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The Hepatitis C Pipeline

Spring 2006

New hepatitis C drugs are desperately needed by people coinfected with HIV and hepatitis C. About 25 to 30% of people living with HIV in the United States are coinfected with hepatitis C, with high rates of coinfection among current and former injection drug users. HIV accelerates the liver damage that is caused by hepatitis C, and liver disease from hepatitis C has become a leading cause of death among people with HIV.

Current treatments (48 weeks of pegylated interferon and ribavirin) have considerable side effects and limited success in people living with HIV. People who achieve a sustained virologic response (SVR) -- defined as an undetectable viral load six months after the end of treatment -- appear to permanently clear the virus, greatly reducing their risk of developing liver cancer and end-stage liver disease. But studies of treatment in coinfected people have found SVR rates of 27 to 40%, significantly lower than SVR rates in HIV-negative people with hepatitis C. Also, treatment is even less likely to work in coinfected people with the most common strain of hepatitis C, genotype 1. For this group, SVR rates range from 14 to 29%.

The reasons for poorer treatment outcomes in coinfected people are not fully known. People living with HIV have higher hepatitis C viral loads than those who are HIV negative, along with varying degrees of immune dysfunction that may hinder the ability of treatment to clear the virus. Coinfected people also have difficulties tolerating treatment, which can cause a range of side effects that includes depression and irritability, fatigue, anemia, flu-like symptoms, and decreases in infection-fighting white blood cells. As a result, anecdotal reports suggest that relatively few coinfected patients receive hepatitis C treatment. Barriers to treatment extend beyond the limitations of current therapy -- many liver doctors have been reluctant to treat people with histories of addiction, and many HIV doctors lack experience with the demands of managing patients taking hepatitis C medications.

The good news is that many companies are developing new hepatitis C treatments, and several new drugs now in clinical trials may reach the market in the next few years. The drugs furthest along in development include alternative forms of interferon and ribavirin, which may increase treatment efficacy or reduce side effects. The most promising new agents, however, are drugs that directly target the hepatitis C virus, similar to the way antiretroviral drugs target HIV. These compounds, which include protease inhibitors and polymerase inhibitors, have generated significant excitement in the hepatitis C community for their potential to revolutionize treatment.

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An ideal hepatitis C drug would dramatically increase the odds of achieving an SVR -- particularly for people with genotype 1 (which accounts for 70% of infections in the U.S.), since 70 to 90% of people with genotypes 2 and 3 respond to current therapies. Better drugs would also help coinfected people, along with African-Americans and people with cirrhosis (advanced liver disease) -- groups that also have low success with pegylated interferon/ribavirin therapy.

Despite grounds for optimism, hepatitis C drug development has seen a number of disappointments, with once-promising new drugs abandoned because of unexpected side effects, limited antiviral activity, or poor absorption and metabolism. Two of the more advanced drugs described below -- viramidine and valopicitabine -- have recently suffered setbacks, and not all of the new agents discussed in this article may ultimately reach the market. Moreover, none of these drugs have been studied so far in people coinfected with HIV, who are typically excluded from clinical trials of new hepatitis C agents, although some companies have announced plans to begin coinfection studies prior to submitting their drugs to the FDA for approval.


Albuferon

Albuferon (albumin-interferon alpha 2b) is an interferon designed to stay in the body for longer periods of time than other interferons, allowing for less frequent dosing. In contrast to the pegylation technology used by Roche and Schering, Albuferon fuses interferon to albumin, a protein found in the human body. In theory, this could allow Albuferon (administered, like the other interferons, by injection under the skin) to be dosed once every two weeks, or even once every four weeks. Less frequent dosing may improve treatment efficacy by extending the period during which the drug is active, or increase tolerability -- many side effects of interferon are most intense in the first two days after each injection.

Human Genome Sciences recently reported early results of two studies of Albuferon. The first study, involving 458 people with hepatitis C genotype 1 and no prior hepatitis C treatment, compares three different doses of Albuferon to Pegasys, with ribavirin, for 48 weeks. In hepatitis C treatment, a significant drop in viral load after 12 weeks of therapy is referred to as an early virologic response, which predicts the likelihood of achieving an SVR. People who don't become undetectable at week 12 of hepatitis C treatment, or who don't experience at least a 100-fold (2 log) drop in hepatitis C viral load, have very little chance of an SVR after a full course of therapy.

