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Triple-Drug Cocktail in the Works for Hepatitis C Therapy

Drugs that are specific to hepatitis C will soon go from trial to clinic, giving more patients hope, but a vaccine is still elusive
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People infected with hepatitis C virus (HCV) face a long road of drug treatment that, in the best cases, can cure their infections and allow their livers to recover from HCV-associated liver disease, whose symptoms range from scarring and cancer to organ failure. Unfortunately, for nearly half of those treated for the most common strain of HCV, the standard antiviral drugs do not succeed in clearing the virus. And, even in cases where the drug regime is effective, flulike symptoms, depression and anemia are common side effects during the 48-week treatment period.

Here is the crux of the current treatment dilemma: When John McHutchison, a liver specialist at the Duke Clinical Research Institute (DCRI) in Durham, N.C., discusses with his patients whether to begin treatment for their chronic HCV infections, he tells them that it would give them about a 40 percent chance of curing their infection. The HCV regime contains two nonspecific antiviral drugs called interferon and ribavirin. But, he also tells his patients nowadays that in about 18 months new treatments could be available that improve their chances. "Many of them who have not responded to our current treatment are waiting for these new [HCV] drugs," he says.

The World Health Organization estimates that about 170 million people worldwide have chronic HCV infection—resulting from their bodies not having been able to fight off the acute onset—and are thus at risk of developing potentially fatal liver disease. Approximately 3.2 million people in the U.S. are chronically infected with HCV, according to the U.S. Centers for Disease Control and Prevention. In the U.S. patients have between a 38 and 41 percent likelihood of responding to the combination of interferon and ribavirin, depending on the level of virus in their bodies as well as the drug dosages. McHutchison says that the likelihood of responding to HCV treatment is higher among European than American patients, but as low as 25 percent among African-Americans, because of differences in mutations in immune genes between these groups.

How long patients like McHutchison's and others will have to wait for new HCV medication depends on the success of the drug candidates that are currently in large-scale phase III clinical trials. The strategy of these pharmaceuticals is to directly undermine HCV's ability to replicate inside cells. In contrast, interferon nonspecifically boosts the immune system (the mechanism of ribavirin is not well understood). One of the new anti-HCV drugs, when given in combination with interferon and ribavirin, increases the percentage of patients who are cured of the virus to 60 and reduces overall treatment time. If the drug, called telaprevir, performs well in the phase III trials that are underway, it could be approved for patients by 2011, says McHutchison, who leads the telaprevir trials.

Although it is at an earlier stage in clinical development, a second type of HCV drug could also become part of the treatment strategy. Rather than going after the virus itself, these compounds would inhibit molecules native to the patient. The right type of cellular target "needs to be mandated by the virus, and then it needs to be dispensable for the host during the duration of treatment," says Henrik Orum, chief scientific officer at Santaris Pharma in Denmark. Orum's group demonstrated that a type of RNA molecule called a microRNA could be that kind of target in a study that was published December 3 in Science. Whereas this microRNA is necessary for HCV replication, its absence does not seem to cause harm to the host.

Of course, the best way to handle HCV infection is to prevent it altogether. T. Jake Liang, chief of the Liver Disease Research Branch at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), says that even if HCV therapy became an effective cure for everyone, "there are still cases of new infections through various means," such as intravenous drug use, sexual and close personal contacts, and tainted medical products or instruments. Because injecting drugs is also a major risk factor for HIV, between 50 and 90 percent of injecting drug users that are HIV-positive are also infected with HCV. Co-infection with HIV accelerates the progression of HCV-associated liver disease, and may compromise the effectiveness of HCV treatment.



In the long run, Liang says, drug treatment is more expensive and complicated than vaccination, adding that it is difficult for developing countries to afford the cost of a 48-week treatment, which currently runs up to $20,000 in the U.S. With current HCV vaccine candidates in the early stages of clinical testing, however, anti-HCV drugs will probably beat vaccines to the marketplace.

Attacking HCV head-on

The forerunners among the new drugs tailored to stem HCV infection are telaprevir and boceprevir. Both drugs are currently in their last, or phase III, trials. If the tests are successful, the companies that developed them will file with the U.S. Food and Drug Administration for approval. Telaprevir, designed by Vertex Pharmaceuticals in Cambridge, Mass., and boceprevir, by Schering–Plough in Kenilworth, N.J., also share a similar mechanism of action and efficacy. Eric Lawitz, president and medical director of Alamo Medical Research in San Antonio, Tex., expects that boceprevir, like telaprevir, should increase the number of patients that respond to interferon and ribavirin by 20 percent. Lawitz has worked with McHutchison at the DCRI on some of the early clinical telaprevir studies.

