Boceprevir

Boceprevir

File:Boceprevir.svg
Identifiers
IUPAC name (1R,2S,5S)-N-[(2Ξ)-4-amino-1-cyclobutyl-3,4-dioxobutan-2-yl)]- 3-{(2S)-2-[(tert-butylcarbamoyl)amino]-3,3-dimethylbutanoyl}- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
CAS Number	394730-60-0
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C27H45N5O5
Molar mass	519.69 g·mol−1

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Assistant Editor-In-Chief: Nina Axiotakis [2]

Overview

Boceprevir (INN) is a protease inhibitor being studied as a treatment for hepatitis C.

It is being developed by Schering-Plough. As of 2008, it is in phase II clinical trials.

The hepatitis C virus, often described as the “silent epidemic,” affects more than 170-180 million people around the world and as the most common blood borne infection worldwide it has become a serious global health crisis. It is currently the leading cause of chronic liver diseases which include cirrhosis, carcinoma and liver failure, and approximately 130 million patients with the disease are at high risk of developing one of these conditions. HCV is an enveloped virus with a 9.6 kb single-stranded RNA genome that serves as a template for viral replication that is translated into a polyprotein and cleaved by proteases to allow for viral assembly.

Before the development of new, more successful drug therapies such as boceprevir, the leading standard treatment therapy included the combination of pegylated interferon and ribavirin over a prolonged period of 24 to 48 weeks. However, for the genotype 1 strain of the virus, which is the most prevalent, this regimen achieves the goal of sustained virologic response (SVR), in only about 50% of treated patients, and it tends to be poorly tolerated and requires injection. Boceprevir is part of a treatment regimen that has been found to easier to administer, less toxic, and overall more effective. It is expected that the development of boceprevir and other new treatment will significantly broaden the treatment options for infected individuals.

The FDA has recently approved the drug boceprevir as a new and improved HCV therapy to be used in combination with peginterferon and ribavirin, the previous standard of treatment. It is widely agreed that boceprevir seems to be a safe and effective treatment innovation. The drug will treat patients with hepatitis C genotype 1.1 Boceprevir, marketed as Victrelis by Merck, is the first HCV protease inhibitor to reach market and it expected to be a major advance in HCV treatment. Throughout its phases of study, boceprevir has been shown to provide more effective treatment than just the combination of peginterferon and ribavirin alone, and will offer a greater chance of cure than the previous standards of therapy.

Clinical Trial Results and Treatment Strategies

Until recently, the HCV treatment relied primarily on boosting the immune system of the infected individual rather than attacking the virus directly, a strategy which resulted in curing less than half of treated individuals. The main goal of chronic HCV treatment using boceprevir is the prevention of cirrhosis and hepatocellular carcinoma by eradicating the virus which is achieved by inhibiting the HCV protease molecule to suppress the virus.8 Treatment options of HCV patients have broadened considerably with the development of new drug therapies such as protease and polymerase inhibitors known as direct-acting antiviral (DAAs) agents. Boceprevir, one of these new DAA drugs that has recently been approved by the FDA and marketed by Merck by the name Victrelis has been proven more effective than the previous combination therapy of pegylated interferon and ribavirin, which had been bringing about favorable results in only 50% of patients.

The final results of this trial showed that combination therapy with boceprevir results in higher sustained SVR rates in patients with HCV genotype 1 who did not respond to or relapse after treatment with PEG-IFN and RBV. After achieving SVR, these patients could be reasonable confident that they would not see virus come back to harmful levels.3 In contrast, the rate for patients getting the standard regimen of pegylated interferon injections and ribavirin pills was about 40%.

Phase II clinical trials of boceprevir and similar DAA drug agents showed favorable results when patients with genotype 1who had not been previously treated for their HCV showed significant improvement after receiving triple therapy with boceprevir, peginterferon alfa-2b and ribavirin for 48 weeks, compared to those receiving only the peginterferon and ribavirin combination treatment. Under the boceprevir regimen, an impressive 75% of patients achieved sustained virologic response (SVR), a success rate similar to Vertex’s telaprevir, a similar DAA drug. Further studies have suggested that it may be possible to shorten treatment duration for those who achieve SVR.

Boceprevir showed favorable clinical trial results when tested in patients with genotype 1 HCV, the most common HCV strain in the U.S., and the strain that is generally considered to be most resistant to treatment. Merck reported that in a phase III trials among never-before-treated patients:

• 66% of patients had an SVR with boceprevir plus the standard treatment for 48 weeks
• 63% had an SVR after 4 weeks of standard therapy and 44 weeks of boceprevir plus standard therapy
• Only 38% on standard treatment (peginterferon and ribavirin) alone had an SVR

In another phase III clinical trial reported by Merck, among patients for whom previous standard treatment regimens failed:

• 66% had an SVR with boceprevir plus standard treatment for 48 weeks
• 59% had an SVR after four weeks of standard therapy and 44 weeks of boceprevir plus standard therapy
• Only 21% on standard treatment alone had an SVR

A common strategy behind boceprevir treatment is to suppress the virus using the standard treatment combination for four weeks before starting the patient on boceprevir. The hope is that this will delay or avoid resistance to the new drug. In boceprevir’s smaller phase II studies, patients on this schedule were five times more likely to achieve an SVR than patients on standard treatment alone, and Paul Y. Kwo, MD, of Indiana University and colleagues found that 75% of patients achieved an SVR on this treatment schedule. Phase III study data for this strategy have not yet been released by Merck so it is not yet clear whether it is as proven success.

Complications and Side Effects

Unfortunately, like the AIDS virus, the hepatitis C virus quickly develops a resistance to protease inhibitors.³ As a consequence, boceprevir cannot be given alone as a treatment and must be given along with peginterferon and ribavirin in a triple therapy regimen. Though the standard combination of peginterferon and ribavirin is made more effective as a treatment strategy when given with boceprevir, their common side effects are still brought about in many patients and are difficult to tolerate. Boceprevir itself, however, has been found to be easier to take, and the its addition to the standard treatment after a 4-week lead-in period has shown the potential to double SVR rates compared to standard treatment alone. The triple therapy regimen has been shown to achieve suppression of the virus that was greater than the additive effects of either peginterferon plus ribavirin alone or boceprevir alone.

Despite boceprevir’s promising results, its downside is that the treatment regimen is highly complex. While it was hoped that the use of boceprevir would allow patients to reduce their use of ribavirin which many patients find difficult to tolerate, the full dose of ribavirin in combination with boceprevir seems necessary for most patients.

The drug carries a number of other hematological side effects, including anemia, neutropenia and thrombocytopenia.1 Anemia has been shown to occur more often with boceprevir than with standard therapy, though it rarely led to treatment discontinuation because it was manageable, and can even be reversible if the drug is discontinued. Sustained virologic response can still be achieved during the manifestation of side effects.

References

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