In the first Albuferon study, early virologic responses were seen in 89% of people receiving Pegasys, compared to 84% of those taking 900mg of Albuferon every two weeks, 90% of those taking 1200mg of Albuferon every two weeks, and 76% of those taking 1200mg of Albuferon every four weeks. The company hopes to explore higher doses taken every four weeks to improve response rates. Side effects to date have been generally similar across the four treatment groups, with chills reported more often in those taking Albuferon compared to Pegasys.

The second study compares five different doses of Albuferon (900 mg, 1200 mg, 1500 mg, and 1800 mg, all given every two weeks, or 1200 mg every four weeks) for 48 weeks in combination with ribavirin, in people who have not responded to prior HCV treatment. Of the 71 people taking one of the three lower doses, 30% had undetectable hepatitis C viral loads at the end of treatment (SVR data have not been reported). Higher doses have not shown a clear advantage, and side effects were generally similar in all dose groups.

Albuferon appears unlikely to replace Pegasys and Peg-Intron unless further research demonstrates a clear advantage in effectiveness or side effects. The convenience of injecting every other week may prove less meaningful to doctors and their patients than the established body of data and clinical experience supporting the pegylated interferons. An interferon that requires only a monthly injection would be more attractive, but if higher doses of Albuferon are needed, they may produce greater side effects. Albuferon could reach the market in 2010. Human Genome Sciences has not announced plans to study Albuferon in HIV-coinfected people.


Viramidine

Viramidine, being developed by Valeant Pharmaceuticals, is a pro-drug of ribavirin, which means it converts to ribavirin in the liver. It was designed to overcome one of ribavirin's major side effects: anemia. Initial research comparing viramidine to ribavirin showed that viramidine results in substantially lower rates of drops in hemoglobin, a protein found in red blood cells used to measure risk of anemia. Viramidine may have particular appeal to people coinfected with HIV, who tend to have higher risks for anemia and more difficulty tolerating ribavirin.

Valeant reported results from one of its two large late-stage studies in March 2006, showing that viramidine caused less anemia than ribavirin when used with Peg-Intron in people who had not taken HCV treatment before, but that SVR rates were significantly lower in people taking viramidine than in those taking ribavirin (38% vs. 52%). Valeant suggested that viramidine may, like ribavirin, require higher doses for people weighing more. At this time, the company still intends to submit viramidine to the FDA for approval in 2007, though whether the FDA will approve the drug without additional studies demonstrating safety and efficacy with higher, weight-based doses of Viramidine is uncertain. Valeant has announced its intention to begin researching Viramidine in coinfected people later in 2006; given the VISER data, a coinfection study would likely examine weight-based doses of Viramidine.


Valopicitabine

Valopicitabine (NM-283), being developed by Idenix Pharmaceuticals, is a nucleoside analogue developed to inhibit hepatitis C's polymerase enzyme, responsible for viral replication (roughly equivalent to the role of HIV's reverse transcriptase). Idenix reported early results from a study of valopicitabine with pegylated interferon in people who had not taken HCV treatment before, showing that after eight weeks of treatment, 48-56% of people had undetectable hepatitis C viral loads, depending on which dose of valopicitabine they received. Early virologic response rates in a study of people who had not responded to prior HCV treatment showed that those taking higher doses of valopicitabine with pegylated interferon had greater viral load drops than those taking pegylated interferon and ribavirin. Sustained virologic response data will not be available until early 2007.

Idenix announced in March 2005 that the highest dose of valopicitabine used in the studies (800 mg/day) would be abandoned due to an increased incidence of moderate to severe gastrointestinal side effects. Side effects were severe enough that 16% of treatment-na?ve participants and 5% of non-responders taking that dose dropped out of the study. While common, nausea and related side effects were mild and temporary for people taking lower doses.

