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What's in the Hep C Pipeline?

Fall 2007

The pressing need for new hepatitis C treatments has spawned a surge of activity in the pharmaceutical industry. Virtually all major drug companies, and a host of small biotech start-ups, have research and development programs aimed at developing new hepatitis C medications. There is potentially a multibillion dollar market for hepatitis C virus (HCV) treatment, providing a strong financial incentive for drug discovery. Yet attempts to develop new medications have been fraught with pitfalls and uncertainty, and many once-promising candidates have failed in clinical trials due to safety concerns or lack of potency.

Based on current progress, it appears that major advances in HCV treatment are unlikely to occur until 2010 at the earliest. Yet many people with HCV choose to delay treatment, often on the advice of their doctors, in the hopes that future drug regimens will be better than the current standard of care, pegylated interferon (Pegasys and PegIntron) and ribavirin.

The limitations of current treatment are well known, including a host of potential side effects and limited success in eradicating HCV (particularly for people coinfected with HIV and for African-Americans). But people considering treatment should know that most new hepatitis C drugs will be added on to the current treatment, peg-interferon and ribavirin. While it is hoped that these new classes of drugs -- specifically protease and polymerase inhibitors -- will increase the success rate of treatment, they will not immediately end the need for peg-interferon and ribavirin, with their well-known side effects.

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At best, new drugs may shorten the length of treatment -- say, from the typical 48 weeks to 24 weeks -- but they will not decrease its side effects. Some companies are developing alternate versions of interferon and ribavirin which may prove more easily tolerated, but these improvements are likely to be modest at best. The greatest hope for a transformation in HCV therapy lies in the goal of developing new drugs that can be used together without peg-interferon or ribavirin (similar to the triple-drug combinations used to treat HIV), and which require only a few months of treatment. This is possible, but lies many years ahead.

In the meantime, people with HCV should weigh the risks and benefits of current treatment against the uncertain promise of future treatment options -- and the potential among some (particularly those with HIV) for worsening liver disease if HCV treatment is delayed.

The role and value of new HCV drugs for people coinfected with HIV is also unknown. In theory, some of these new drugs may have negative interactions with HIV drugs, perhaps limiting their use. A 2006 hearing of the Antiviral Drugs Advisory Committee of the Food and Drug Administration (FDA) recommended that new HCV treatments be studied in people with HIV prior to FDA approval. This recommendation was echoed in the Sitges Statement, issued earlier this year at a meeting in Spain which convened advocates, community members, researchers, clinicians, and pharmaceutical companies to discuss HIV and HCV. No clear standard exists, however, for how much research would be needed to prove safety and efficacy in coinfected people prior to a new HCV drug reaching the market. Currently, no clinical trials of new HCV treatments include people with HIV.

Despite these hurdles, the field of HCV drug development has made considerable strides, with several promising candidates currently under investigation. Most likely, some of the drugs described in this article will gain FDA approval in the next few years. Improvements in treatment over the near future will likely remain incremental and uneven, with early gains in treatment success tempered by persistent problems with side effects. But, ultimately, a new generation of HCV drugs holds out the promise of highly effective, well-tolerated, short-term treatment -- challenging us to begin planning for the kinds of healthcare systems and community support needed to realize these gains for everyone.


Hepatitis C Protease Inhibitors

Like HIV, HCV contains an enzyme called protease that is essential for viral replication. The success of protease inhibitors in HIV treatment generated significant interest in drugs that could target HCV's protease. Early studies in the test tube and in people with HCV indicated that protease inhibitors could produce a rapid and substantial reduction in HCV viral load. As with HIV meds, however, HCV protease inhibitors can also lead to resistant virus. So, treatment will require using an HCV protease inhibitor in combination with other drugs (such as the current standard of interferon and ribavirin) in order to prevent resistance.

Telaprevir

Two HCV protease inhibitors have advanced to phase II clinical trials. Telaprevir (formerly VX-950), developed by Vertex Pharmaceuticals, is currently in studies exploring different treatment lengths in people who have never taken HCV treatment (another study is examining the drug in people who did not respond to previous treatment).

Treatment lengths being studied include:

  • 12 weeks in combination with peg-interferon and ribavirin.
  • 24 weeks (12 weeks of triple therapy, followed by 12 weeks of peg-interferon and ribavirin alone).
  • 48 weeks (12 weeks of triple therapy, followed by 36 weeks of peg-interferon and ribavirin alone).

Early results indicate that 12 weeks of triple therapy can clear HCV in some people, but the success rate is disappointing. Most people will likely require at least 24 weeks, and the first results for people taking the drug for that length of time will be presented at a scientific meeting in November. While telaprevir appears to be relatively well tolerated, concerns have emerged over a rash that can be severe enough to require some people to stop the drug.

Boceprevir

Schering-Plough also has an HCV protease inhibitor, boceprevir (formerly SCH 50304), in phase II trials, though no results have been made public. Like telaprevir, boceprevir needs to be taken three times a day, raising concerns about drug adherence. Dosing could be simplified by adding a small dose of the HIV med Norvir, which boosts the levels of these drugs in the body, but neither company is currently focusing on this line of research.

Both these drugs will likely enter into large phase III studies in 2008 -- the final stage of research before submitting a new drug to the FDA for approval.

Other Protease Inhibitors

A third protease inhibitor under development by Intermune, ITMN 191, may allow for twice daily dosing, but this compound is further behind in development and is currently in small phase I studies. First results are expected early next year. Medivir, in collaboration with Tibotec, recently presented the first results of its protease inhibitor, TMC 435350, in people without HCV and has begun Phase I trials in people with HCV.


Polymerase Inhibitors

Polymerase inhibitors targeting HCV replication also hold out considerable promise for improving treatment. Polymerase inhibitors are similar in function to two classes of HIV treatment: nucleoside analogues (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Unfortunately, research on the HCV polymerase inhibitor that was furthest along in development, valopicitabine, was halted this summer due to FDA concerns that its side effects (especially nausea) outweighed its potential benefits.

However, several other investigational drugs are moving through early stages of testing, including R1626 from Roche, GS-9190 from Gilead, and R7128 from Pharmasset (in collaboration with Roche). Preliminary data suggests that these drugs may be more potent than valopicitabine, though all are several years away from reaching the clinic. As with HCV protease inhibitors, polymerase inhibitors can result in the development of drug-resistant virus, and will need to be taken with other HCV meds.


New Interferons

Some companies are developing interferons that improve on the current standard -- peg-interferon, which is taken once a week. Albuferon, a new interferon developed by Human Genome Sciences, is currently in two large phase III studies that compare it to peg-interferon (both in combination with ribavirin). Albuferon may allow for dosing once every two weeks, or perhaps once every four weeks. Early research suggests that taking it once every two weeks is roughly comparable to weekly dosing with peg-interferon. The fate of albuferon depends on whether it can match or even exceed peg-interferon in treatment success, with comparable or milder side effects. Biolex Therapeutics also has a long-acting interferon called Locteron, which may allow for dosing every two weeks, in phase II studies.


Other Drugs

Several other drugs are also in development -- including new classes of drugs targeting different aspects of hepatitis C -- though they are generally in very early stages of research. The multiple approaches to drug development, along with the significant investment by the pharmaceutical industry, bodes well for the future of HCV treatment. However, the history of HCV drug development is littered with failures, and the future is impossible to predict with any certainty. As we keep an eye to the future, people with hepatitis C still face challenging treatment decisions in the present.

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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