Video/ Boceprevir In The Lancet

[Guest guest]

Video/ Boceprevir In The Lancet

Click on the bottom link to access the video.

New anti-viral drug shows promise for dramatic improvement in hepatitis C treatment

Adding a direct acting anti-viral drug to the standard treatment regimen for hepatitis C significantly increases the cure rate in the most difficult to treat patients, according to a research report published Monday in the online edition of the journal The Lancet. August 8, 2010 -->

The research team, led by Kwo, M.D., of Indiana University School of Medicine, reported that adding the drug nearly doubled the treatment's effectiveness when given for 48 weeks in one treatment arm of the study.

An estimated 3.2 million Americans and 170 million people worldwide are infected with the hepatitis C virus, but many do not know it. In the United States, 70 percent of affected individuals are infected with genotype 1 hepatitis C, the most difficult to treat. Although there may be no symptoms for years, long-term infection can cause cirrhosis and the disease is a leading cause of liver cancer and liver transplantation. Hepatitis C infections occur mainly through transmission of infected blood, such as via injection drug use, and there is no vaccine.Currently fewer than half of patients with genotype 1 hepatitis C are treated effectively by the standard combination of two drugs, peginterferon alfa-2b plus ribavirin, which is typically given for 48 weeks. The treatment can be difficult for some patients due to anemia and other side effects.

Adding the drug boceprevir increased the cure rate to as high as 75 percent in those who received 48 weeks of the three-drug combination therapy, compared to 38 percent of those in the control group, who received the standard two-drug treatment for 48 weeks, said Dr. Kwo, associate professor of medicine at the IU School of Medicine. The two-year phase 2 trial was conducted at 67 sites with 520 patients in the U.S., Canada and Europe

Adding a direct acting anti-viral drug to the standard treatment regimen for hepatitis C significantly increases the cure rate in the most difficult to treat patients, according to a research report published Monday in the online edition of the journal the Lancet. The research team, led by Kwo, M.D., of Indiana University School of Medicine, reported that adding the drug nearly doubled the treatment’s effectiveness when given for 48 weeks in one treatment arm of the study. Credit: Indiana University School of MedicineIn the boceprevir study, known as the SPRINT-1 trial, researchers tested several different options to evaluate the effectiveness of the combination therapy:To test whether the addition of boceprevir could make it possible to shorten treatment times, some patients were randomly selected to receive the three-drug combination for 28 weeks, some for 48 weeks. Researchers also investigated whether a 4 week lead-in with the standard two-drug combination prior to the addition of boceprevir to the treatment regime could improve sustained virologic response rates. The goal was to see if allowing the interferon and ribavirin to reach steady state levels -- which would activate the immune system and reduce virus levels -- before adding boceprevir would improve the response rates as well as reduce the virus' ability to develop resistance to boceprevir, said Kwo. In another arm of the trial, researchers tested whether a lower dose of ribavirin could reduce the anemia side effects while still treating the virus effectively."Both 28- and 48-week boceprevir regimens significantly increased sustained virologic response rates - which is the best definition of a cure we have - compared to the 48 week control," said Dr. Kwo. "The 48-week treatment arm with 4 weeks of peg interferon lead-in and 44 weeks of peg interferon, ribavirin, and boceprevir led to the largest improvement over the control group ever reported. That's very impressive."Boceprevir, a product of Merck & Co., is an HCV protease inhibitor - a compound designed to block a function key to viral reproduction in the cell. Boceprevir directly targets the hepatitis C virus, Kwo noted, while peginterferon and ribavirin are less specific, acting more generally to stimulate the body's virus-fighting immune system.

The best results were reported for the 103 patients who were treated for four weeks with the standard two drug regiment, followed by 44 weeks of the three-drug regimen including boceprevir: 75 percent of these patients tested negative for evidence of the virus six months after the end of treatment. Results for the other treatment arms were:67 percent of those who received the three drug regimen for 48 weeks with no lead-in treatment tested negative for the virus (103 patients).56 percent of those who received the two-drug lead-in for four weeks, followed by 24 weeks of the three drug treatment tested negative for the virus (103 patients).54 percent of those who received the three-drug treatment for 28 weeks with no lead-in tested negative for the virus (107 patients). 38 percent of the control group, who received the standard two-drug treatment for 48 weeks tested negative for the virus (104 patients).Patients receiving the low-dose of ribavirin did not fare as well - just 36 percent were virus-free after 48 weeks of treatment."Based on this phase 2 study, it appears that if this drug receives final approval approximately two-thirds of patients will be able to be treated successfully with 28 weeks of treatment and one-third will need 48 weeks of treatment, though this will require confirmation from the phase 3 trials, from which preliminary results were recently released," said Dr. Kwo.Provided by Lancet