Idenix will conduct more studies of valopicitabine in combination with both pegylated interferon and ribavirin (pending research on drug interactions between ribavirin and valopicitabine), and the company has announced a study in coinfected persons to begin later in 2006. The launch of a phase III study has been delayed to late 2006 as a result of the discontinuation of the 800 mg dosing, meaning FDA approval could not happen until 2009 at the earliest. Since previous data demonstrated that the 800 mg dose of valopicitabine was significantly more potent in antiviral activity than lower doses, the ultimate value of this drug at more tolerable doses is unclear.


VX-950

VX-950 is a hepatitis C protease inhibitor developed by Vertex Pharmaceuticals that has shown strong antiviral activity in small studies, both alone and in combination with pegylated interferon. In early 2006, Vertex reported that all 12 participants given VX-950 with pegylated interferon and ribavirin for 28 days achieved undetectable viral loads at the end of treatment. They all had hepatitis C genotype 1, and had not taken any prior hepatitis C therapy. While the study participants did not achieve a sustained virologic response (indicating that longer courses of treatment would be necessary to clear hepatitis C), Vertex predicts that the potency of VX-950 may shorten hepatitis C treatment to as little as three months, compared to the current 12 months that is standard for people with genotype 1.

A three-month study comparing VX-950 and pegylated interferon (with or without ribavirin) to pegylated interferon and ribavirin in people who have not taken HCV treatment before is planned for 2006, and Vertex will likely launch an additional phase II study in non-responders. No significant side effects for VX-950 have emerged in the small, short-term studies reported to date; however, the current formulation of VX-950 requires dosing three times a day, and poor adherence poses the risk of emergence of drug-resistant virus. Vertex has set an aggressive timetable for completing the clinical trials necessary for FDA approval, and plans to submit VX-950 to the FDA in 2008. The company has not announced any timetable for starting a coinfection study.


SCH 503034

SCH 503034 is a hepatitis C protease inhibitor in development by Schering-Plough, makers of Peg-Intron. While Schering's drug has not yet demonstrated the dramatic drops in viral load seen with VX-950, SCH 503034 still has considerable potency, especially in combination with Peg-Intron. Side effects are similar to those seen in people taking a placebo pill, with headaches the most commonly reported. As with VX-950, SCH 503034 is taken three times daily, and monotherapy studies have documented the potential for developing drug-resistant virus. Schering has arguably taken a more conservative and methodical approach to the clinical development of SCH 503034 than Vertex' VX-950 program, focusing on studies of non-responders, while VX-950 has been researched solely in people who are treatment-na?ve.

A phase II study is currently under way to evaluate different doses of SCH 503034 in combination with Peg-Intron (with or without ribavirin) in non-responders, with a comparison arm receiving Peg-Intron and ribavirin. When the study opened in the fall of 2005, Schering made the controversial decision to exclude African-Americans, who usually have lower virologic response rates to interferon-based treatment. Schering has subsequently amended the study to add a higher-dose SCH 503034 arm open to African-Americans. Given these choices, Schering has a responsibility to ensure adequate representation of African-Americans in future SCH 503034 studies. As with VX-950, no coinfection studies have been announced, but they will likely be initiated prior to submitting SCH 503034 for FDA approval (expected some time in 2009).


Watching and Waiting

The new drugs described above represent only a small fraction of what's in the hepatitis C pipeline. Many other agents are in development, including additional protease and polymerase inhibitors from other companies, along with compounds targeting other parts of the hepatitis C viral replication cycle. People coinfected with HIV and hepatitis C may have several new treatment options by the end of the decade, though the uncertainties of drug development suggest that those with advanced liver disease should not delay hepatitis C treatment until better drugs are available.

Interferon -- with all its side effects -- will remain the backbone of hepatitis C treatment for years to come, though ribavirin may be replaced in the near future with safer or more potent drugs. Meanwhile, activists are pressing companies to conduct timely, well-designed studies of their drugs in coinfected people, as well as other groups in need of better treatments (such as African-Americans, people with cirrhosis, and liver transplant recipients), while carefully evaluating their compounds for potential interactions with HIV medications. If all goes as planned, the future of hepatitis C treatment will mean shorter, safer, more effective therapy for all groups.

Daniel Raymond is the Policy Director at the Harm Reduction Coalition in New York City.




  
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This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.
 
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