Showing posts with label MK-5172. Show all posts
Showing posts with label MK-5172. Show all posts

Sunday, November 3, 2013

Merck's 'breakthrough' hep C combo plays catch-up

 Investment Commentary

Merck's 'breakthrough' hep C combo plays catch-up with promising PhII results

November 3, 2013 | By


Merck may be playing catch-up in the race to develop the first all-oral combo treatment for hepatitis C, but it made a good case over the weekend that it has a real contender in the pipeline.
Now its combination of MK-5172, an NS3/4A protease inhibitor, and the NS5A treatment MK-8742 produced cure rates ranging from 96% to 100% among small groups of genotype 1a and 1b patients. A total of 58 evaluable patients were included in the readout with the combo provided both with and without ribavirin.

Read more.....

Related:
AASLD-High cure rates seen with Merck oral hepatitis drugs -study

Saturday, November 2, 2013

AASLD-High cure rates seen with Merck oral hepatitis drugs -study

Sat Nov 2, 2013 1:30pm GMT

Nov 2 (Reuters) - A combination of two oral hepatitis C treatments developed by Merck & Co led to high cure rates in previously untreated patients, indicating the company is a contender in the race to find new treatments for the liver destroying virus.

The treatments tested with and without the older drug ribavirin led to cure rates of 96 percent to 100 percent, according to interim data from a small midstage clinical trial.

The results appear to confirm Merck will be competitive in the crowded race to develop interferon-free treatments for hepatitis C, assuming they are repeated in larger studies that include more difficult to treat patient populations, such as those not helped by prior therapy.

The 65-patient, 3-arm study tested MK-5172, a protease inhibitor, combined with MK-8742 from a highly promising new class of drugs called NS5A inhibitors for 12 weeks of treatment.

Based on data available at the time the interim results were released, 55 of 56 patients who completed the therapy were considered to be cured of the virus which is transmitted through infected blood from sources such as infected hypodermic needles or blood transfusions.

Patients who have no detectable levels of the virus in their blood 12 weeks after completing 12 weeks of treatment were deemed to be cured - a measure known as SVR 12, for sustained virologic response.

In the arm of the study that did not include the older oral medicine ribavirin, all 11 patients who completed therapy with MK-5172 and the higher 50 milligram dose of MK-8742 taken once a day achieved SVR 12.

All 12 patients who began that arm of the study had Genotype 1b of the liver disease, which is prevalent in Europe and Japan. It is considered somewhat easier to treat than Genotype 1a, the most common form of the virus seen in the United States, which may require a third drug in the regimen to achieve similarly high cure rates.

The other two arms - one testing 50 mg of MK-8742 and one using 20 mg - did include ribavirin given twice a day.

With the lower dose of the NS5A inhibitor, all 21 patients who completed therapy were deemed cured. In the group that received the higher dose in the three-drug combination, 23 of 24, or 96 percent, reached SVR 12. About three quarters of the patients in those arms were Genotype 1a.

Of the 65 patients in the study, only one had experienced a relapse of the virus, according to the data to be presented on Sunday at the American Association for the Study of Liver Diseases (AASLD) meeting in Washington.

"We are encouraged by these preliminary data for the combination of MK-5172 and MK-8742. It's a one-two punch with both arms equally strong," said Eliav Barr, head of infectious diseases for Merck.

SHORTER TREATMENT DURATION

Current standard treatment regimens for hepatitis C take 24 or 48 weeks and includes injected interferon, which causes miserable flu-like symptoms that lead many patients to avoid or discontinue treatment.

Several companies are developing new all-oral combinations that in clinical trials have cut treatment duration to 12 weeks for many patients while significantly increasing cure rates from about 75 percent with current drugs.

Ultimately, physicians would like to also see regimens that do not require ribavirin, which has its own side effect issues, including anemia and rash.

It is believed that tens of thousands of hepatitis C patients have delayed treatment while awaiting the new drugs expected to start reaching the market next year.

Gilead Sciences is widely seen as being in the lead with a safe and effective all-oral combination, with Bristol-Myers-Squibb and AbbVie close behind.

Gilead last week won an approval recommendation from a U.S. Food and Drug Administration advisory panel for its highly regarded sofosbuvir.

Some analysts believe the market for all-oral hepatitis C treatments could reach $20 billion as many more people get tested for the virus, given the very high cure rates, shorter treatment durations and tolerable side effects.

