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Cover Story

May 3, 2010
Volume 88, Number 18
pp. 12 - 17

The Waiting Game

In the next year, the expected approval of small molecules targeting hepatitis C will usher in a new era in treatment

Lisa M. Jarvis

VIRAL CLEARING: New compounds quickly wipe out the hepatitis C virus. Bristol-Myers Squibb
VIRAL CLEARING New compounds quickly wipe out the hepatitis C virus.
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NEXT GENERATIONS</span> Scynexis researchers are focused on cyclophilin inhibitors. Scynexis
NEXT GENERATIONS Scynexis researchers are focused on cyclophilin inhibitors.

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A virtual queue is forming outside virologists’ doors. People with hepatitis C are anxiously awaiting access to two new antiviral drugs, Vertex Pharmaceuticals’ telaprevir and Merck & Co.’s boceprevir. Both are expected to be approved in 2011, and doctors are hailing their addition to the current standard of care, the combination of interferon and ribavirin, as a significant advance in the field.

But telaprevir and boceprevir are just the beginning of what many view as a new era of treatment for the hepatitis C virus (HCV). The drug pipeline is chock-full of second-generation compounds and new drug classes that are potentially safer, more potent, and more convenient to take than telaprevir and boceprevir. Even better, the new compounds can be combined to create antiviral cocktails that doctors hope will one day replace interferon and ribavirin altogether.

“There’s no modern therapy,” says Bob Kauffman, Vertex’ chief medical officer, about HCV. “This field has languished under ribavirin and interferon for 20 or 30 years. It is ready for something really different.”

HCV is a blood-borne infection that lives in the liver. Many people living with HCV were infected decades ago, before blood used in transfusions was tested for the virus. The majority of new infections occur when intravenous drug users share needles.

Because the liver is such a hefty organ, the virus has millions of cells at its disposal, allowing it to replicate at an astounding rate. Still, most people don’t know they’re infected for years, giving the virus a lot of time to generate scar tissue on the liver. As the scarring, or cirrhosis, worsens, it can lead to liver failure or liver cancer.

For now, the standard of care for HCV patients is a combination of PEGylated interferon, an immunoregulatory protein that prompts the body to fight against the virus, and ribavirin, an antiviral with an unknown mechanism of action. To endure treatment with the drugs is an act of will: For nearly a year, patients must live with side effects that include anemia, headaches, nausea, flulike symptoms, and depression.

Worse, the treatment is not widely effective. Because symptoms rarely appear until liver damage is under way, fewer than half of the 3.2 million Americans thought to be infected with HCV have been diagnosed. The interferon-ribavirin combination works for only half of those people. Factor in the side-effect profile—people with psychiatric problems can’t take the drugs and others can’t handle the misery—and the number of people with HCV who complete a successful treatment is not much more than 10%, according to health care consultancy Decision Resources.

In contrast, if telaprevir and boceprevir reach the market next year—and nearly everyone involved believes they will—the portion of patients treated could quickly jump to 30%, says Decision Resources analyst Alexandra Makarova. As more drugs are launched and awareness of the disease increases, the treatment rate will only grow.

The availability of the two new drugs—both are protease inhibitors that block an enzyme involved in virus replication—“may dramatically change the treatment of hepatitis C,” says Adrian M. Di Bisceglie, chief of hepatology at Saint Louis University’s School of Medicine. Di Bisceglie conducted a midphase trial of telaprevir that was recently published in the New England Journal of Medicine (2010, 362, 1292).

Doctors say a large group of patients who don’t respond to the current standard of care—mostly patients with genotype 1 HCV—are anxiously awaiting the arrival of these new drugs. In fact, many diagnosed, but untreated, patients are delaying therapy until next year. “We’ve been accumulating increasing numbers of nonresponders waiting for the next thing,” Di Bisceglie says. “My colleagues and I are beginning to think about what we are going to be doing a year from now to accommodate a big surge in patients.”

Paul Kwo, medical director for liver transplantation at the Indiana University School of Medicine, adds that “genotype 1 will now enter the era where the majority of people will be treated,” and most can get rid of their disease in just six months rather than a year. Kwo was the lead investigator of a Phase II trial study of boceprevir.

