Nature Reviews Drug Discovery 9, 501-503 (July 2010) doi:10.1038/nrd3214
Alisa Opar
Data from a late-stage trial of the most advanced of a new class of drugs targeting the hepatitis C virus protease fuel hopes for major improvements in treatment outcomes.
In May this year, Vertex Pharmaceuticals announced the first set of highly anticipated data from Phase III trials of telaprevir, which is competing to be the first protease inhibitor for the treatment of hepatitis C virus (HCV) infection to reach the market. The findings did not disappoint: telaprevir in addition to the current standard therapy was shown to be considerably more efficacious than the standard therapy alone.
Merck is hot on Vertex's heels with its drug boceprevir, which, like telaprevir, targets the key role of the HCV protease in the viral life cycle. Merck plans to release Phase III data for boceprevir later this year and Vertex expects results from two additional Phase III trials of telaprevir in the third quarter. If all goes well, both companies could file for regulatory approval this year and launch their drugs in 2011.
Protease inhibitors could represent a “revolution” in HCV treatment, says Stefan Zeuzem, Professor and Chief of Medicine at the J. W. Goethe University Hospital in Frankfurt, Germany. “The addition of a protease inhibitor to standard therapy is a milestone,” he says. “It's increased the cure rate by more than 30%. That is almost unprecedented within internal medicine. It is really, really rare that you have these breakthroughs.”
"The addition of a protease inhibitor to standard therapy is a milestone."
One of the biggest challenges in HCV treatment is that only about half of the patients with the genotype 1 strain of the virus — HCV1, the most common form in the United States and in Europe, and typically considered the most difficult to treat — obtain a sustained viral response (SVR), or cure, after completing standard therapy. Current treatment is a 48-week course of injections of pegylated interferon combined with the generic antiviral pill ribavirin. The arduous side effects of interferon, which include anaemia, depression and flu-like symptoms, lead many patients to curtail their treatment. Experts are hoping that protease inhibitors and other novel agents in the pipeline (Table 1) will shorten treatment duration, have better tolerability and cure more people.
Table 1 Selected drugs in Phase II or III trials for the treatment of HCV*
In Vertex's recently reported Phase III study, known as ADVANCE, 75% of patients infected with HCV1 who had not been previously treated achieved an SVR after receiving 12 weeks of telaprevir, pegylated interferon and ribavirin, followed by a course of standard therapy for at least another 12 weeks. The ADVANCE trial was response-guided, meaning that if in the telaprevir group the virus was sufficiently suppressed after 4 weeks, patients received only 24 weeks of total treatment — half the standard treatment time. Notably, about 70% of those who achieved SVR only received 24 weeks of therapy. Patients in the control group underwent standard therapy for 48 weeks and 44% achieved an SVR.
Both telaprevir and boceprevir might halve treatment duration to 24 weeks, although telaprevir might have an edge over boceprevir as its side effects seem to be milder; telaprevir causes rash and increases anaemia, but not to the same extent as boceprevir. The picture will be clearer later this year after Vertex and Merck report results of Phase III studies for treatment-experienced and treatment-naive patients with HCV1.
In addition to offering patients who have failed standard therapy another option, better drugs for HCV could spur more people to seek treatment. In fact, because the novel therapies seem so promising, a growing number of patients are delaying treatment until they become available. This phenomenon, called warehousing, is widespread, says Ira Jacobson, Chief of the Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, USA, and an investigator for the ADVANCE trial. For many people, waiting a year or so to start therapy makes sense because the illness progresses slowly, scarring the liver over years or even decades and eventually leading to cirrhosis, liver cancer or other conditions. “The idea is, why take therapy now if you have a 40–45% chance of success when you can wait and have something that might confer a 70% chance of success perhaps with the added advantage of shorter duration of therapy, as suggested by clinical trial data so far,” Jacobson explains.
Initially, telaprevir and boceprevir would be used in combination with interferon and ribavirin, but experts hope that new drugs will ultimately remove the need for interferon. However, it is unlikely that a protease inhibitor will be used alone because of problems with resistance. “The first monotherapy studies with telaprevir have shown that resistance develops within the first 2 weeks. The data have also shown that the [viral] mutants exist before treatment,” says Michael Manns, Head of the Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany. “As resistance is a problem, the FDA has restricted the use of monotherapy to 3 days in early studies, and then interferon plus ribavirin has to be added because the mutants for the protease are sensitive to interferon.”
To combat resistance, researchers are looking at using combinations of direct-acting antivirals. “This approach has been very successful at preventing resistance in HIV treatment,” says Robert Kauffman, Vertex's Chief Medical Officer. “If you have two drugs against two different viral targets for which there is no cross-resistance, to get a resistant variant, resistance needs to develop to both drugs, which is obviously much less likely than with just one drug.” Still, whether interferon-free regimens are possible, and, if they are, what will be the best combinations of direct-acting antivirals are “open questions,” says Manns.
Several companies are already tackling these questions. In addition to boceprevir and telaprevir, which are taken orally three times a day, second-generation protease inhibitors taken once a day are in Phase II trials (Table 1). “The big advantage we are hoping for from the second-wave protease inhibitors are improvements in the pharmacokinetic profile, dosing intervals, and perhaps some advances with respect to safety and tolerability,” says Zeuzem.
Although protease inhibitors are expected to reach the market first, investigational agents that block other HCV enzymes, such as non-nucleoside and nucleoside polymerase inhibitors, are also in development (Table 1). “Nucleoside polymerase inhibitors in particular appear to have a high genetic barrier to resistance, but the non-nucleosides also offer great promise in combination with other drugs,” says Jacobson. NS5A inhibitors are another novel class of agents that block a protein critical to viral replication; there is a “great deal of focus” on these compounds, Jacobson adds, because they show marked antiviral activity. In addition, trials of immunological therapies, new formulations of interferon, and antagonists to cyclophilins, which are human proteins used by the virus to augment its own replication, are all underway.
As yet, nobody knows what the most effective strategy might be. “We are now entering a phase where we have a large number of companies combining direct-acting antiviral drugs together, which have non-cross resistance patterns — a protease inhibitor with a NS5A inhibitor, a protease inhibitor with a non-nucleoside polymerase inhibitor, a protease inhibitor with a nucleoside inhibitor,” says Zeuzem. One of the key challenges in the clinical trials of such agents will be learning how to manage resistance and side effects related to the direct-acting antivirals, says Kaufmann, noting that these challenges will be compounded when the agents are combined.
“I think it will be a potentially breathtaking event when any of those trials gives us proof of concept that you can induce a sustained virologic response with combinations of pure antiviral drugs in the absence of interferon,” says Jacobson. “If such proof of concept materializes soon, I think it will further accelerate the development of interferon-free regimens.”
http://www.nature.com/nrd/journal/v9/n7/full/nrd3214.html
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