An estimated 170 million people worldwide are infected with hepatitis C, which if left untreated can lead to cirrhosis, need for a transplant or liver cancer.

The Merck drugs were well tolerated with no serious adverse side effects reported. The most common side effects were fatigue, headache and nausea.

Merck plans to expand the Phase II trial to about 400 additional patients, testing its drugs with and without ribavirin, and including those also infected with the HIV virus, those with cirrhosis and patients who have failed to be cured by prior treatments. It is also looking at a regimen of only 8 weeks in previously untreated patients that would include ribavirin.
(Reuters)

Merck Announces Presentation of Interim Data from Study of Investigational Combination of HCV Therapies MK-5172 and MK-8742 at the 2013 American Association for the Study of Liver Diseases (AASLD) Annual Meeting
          
Sustained virologic response at post-treatment follow-up week 12 (SVR 12) seen in 100 percent of patients to date in two of the three combination arms studied
 
WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside of the United States and Canada, announced the presentation of interim data from the ongoing C-WORTHY Study, a Phase II clinical trial evaluating the efficacy and safety of an all-oral regimen combining once-daily MK-5172, an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor, and MK-8742, an investigational HCV NS5A replication complex inhibitor, with or without twice-daily ribavirin, administered for 12 weeks to treatment-naïve, non-cirrhotic patients with HCV genotype 1a and 1b infection. The interim data show that the administration of MK-5172 and MK-8742 in combination is associated with a sustained virologic response (lack of detectable and quantifiable HCV) 12 weeks following the end of study therapy (SVR12). Merck previously announced that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to MK-5172/MK-8742 for treatment of chronic HCV infection.    
 
“We are encouraged by these preliminary data for the combination of MK-5172 and MK-8742,” said, Dr. Eliav Barr, vice president, Infectious Diseases, Merck Research Laboratories. “These data provide further support that we can advance these candidates, which are currently in Phase IIB clinical development, into a broader evaluation in a diverse range of HCV patients.”

C-WORTHY Study
In the C-WORTHY Study, 65 patients (45% male, 11% African American, and 58% genotype 1a infection) were enrolled in one of three 12-week treatment arms (see TABLE). The ribavirin (RBV) arms were stratified by genotype 1a versus genotype 1b. The RBV-free arm included only genotype 1b-infected patients. Virologic response was assessed each week during treatment and at 2, 4, 8, 12 and 24 weeks after the end of treatment. The primary efficacy endpoint of the trial was the proportion of patients who achieved sustained virologic response at post-treatment follow-up week 12 (SVR12).
The primary analysis population was per protocol, including patients who did not have protocol violations and had received the correct study medications. A total of 58/65 enrolled patients met these criteria (see TABLE).
   
Of the seven patients who were not in the per-protocol population, four achieved SVR12 and three discontinued early for reasons other than adverse experiences or virologic failure.
Among the entire study population of 65 patients, one patient (1.5%) experienced a relapse with detectable HCV RNA at follow-up week 4 and 12.
   
TABLE
Primary Analysis Population: Per Protocol*
Arm Regimen N GT1a / GT1b SVR4 SVR12#
1 MK-5172 (100 mg) + MK-8742 (20 mg) + ribavirin 22 76% / 24% 22/22
(100%)
21/21
(100%)
2 MK-5172 (100 mg) + MK-8742 (50 mg) + ribavirin 24 70% / 30% 23/24
(96%)
23/24
(96%)
3 MK-5172 (100 mg) + MK-8742 (50 mg) 12 0% / 100%
12/12
(100%)
11/11
(100%)
* Seven Patients were excluded from the Per Protocol Population
 
  • 4 patients received incorrect RBV doses (3 received <50% of the prescribed dose:1 given RBV in the RBV-free arm); all achieved HCV-RNA <25 IU/mL at FU12
  • 3 patients discontinued early:1 patient at Day 3 (violated protocol inclusion criterion), and 2 patients at Day 22 and Day 35 (withdrew consent – patients had undetectable HCV RNA at the time of discontinuation)
#Two patients have not reached SVR12

      The most frequently reported adverse events occurring in the study were fatigue (26%), headache (22%), nausea (18%), diarrhea (12%), dizziness (11%) and rash (11%). The incidence of anemia (<10 mg/dL hemoglobin) and elevated total bilirubin levels to 2 times the upper limit of normal was 19 percent and 4 percent, respectively, in the RBV-containing arms (combined arms 1 and 2), and 0 percent and 0 percent, respectively, in the RBV-free arm. No grade 3 or 4 laboratory abnormalities were observed. There were eight cases of rash. Seven cases of rash were observed in the RBV-containing arms; half of these cases were attributed to RBV. The single case in the RBV-free arm was not study drug related and was mild in intensity. No early discontinuations due to drug-related adverse events were recorded.
   