It’s no surprise, then, that the sales potential for the new HCV drugs is vast. Despite their drawbacks, interferon and ribavirin still bring in healthy sales for their marketers, Roche and Merck & Co. In 2008, the global HCV drug market was roughly $2.0 billion, according to Decision Resources. The consultancy forecasts that by 2013, just two years after the anticipated launch of the two new drugs, sales will reach $7.4 billion.

“Our friends at Vertex in the early days were criticized for their exuberant forecasts. These days, we’re beginning to wonder if they weren’t being conservative,” Michael D. Kishbauch, chief executive officer of Achillion Pharmaceuticals, said last month at a hepatitis C conference sponsored by the investment firm Canaccord Adams.

And because everyone expects the field to move toward treating patients with combinations of small molecules, any drug candidate that shows promise has become a hot commodity. HCV drug developers want to be the next Gilead Sciences, which dominates the HIV market with Atripla, a pill that combines three antivirals. Many physicians draw parallels between how the HIV field has evolved and how HCV treatment is expected to change in coming years.

Researchers expect three waves of small-molecule drug approvals, each of which will improve HCV treatment. First, telaprevir and boceprevir are likely to be approved next year as add-ons to the current treatment regimen. The second wave, in three to five years, will bring second-generation protease blockers, a crop of polymerase inhibitors, and new classes of compounds such as Bristol-Myers Squibb’s NS5A inhibitor and Debiopharm’s cyclophilin inhibitor. Finally, researchers hope that in the next five to 10 years they will reach the ultimate goal—enough data to convince doctors and the Food & Drug Administration that the virus can be quieted with combinations of small molecules alone.

That first wave is just around the corner. Merck will likely unveil its Phase III clinical trial data for boceprevir at the annual meeting of the American Association for the Study of Liver Diseases in October and then file a New Drug Application with FDA at the end of the year, a company official says.

Meanwhile, Vertex plans to broadcast the results from one of three Phase III trials testing telaprevir in combination with interferon and ribavirin sometime this quarter. The company is expected to file for U.S. approval shortly thereafter.

According to the limited data from Phase II trials, telaprevir and boceprevir appear to be equally effective in patients with genotype 1 HCV, the most prevalent form of the virus in the U.S.

Jason Zhang, a stock analyst at BMO Capital Markets, recently analyzed the Phase II data, Phase III clinical trial designs, and the overall U.S. market for HCV drugs. In a note to investors, Zhang said he expects the Phase III data to show a sustained viral response—the measure doctors use to say a patient is cured—of 75% and 74% for telaprevir and boceprevir, respectively.

Given the comparable efficacy of the two drugs, doctors’ prescribing decisions will be based on which one shortens the duration of treatment, offers milder side effects, and is more cost-effective.

Boceprevir seems to trail on all three fronts. Zhang calls telaprevir “a clear winner” on shortening treatment, with most patients expected to clear the virus in 24 weeks. Both drugs have mild side effects; telaprevir most often gives patients a rash, while boceprevir exacerbates the anemia that patients already experience with ribavirin.

Zhang expects telaprevir to capture more than half the U.S. and European HCV market, bringing in $3.6 billion in peak sales in 2013, whereas he forecasts boceprevir to have peak sales of $1.2 billion in 2014.

Despite the excitement because of the two new drugs, companies are already hard at work on a next generation of molecules that will be more potent, can be taken less often, and will have fewer side effects.

Indeed, the buzz at the annual meeting of the European Association for the Study of the Liver (EASL), held in Vienna last month, surrounded the data for the second generation of antivirals. Decision Resources counts some 49 HCV-treating molecules in Phase II studies right now.

Because the ultimate goal is a small-molecule cocktail that replaces interferon and ribavirin, the drug candidates coming after telaprevir and boceprevir were all designed with combination therapy in mind. The compounds not only need to be highly specific, safe, and able to evade resistance, they also need to play well with others: They must avoid drug-drug interactions and need to be taken no more than once or twice a day to create a regimen patients can follow.

Several second-generation protease and polymerase inhibitors are garnering attention, among them Pharmasset’s polymerase blocker R-7128. The biotech company’s development partner, Roche, has already tested it in combination with a protease inhibitor being developed by InterMune.