;

New Anti-Viral Drug Shows Promise For Dramatic Improvement In Hepatitis C Treatment

Date: 09 Aug 2010 - 2:00 PDT

Adding a direct acting anti-viral drug to the standard treatment regimen for hepatitis C significantly increases the cure rate in the most difficult to treat patients, according to a research report published Monday in the online edition of the journal The Lancet. Currently fewer than half of patients with genotype 1 hepatitis C are treated effectively by the standard combination of two drugs, peginterferon alfa-2b plus ribavirin, which is typically given for 48 weeks. The treatment can be difficult for some patients due to anemia and other side effects. Adding the drug boceprevir increased the cure rate to as high as 75 percent in those who received 48 weeks of the three-drug combination therapy, compared to 38 percent of those in the control group, who received the standard two-drug treatment for 48 weeks, said Dr. Kwo, associate professor of medicine at the IU School of Medicine. The two-year phase 2 trial was conducted at 67 sites with 520 patients in the U.S., Canada and Europe. In the boceprevir study, known as the SPRINT-1 trial, researchers tested several

different options to evaluate the effectiveness of the combination therapy:To test whether the addition of boceprevir could make it possible to shorten treatment times, some patients were randomly selected to receive the three-drug combination for 28 weeks, some for 48 weeks. Researchers also investigated whether a 4 week lead-in with the standard two-drug combination prior to the addition of boceprevir to the treatment regime could improve sustained virologic response rates. The goal was to see if allowing the interferon and ribavirin to reach steady state levels -- which would activate the immune system and reduce virus levels -- before adding boceprevir would improve the response rates as well as reduce the virus' ability to develop resistance to boceprevir, said Kwo. In another arm of the trial, researchers tested whether a lower dose of ribavirin could reduce the anemia side effects while still treating the virus effectively. "Both 28- and 48-week boceprevir regimens significantly increased sustained virologic response rates - which is the best definition of a cure we have - compared to the 48 week control," said Dr. Kwo. "The 48-week treatment arm with 4 weeks of peg interferon lead-in and 44 weeks of peg interferon, ribavirin, and boceprevir led to the largest improvement over the control group ever reported. That's very impressive." Boceprevir, a product of Merck & Co., is an HCV protease inhibitor - a compound designed to block a function key to viral reproduction in the cell. Boceprevir directly targets the hepatitis C virus, Kwo noted, while peginterferon and ribavirin are less specific, acting more generally to stimulate the body's virus-fighting immune system. The best results were reported for the 103 patients who were treated for four weeks with the standard two drug regiment, followed by 44 weeks of the three-drug regimen including boceprevir: 75 percent of these patients tested negative for evidence of the virus six months after the end of treatment. Results for the other treatment arms were: 67 percent of those who received the three drug regimen for 48 weeks with no lead-in treatment tested negative for the virus (103 patients).56 percent of those who received the two-drug lead-in for four weeks, followed by 24 weeks of the three drug treatment tested negative for the virus (103 patients).54 percent of those who received the three-drug treatment for 28 weeks with no lead-in tested negative for the virus (107 patients). 38 percent of the control group, who received the standard two-drug treatment for 48 weeks tested negative for the virus (104 patients). Patients receiving the low-dose of ribavirin did not fare as well - just 36 percent were virus-free after 48 weeks of treatment. "Based on this phase 2 study, it appears that if this drug receives final approval approximately two-thirds of patients will be able to be treated successfully with 28 weeks of treatment and one-third will need 48 weeks of treatment, though this will require confirmation from the phase 3 trials, from which preliminary results were recently released," said Dr. Kwo. The research was funded by Schering Corp. a division of Merck & Co., which provided assistance with the trial, data collection and analysis, and the manuscript. Source: SchochIndiana University School of Medicine

Novel HCV Drug Can Double Response RateBy , North American Correspondent, MedPage TodayPublished: August 08, 2010Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine

An investigational protease inhibitor aimed at blocking hepatitis C replication can double the response rate compared with standard care, researchers said. In an open-label randomized phase II trial, adding the compound -- boceprevir -- to standard therapy in various combinations increased the so-called sustained virological response compared with a control group who got only standard care, according to Kwo, MD, of the Indiana University School of Medicine in Indianapolis, and colleagues.