The C-WORTHY trial has been expanded to evaluate the safety and efficacy of MK-5172 and MK-8742, with or without RBV, in difficult-to-cure HCV genotype 1-infected patient populations. Approximately 400 additional HCV genotype 1-infected patients have been enrolled in this trial. The expanded C-WORTHY study is testing:
   
  • 8 week regimen of MK-5172/MK-8742 + RBV in treatment naïve non-cirrhotic patients
  • 12 week regimen of MK-5172/MK-8742 without RBV in treatment-naïve non-cirrhotic patients
  • 12 week regimens (MK-5172/MK-8742 with or without RBV) among HIV co-infected patients
  • 12 or 18 week regimens (MK-5172/MK-8742 with or without RBV) in patients with cirrhosis
  • 12 or 18 week regimens (MK-5172/MK-8742 with or without RBV) in patients who had failed to respond to prior peginterferon and RBV therapy (“null responders”).

Details on the C-WORTHY Study, as well as additional phase II trials for MK-5172 and MK-8742, can be viewed on ClinicalTrials.gov.

About Merck
Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside of the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.
   
Merck Forward-Looking Statement
This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.
   
Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.
   
Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2012 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

Tuesday, October 22, 2013

Hepatitis C-Merck MK-5172/MK-8742 all-oral combination Gets Breakthrough Therapy Designation

Merck Receives Breakthrough Therapy Designation for MK-5172/MK-8742, an Investigational Oral Combination Regimen for the Treatment of Chronic Hepatitis C Virus (HCV) Infection

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, announced today that the U.S. Food and Drug Administration (FDA) has granted MK-5172/MK-8742 Breakthrough Therapy designation for treatment of chronic hepatitis C virus infection. MK-5172/MK-8742 is an all-oral combination regimen consisting of MK-5172, an investigational HCV NS3/4A protease inhibitor, and MK-8742, an investigational HCV NS5A replication complex inhibitor. Interim data from an ongoing Phase IIB clinical trial evaluating MK-5172/MK-8742 in genotype 1 infected patients (C-WORTHY Study) is scheduled to be presented at the 64th American Association for the Study of Liver Disease Annual Meeting, Washington D.C., Nov. 1-5.

“The designation of MK-5172/MK-8742 as a Breakthrough Therapy for chronic hepatitis C is an important milestone for Merck,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. “There remains significant unmet medical need in hepatitis C, and we are looking forward to working with the FDA to advance this program as quickly as we can to bring this investigational combination to HCV specialists and their patients.”

According to the FDA, the designation of an investigational drug as a Breakthrough Therapy is intended to expedite the development and review of a candidate that is planned for use, alone or in combination, to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

Chronic hepatitis C is a priority focus of research and development at Merck. MK-5172 and MK-8742 are being investigated in a broad clinical program that includes studies in patients with multiple HCV genotypes who are treatment-naïve, treatment failures as well as other important HCV subpopulations such as patients with cirrhosis and those co-infected with HIV. For more information please see www.clinicaltrials.gov.

About Merck

Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2012 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

http://www.mercknewsroom.com/news-release/research-and-development-news/merck-receives-breakthrough-therapy-designation-mk-5172mk



Tuesday, October 1, 2013

AASLD-Merck data for MK-5172 and MK-8742 in Hepatitis C Patients to be Presented

Merck & Co., Inc. : Data from Merck's Investigational Hepatitis C Treatment Portfolio to be Presented at the 64th American Association for the Study of Liver Diseases Annual Meeting


Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the presentation of data from studies evaluating the company's investigational oral chronic hepatitis C virus (HCV) treatments MK-5172 and MK-8742 at the 64th American Association for the Study of Liver Diseases Annual Meeting (AASLD). The meeting is scheduled to take place in Washington, D.C., Nov. 1-5, 2013.