Pharmasset began looking at antivirals for HCV nearly a decade ago, focusing on nucleoside polymerase inhibitors. On the basis of its work in the lab and experiments reported in the literature, the biotech firm identified several potential drugs that were notable for having a fluorine atom in place of one of the hydroxyl groups on the sugar piece of a nucleoside.

The compounds kill the virus, but many also kill human cells. After some elbow grease, Pharmasset chemists came up with the fluorine-containing nucleoside PSI-6130. “The fluorine atom and a methyl substituent at the 2ʹ position of the nucleoside appeared to impart some unique properties,” explains Michael Sofia, Pharmasset’s vice president of chemistry.

Although safe, PSI-6130 hit a stumbling block in the clinic. Its bioavailability, or the amount that goes into circulation after the drug is ingested, was only 25%. Furthermore, it also partially metabolized into a molecule that displayed no activity at all.

Pharmasset chemists and their partners at Roche went back to work to create a PSI-6130 prodrug, a compound that would be inactive until it was metabolized. The result was R-7128, which Sofia says improves bioavailability to 75%. Phase II studies of R-7128 show the drug could be effective in treating a broad spectrum of HCV genotypes. Pharmasset has since built upon its knowledge of how PSI-6130 is metabolized to develop a more potent follow-on compound. PSI-7977 is in Phase II studies, although it has yet to be licensed to a partner.

Many other promising compounds have yet to be licensed. Mansi Shah, an infectious diseases analyst at the health care consultancy Datamonitor, cites two unpartnered drug candidates as demonstrating particularly good results at EASL: Anadys Pharmaceuticals’ nucleoside polymerase inhibitor and Idenix Pharmaceuticals’ protease inhibitor.

Early data from a Phase II study testing Idenix’ IDX184, a nucleotide prodrug of 2ʹ-methyl guanosine monophosphate, in combination with interferon and ribavirin indicated the drug is more potent then the first-generation antivirals.

Meanwhile, Anadys reported that 72% of patients in a Phase II trial had undetectable levels of the virus after eight weeks on its lead HCV compound, ANA598, with interferon-ribavirin. Moreover, none of the patients experienced what is known as a “viral breakthrough”—a resurgence of the virus despite treatment.

The absence of viral breakthroughs suggests this next-generation antiviral could work well in a cocktail of small molecules. ANA598 was specifically designed to thwart resistance by targeting a binding site on the HCV polymerase that is different from the one hit by other compounds in the clinic, says Steve Worland, Anadys’s CEO.

“It’s all hypothetical as to whether we’ll be able to achieve sustained virological responses.”

Improved protease and polymerase inhibitors aside, EASL attendees say the most-talked-about compound at the conference last month was part of a new class of drugs. Bristol-Myers Squibb’s lead candidate, BMS-790052, is a potent inhibitor of NS5A, a protein that seems to play a role in HCV replication.

The discovery of BMS-790052 was made possible by the development of cell-based assays that allowed researchers to probe for inhibitors of every protein potentially involved in viral replication, explains Nicholas Meanwell, executive director of virology chemistry at BMS. Using a chemical genetics approach and three assays, BMS screened more than 1 million compounds simultaneously to come up with an NS5A inhibitor.

The compound, BMS-858, is an imino­thi­azo­lidio­none that is a highly specific—albeit weakly potent—inhibitor of HCV RNA replication. Through a medicinal chemistry campaign to improve the compound’s potency and pharmacokinetics, the company gained insights into its structure-activity relationship. By plucking out the parts of the molecule responsible for its activity, BMS came up with a symmetrical structure that appears key to its ability to shut down the virus. “It was an awful lot of work to make the leads into a druglike molecule,” Meanwell says.

Despite its promise as a drug target, NS5A is still a bit of a mystery. It is clearly important to the survival of HCV, but its role in the life cycle of the virus is not fully understood. Regardless, NS5A has been a boon for BMS. In a recent letter in Nature, BMS said BMS-790052 is the most potent in vitro blocker of HCV replication reported to date (Nature, DOI: 10.1038/nature08960). It seems equally powerful in patients: In a Phase II trial involving people with HCV who had never been treated, adding the drug to interferon and ribavirin shut the virus down in four weeks, with no viral breakthroughs even after 12 weeks in 83% of those given higher doses of the drug.