But the response rate was doubled when patients were first treated with four weeks of standard therapy -- peginterferon alfa-2b and ribavirin -- before boceprevir was added for another 44 weeks, they reported online in The Lancet.

The current standard therapy for hepatitis C aims to stimulate the immune system in general without specific interference in viral replication. For patients with the difficult-to-treat genotype 1 of the virus, the therapy yields a sustained virological response in between 40% and 50% of patients.

In contrast, boceprevir (and a second drug, telaprevir, being investigated separately) blocks the action of the NS3 protease enzyme of hepatitis C, directly preventing viral replication. Early results of this trial were reported last year. (See Sustained Response Seen with New Hepatitis C Drug)

The researchers tested various drug combinations and treatment schedules in 520 treatment-naive patients with genotype 1 virus. They were randomly assigned to get:A control standard therapy of peginterferon alfa-2b plus ribavirin for 48 weeksStandard care for four weeks, then standard care plus boceprevir (at 800 milligrams three times a day) for 24 weeks Standard care for four weeks, then standard care plus boceprevir (at the same dosage) for 44 weeks Standard care and boceprevir for 28 weeksStandard care and boceprevir for 48 weeks In a second part of the study, 75 patients were randomly assigned to get 48 weeks of the triple combination or a 48-week variant in which the ribavirin dose was reduced from 800 to 1,400 milligrams daily to 400 to 1,000 milligrams.

All of the combinations that included boceprevir did better than standard therapy, the researchers reported, with sustained virological response rates ranging from 54% to 75%, compared with 39% for patients in the control arm.The 75% response rate occurred in the patients who got standard care for four weeks, followed by peginterferon alfa-2b, ribavirin, and boceprevir for 44 weeks. The difference from the control arm was significant at P<0.0001.

Next best was a 67% response rate seen in patients who got all three drugs for 48 weeks. The difference from the control arm was also significant at P<0.0001.

In the second part of the trial, the low-dose ribavirin combination yielded a response rate of 36% and was associated with a high rate of both viral breakthrough (caused by resistance mutations) and relapse, the researchers wrote.

In both parts of the study, they reported, boceprevir-based groups had higher rates of anemia and dysgeusia (altered sense of taste) than did the control group -- 55% versus 34% and 27% versus 9%, respectively.

The new NS3 protease inhibitors are a step forward in the treatment of hepatitis C, according to Milazzo, MD, and Spinello Antinori, MD, both of the University of Milan.Writing in an accompanying editorial, they said the results of the study suggest that adding boceprevir to the standard treatment substantially improves outcomes, "although not to the desired proportion."

But, they added, the emergence of resistance is an issue that needs to be addressed. "Such resistance will be the biggest challenge in the future," they wrote.Lessons from the HIV pandemic, they commented, demonstrate that only complete suppression of viral replication can prevent drug resistance, so that new strategies are needed to explore combinations of drugs, improve adherence, improve the pharmacokinetics of the drugs, and develop resistance testing.

Limitations of the study included its open-label design (although the authors noted that the endpoints were hepatitis C RNA levels which were blinded laboratory measurements) and classification of patients as with or without cirrhosis based on liver biopsy, which could have been as much as five years old.

The study was supported by Merck.Kwo reported financial links with Schering-Plough/Merck, Vertex, Tibotec, Roche, Abbott, Bristol-Myers Squibb, Gilead, Idenix, Valeant, Novartis, Anadys, GlaxoKline, and Human Genome Sciences. Several other authors reported financial links with Schering-Plough/Merck, as well as with a range of other pharmaceutical companies.The editorialists declared they had no competing interests.

Primary source: The LancetSource reference:Kwo PY, et al "Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial" Lancet 2010; DOI: 10.1016/S0140-6736(10)60934-8. Additional source: The LancetSource reference:Milazzo L, Antinori S "STAT-C: a full revolution or just a step forward?" Lancet 2010; DOI: 10.1016/S0140-6736(10)61056-2.

,

http://www.medpagetoday.com/InfectiousDisease/Hepatitis/21570

http://Hepatitis Cnewdrugs.blogspot.com/2010/08/video-boceprevir.html