkably specific, but fell by the wayside due to animal toxicity concerns.
The partial promise left unanswered another another vital question: "A puzzle with any persistent viral infection is why it persists," Boger says. "Why doesn't the host's immune system just wipe it out?"
In this case, research suggests, the hepatitis C protease not only helps the virus copy itself but also blocks the liver's ability to naturally produce interferon, and hence, its ability to eradicate the virus. Earlier this year, scientists in Texas and Maryland discovered how the protease halts the cell's emergency response. The situation, Boger says, is akin to a burglar cutting a home's telephone wires to block the police from coming to the rescue.
A drug that blocks the protease, then, could halt the viral one-two punch with one of its own, and Vertex and its competitors are scrambling to deliver the first blow. In an early Phase Ib double-blind trial with VX-950, 34 European volunteers with pre-existing genotype-1 hepatitis C infections received either a placebo or one of three doses of the experimental drug over a two-week period, during and after which doctors examined their viral loads.
Patients who received 750 milligrams of the drug every eight hours achieved a 10,000-fold decrease in viral levels, on average, after two weeks, with a reduction to undetectable levels observed in two of eight patients.
New drug well tolerated
Boger says the drug has been well tolerated so far and has not been associated with any serious adverse events in the limited clinical trials.
"Right now, there's no single-agent drug that shows much more than a log drop in the virus and for a virus that's five to six logs, that's only a small piece of the puzzle," he said before the VX-950 results were announced earlier this month.
"Anything more than a log drop would have the potential to be a paradigm shift."
Even if a shift occurs, however, no one expects an outright replacement of alpha-interferon, at least right away.
"If they're trying to escape interferon, they are not going to be able escape interferon for eight to 10 years," Dieterich insists, a sentiment shared by Long Island-based hepatitis C specialist Dr. Melissa Palmer.
But the approach, if all goes as planned, may eventually tip the balance toward a therapy that successfully treats many more hepatitis C patients than those it leaves behind.