These drugs target the HCV protease—one of the virus's enzymes. When the virus infects a cell its RNA genome gets translated into one long polyprotein. The HCV protease, along with some cellular proteases, must cleave this polyprotein into distinct viral proteins that can carry out other jobs in the viral life cycle, such as making more copies of the viral genome. Lab strains of HCV that harbor mutations crippling the protease fail to replicate in cells in a petri dish and cannot establish an infection in chimpanzees, the animal model for studying HCV. Because of the importance of the HCV protease, scientists at Vertex and Schering designed small molecules, based on the structure of the protease protein, that could fit into the protease's active site. They then tested them for their ability to disarm the enzyme. The winners were telaprevir and boceprevir.

In the most recent phase II clinical trial, a team of investigators, which included McHutchison, found that 61 percent of patients who received a triple treatment of telaprevir with interferon and ribavirin responded to treatment compared with 41 percent in the control group that received the usual 48-week regime of interferon and ribavirin. Treatment response meant that the patient had undetectable levels of virus for at least 24 weeks after the end of treatment, indicating that they could be cured of HCV. Moreover, instead of 48 weeks, patients were on the triple therapy for 12 weeks, followed by 12 weeks of double therapy (interferon and ribavirin). The results of the trial were published in the April 30 issue of The New England Journal of Medicine.

The drawback of triple therapy, however, is its side effects. Rash was the most common as well as an overall heightened degree of the nausea and anemia associated with double therapy. Because of such effects, 21 percent of the triple-therapy group dropped out of the study, compared with 11 percent of the control group.

McHutchison attributes the success of triple therapy at bringing down the level of virus to the fact that "we're just attacking viral replication another way." But there could be some overlap between the action of the protease inhibitors and that of interferon. Along with cleaving the viral polyproteins, which benefits the virus, the HCV protease also cleaves cellular proteins involved in the immune response, which may compromise patient immunity. Interferon treatment restores some of this innate immune response. And, if a protease inhibitor were added in the treatment mix, it could prevent some of the destruction of the host's immune response.



As is the problem with any drug that targets an HCV protein, viruses have emerged that are resistant to protease inhibitors. Because patients harbor a heterogeneous mix of HCV species, there could easily be a few in the population that are able to grow despite protease inhibitors, causing a so-called "viral breakthrough". This heterogeneity is due to the facts that HCV replicates at a high rate and the viral polymerase, which makes copies of the RNA genome, is prone to error. In fact, studies have estimated that, in a day's worth of gene replication, every site in the viral genome mutates at least once.

In the recent phase II study of telaprevir, viral breakthrough occurred in 7 percent of the patients that received triple treatment. "[But] the hope is that most of those [viruses that break through will] respond to the interferon and ribavirin," Alamo Medical's Lawitz says.

The protease inhibitors could be just the beginning of anti-HCV drugs that are added to the treatment regime. Compounds that inhibit the HCV polymerase are currently in phase II trials and, if all goes well, could get to market about a year after protease inhibitors. Although it would be less likely for a viral species to have mutations that made it resistant to both protease and polymerase inhibitors, the idea is that multidrug-resistant HCV strains could still emerge, as HIV strains have in spite of antiretroviral therapy.

Indirectly inhibiting HCV infection

To reduce the risk of viral resistance and give HCV-infected patients another treatment option, scientists are looking to inhibit cellular molecules that are important for HCV replication. In 2006 scientists discovered that HCV needs a microRNA, a regulatory RNA that does not get translated into protein, in order to replicate. Although this microRNA, called miR-122, binds directly to the viral genome, it is not entirely clear how miR-122 helps the viruses replicate.

Based on HCV's dependence on miR-122, scientists at Santaris decided to try a technology that they have also been developing to treat various cancers, such as leukemia and solid tumors. The team synthesized an RNA molecule called SPC3649 that is designed to base pair with miR-122 and has a chemical modification locking it in one of its two possible confirmations. Locking the molecule allows it to bind to miR-122 more effectively, thereby preventing miR-122 from binding HCV RNA.