"Merck is committed to developing HCV therapies that have the potential to offer new options for a broad range of patient types," said Dr. Eliav Barr, vice president, Infectious Diseases, Merck Research Laboratories. "We continue to build upon our strong legacy in HCV and look forward to sharing the latest clinical data for our investigational HCV therapies, MK-5172 and MK-8742."
MK-5172 is an investigational, once-daily, oral HCV NS3/4A protease inhibitor currently in Phase IIB development. MK-8742 is an investigational, once-daily, oral HCV NS5A replication complex inhibitor currently in Phase IIB development. Both candidates are being evaluated in broad clinical programs that include investigations in various HCV segments, multiple HCV genotypes and patients who have previously failed prior therapy.

Selected presentations of clinical data for MK-5172 and MK-8742
 
  • High Efficacy and Safety of the All-Oral Combination Regimen, MK-5172/MK-8742 +/- RBV for 12 Weeks in HCV Genotype 1 Infected Patients: The C-WORTHY Study. Lawitz, E., et al. Oral Presentation #76: Sunday, Nov. 3, 2013, 5:30-5:45 p.m.
  • Kinetic Analyses of Antiviral Suppression by NS5A Inhibitors Reveal Early and Potent Inhibition of Viral Assembly and Release. McGivern, D.R., et al. Oral Presentation #78: Sunday, Nov. 3, 2013, 6:00-6:15 p.m.
  • High Efficacy at Lower Doses of MK-5172 25mg and 50mg Daily for 12 weeks in HCV Genotype (G) 1 Treatment-Naïve Non-Cirrhotic Patients. Vierling, J., N et al. Poster #1123. Sunday, Nov. 3, 2013, 8:00 a.m. to 5:30 p.m.
  • Efficacy and Safety of an Interferon-Free Regimen of MK-5172 + Ribavirin for 12 Weeks or 24 Weeks in Treatment-Naïve, Non-Cirrhotic Subjects with HCV GT1 Infection: The C-SPIRIT Study. Gane, E.J., et al., Poster #1110. Sunday, Nov. 3, 2013, 8:00 a.m. to 5:30 p.m.
  • MK-8742, a HCV NS5A Inhibitor with a Broad Spectrum of HCV Genotypic Activity, Demonstrates Potent Antiviral Activity in Genotype-1 and -3 HCV-Infected Patients. Yeh, W. W., et al. Poster #479. Saturday, Nov. 2, 2013, 2:00-7:30 p.m.

The abstracts were published today and can be accessed on the AASLD website. For program information, please visit: http://www.aasld.org/livermeeting/program/Pages/default.aspx

About Merck
Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Forward-Looking Statement
This news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck's ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck's patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2012 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).

Revatio® and Adcirca® are trademarks of their respective owners and are not trademarks of Merck & Co., Inc., Whitehouse Station, N.J., USA.

Merck
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Wednesday, May 15, 2013

Hepatitis C Therapy Update 2013-What About Interferon-free Regimens?


Hepatitis C Virus Therapy Update 2013

Lisa C. Casey, William M. Lee

Curr Opin Gastroenterol. 2013;29(3):243-249.

Medscape Today

Abstract and Introduction
Abstract

Purpose of review: We review here the recent literature regarding hepatitis C virus (HCV) therapy through January 2013. We discuss current therapies, targets for new therapies, and what might be expected in this rapidly changing field.

Recent findings: Boceprevir-based and telaprevir-based triple therapy with pegylated interferon and ribavirin marked the beginning of a new era in HCV therapy for genotype 1 patients. New direct-acting antivirals (DAAs) are being developed and new antiviral drug targets are being explored. New combination treatment regimens are expected to emerge soon and there is hope for interferon-free regimens.

Summary: The standard of care for treatment of HCV genotype 1 changed dramatically with the approval of two new DAA drugs – telaprevir and boceprevir – for use in pegylated interferon-based and ribavirin-based triple therapy in mid-2011. Experience has shown improved response rates and treatment durations for many patients with genotype 1 HCV infection. However, persistent limitations to HCV treatment still exist for patients with prior treatment failure and comorbid conditions and patients on newer therapies suffer additional therapy-limiting side effects and drug–drug interactions. Genetic testing may provide some guidance but additional options for therapy are still needed for HCV. Many new drugs are currently under investigation and there is hope that effective and well tolerated interferon-free regimens may become a part of future therapy.