In addition to NS5A inhibitors, a handful of companies are looking at cyclophilin inhibitors with the idea that they could provide a resistance profile that is entirely different from those of protease and polymerase inhibitors. “The idea was to find a mode of action that was completely orthogonal to the others, so that if we generated resistance it would be different,” explains Yves Ribeill, CEO of Scynexis, a Research Triangle Park, N.C.-based biotech firm with a cyclophilin inhibitor in development.

Inhibitors of cyclophilins, which are enzymes that help fold and shuttle other proteins in the cell, aren’t new: One example is cyclosporine, the immunosuppressant given to people who have undergone an organ transplant. For HCV, the goal was to find compounds that killed the virus but did not have the immunosuppressive effects of cyclosporine.

Among cyclophilin inhibitors, Debiopharm’s alisporivir, an oligopeptide, has reached the most advanced stage of development. Early Phase II data on the drug was enough to attract Novartis, which in February bought the rights to alisporivir. Novartis has its own cyclophilin inhibitor, NIM811, in Phase II studies.

Scynexis’ cyclophilin inhibitor, SCY-635, showed promise in Phase I studies, and the compound seems to have benefits besides lowering viral load. The biotech firm presented data at EASL showing SCY-635 helps prevent the scar tissue that is often found on the livers of people with HCV.

Despite the excitement around the new hepatitis C treatments, industry observers caution that it’s too soon to tell how many will actually make it to the finish line. Many compounds have stumbled in Phase II trials, where a drug’s toxicity often first rears its ugly head.

As companies test molecules in early-stage trials, many are looking ahead to what they expect will be the next standard in treatment: a cocktail of small molecules. Four clinical trials now are looking at the potential to eliminate one or both of the currently approved drugs by giving patients combinations of two small molecules. Roche conducted a small trial in New Zealand, where regulatory authorities were more amenable than FDA to getting rid of interferon and ribavirin. The study combined two drug candidates Roche had licensed: InterMune’s danoprevir and Pharmasset’s R-7128.

Vertex is poised to start a trial with four arms, two in which patients will receive its two lead antivirals in addition to interferon-ribavirin and two in which patients will receive the small molecules alone. Meanwhile, BMS is testing its NS5A inhibitor in combination with its NS3 protease inhibitor. And Gilead is studying a combination of its protease inhibitor, GS-9256, and a non-nucleoside polymerase inhibitor, GS-9190.

Resistance is the biggest hurdle to ditching interferon and ribavirin in favor of a cocktail of antivirals or other small molecules. Vertex saw resistance emerging less than two weeks after patients took telaprevir alone during early tests of its safety, and FDA subsequently told companies they could test their molecules as a monotherapy for only three days.

The worry is that if a patient is treated with these powerful new drugs and isn’t cured, the virus that remains will be even tougher to tackle. “The jury is out on what the impact of resistance in hepatitis C is going to be,” says Steve Schnittman, global development lead for HCV at BMS. “It’s all hypothetical as to whether we’ll be able to achieve sustained virological responses.”

Furthermore, scientists don’t know how many drugs it will take to fully knock out the virus. Statisticians have proposed a combination therapy that has three to five drugs—enough to suppress the virus and prevent it from rebounding, Schnittman notes. “The best way to do that is to come up with different targets,” he adds.

In terms of maximizing returns on investments, companies developing small-molecule antivirals are in a race against time. The number of new HCV infections has declined substantially over the past decade, and the majority of those currently infected in the U.S. are from the baby boomer generation. Once they are diagnosed, treated, and cured, demand for HCV drugs is expected to wane. Decision Resources projects that after the spike in sales in 2013, they will drop to $3.3 billion by 2018.

“This is an epidemic that already occurred,” Kwo, the Indiana researcher, says. “But remember, there’s a huge pool of individuals who haven’t figured out that they have hepatitis C—some don’t want to know, others are asymptomatic.” And doctors expect that as more effective therapies reach the market, more people will be willing to be screened for the disease.

For the winners, the payoff should be a windfall in drug sales over the next decade. And for people with HCV and the doctors who treat them, the next few years will be transformative. “Isn’t this going to be an exciting, interesting time?” Kwo asks.

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