The results that the Santaris group saw in HCV-infected chimpanzees, which were published November 30 in Science, encouraged the scientists to conduct phase I trials of SPC3649 that are currently ongoing. They found that the level of HCV plummeted in all four of the chronically infected chimpanzees that they injected with SPC3649 weekly for 12 weeks. These results do not resolve, however, whether SPC3649 can clear a chronic infection because the levels of virus rebounded after the scientists stopped treatment. "Future studies in human patients will be investigating that point further," says Orum, who is leader of the project, adding that "12 weeks is a fairly short period of time for eradicating HCV virus."



Before SPC3649's potential as an HCV drug can be tested in humans, Orum's team has to address its safety. The current phase I trial testing four different doses of SPC3649 in healthy, HCV-negative patients should shed light on this question when it is finished in the first half of 2010. Because miR-122 normally regulates cholesterol levels, the most likely side effect would be upsetting the levels of cholesterol particles—both the "good" (HDL) and "bad" (LDL) varieties. In chimpanzees SPC3649 reduced cholesterol levels by about 40 percent, which Orum says did not affect their health and is similar to the effect of cholesterol-lowering drugs, namely statins. In general, he does not expect that inhibiting a microRNA would completely upset a cellular process. "MicroRNAs do not act as on/off switches; they act as fine tuners of physiological pathways," he says.

If SPC3649 helps to eradicate HCV in humans, clinicians would have reduced fear of the virus developing resistance. To do so, a virus would have to emerge that has acquired a different mode of replication, which would likely involve multiple mutations. If the virus were able to adapt to replicate without miR-122, "we would have very likely have picked up mutations during the [period of miR-122] suppression that would have repopulated the chimps," Orum says. "With direct-acting drugs [such as protease inhibitors], you pick up escape mutants with days of treatment."

The search for a vaccine

Groups working to develop a vaccine against HCV have several obstacles to contend with. "Basically we're facing the same issues as people trying to develop an HIV vaccine," NIDDK's Liang says. These groups face "all the same problems," adds Liang, who is trying to show the effectiveness—first in chimpanzees—of his own vaccine candidate.

These problems are threefold, as Liang explains: The first is that the envelope proteins that coat the virus's outer membrane do a poor job of stimulating an antibody response in the host. This poor immunogenicity is probably part of the reason, Liang says, that HCV is the only RNA virus (though HIV has an RNA genome, it is considered a retrovirus)  that is able to persist in the host and cause chronic infection. Secondly, any vaccine would have to protect against the mix of viral species in a patient, by finding a region of envelope proteins that is important enough to be conserved between the different species. Lastly, the virus has evolved strategies to evade the immune response, for example, by repressing the host's interferon response

Still, several vaccine candidates are in clinical testing, albeit in early, safety trials. Liang says that it will probably be possible to eventually find regions of envelope proteins that are conserved between different species. Another question will be how to deliver them to the host. Although some groups, like the vaccine development team at Novartis Pharmaceuticals, are testing these protein fragments in solution, Liang and his colleagues are trying to assemble them in "viruslike particles." "We think that viruslike particles mimic the virus much better than soluble proteins," Liang says.



If some of these candidate vaccines make it to large-scale clinical trials, scientists will then face the next hurdle: how to test them on the general population. Because HCV prevalence is low in the U.S., testing a vaccine's ability to prevent infection would probably require thousands of U.S. volunteers or conducting the trial in high-incidence areas such as China, India or Egypt. Liang says that many groups involved in HCV vaccine development will probably first test their vaccine as a therapeutic vaccine to cure people chronically infected with HCV.

Even if one of the vaccine candidates is a success, it could take years to demonstrate its effectiveness, leaving time for the anti-HCV drugs to finish moving through the development-to-market pipeline. Alamo's Lawitz predicts that "in 2011 three drugs will be the standard treatment [for HCV]." The addition of telaprevir and other pending anti-HCV drugs to the armory would make the treatment of HCV more customized, similar to how antiretroviral treatment has become for HIV.

McHutchison hopes that by early 2010, people who are diagnosed with HCV will be tested to see which mutations they possess in the immune genes that predict response to interferon and ribavirin treatment. The people who bear the least likelihood of responding to the current treatment, those of African-American descent, may want to hold off for more promising treatments like telaprevir. On the flip side, "if you're genetically predisposed to have [a higher] chance, maybe you only need eight to 12 weeks [on therapy]," McHutchison says.
 
He adds, "To be able to go from saying [to a patient that you have a 40 percent chance of clearing the virus] to sitting down and saying that we're going to have to treat you for six months and you have a two-thirds chance is a very different conversation."

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