Introduction
An estimated 130–170 million people are infected with hepatitis C worldwide leading to significant morbidity, mortality, and financial burden on healthcare.[1] Out of 100 people who contract the infection, 75–85% will develop chronic infection, 60–70% will develop chronic liver disease, 5–20% will develop cirrhosis over the course of their chronic infection, and 1–5% will die of complications including hepatocellular carcinoma (HCC).[1,2] The majority of the infected population in the United States, an estimated 3.2–3.7 million people, are believed to have been born between 1945 and 1965 and likely contracted the virus when transmission rates were highest in the 1970s and 1980s.[3,4] Hepatitis C virus (HCV) has a long and relatively symptom-free incubation period prior to causing serious illness. Although the contribution of blood product screening, disposable medical equipment, and public health education efforts over the years has led to a decrease in the incidence of HCV in the United States, an estimated 65–75% of currently infected individuals in the United States are unaware of their infection. The consequences of these undiagnosed and untreated chronic infections are expected to be staggering as this population ages with predictive models suggesting a two-fold increase in HCV-related deaths with direct medical costs exceeding $6.7 billion between 2010 and 2019[5] and, without intervention, a four-fold rise in the incidence of end-stage liver disease related to hepatitis C within the next 20 years.[6] An effort to capture these patients has led to the recent Centers for Disease Control and Prevention recommendations for birth cohort screening of the population born between 1945 and 1965 in the United States.[4]
                       
Outside of the United States, many other countries worldwide face significant HCV infection rates. Despite aggressive programs toward education, care, and treatment over the last 10 years, Egypt faces the largest burden of HCV infection in the world with a 10% prevalence of chronic hepatitis C infection among persons aged 15–59 years, predominantly genotype 4.[7] In many parts of the world the virus remains unchecked because of continued unsafe medical practices, lack of public health education, and lack of funding for research and treatment. Perz et al. [8] looked at 11 WHO-based regions in 2006 and estimated that globally 27% of cirrhosis was attributable to HCV and 25% of HCC was attributable to HCV. In many countries and populations, only a small number of patients with known infection actually receive treatment and yet successful treatment has been shown to have a significant impact on outcomes.[6,9] A sustained virological response (SVR) to hepatitis C therapy reduces liver-related as well as all-cause mortality for patients with hepatitis C[3,8] including a 70–80% reduction in overall liver-related mortality and hepatic decompensation and a 75% reduction in risk of HCC at all stages of fibrosis.[4,10]
                       
Until 2011, the historically accepted standard therapy with pegylated interferon and ribavirin produced an SVR rate of approximately 40–50% for genotype 1 patients and higher rates up to 80% for alternate genotypes after 24–48 weeks of therapy.[11] The limitations of this therapy are well recognized. Pregnant patients or those with advanced renal disease are contraindicated from using ribavirin. Likewise, interferon therapy excludes patients with autoimmune diseases, uncontrolled depression and mental illness, decompensated liver disease (child turcotte pugh > 6) or decompensated cardiac or pulmonary disease. Patients experienced frequent side effects and those failing therapy due to relapse, non or null response had few options. This led to aggressive research into additional treatment targets and ways to predict patient response to treatment.

Viral Structure
What was first known as non-A, non-B hepatitis was designated hepatitis C in 1989 by Michael Houghton and scientists at Chiron Corporation while searching for the blood-borne cause of hepatitis in transfusion recipients (see Fig. 1).[12] Hepatitis C is a single-stranded RNA flavivirus of the hepacivirus genus. Of the six genotypes, genotype 1 is the most prominent in the United States and Europe. The virus lacks proofreading ability leading to significant genetic variation, historically making drug development against the virus challenging. When the virus enters a liver cell, it releases its RNA and is translated into a poly-protein containing structural and nonstructural regions. The poly-protein is processed by proteases into several polypeptides with different functional roles in the virus life cycle. The virus is replicated with the help of a polymerase and then assembled, transported, and released from the cell. The nonstructural region codes for the polypeptides NS2, NS3, NS4A, NS4B, NS5A, and NS5B. All are potential targets for drug therapy. Initial cleavage of the poly-protein is performed by the NS3/NS4A protease, which seems to be highly conserved across most strains, and, without which, the HCV life cycle cannot proceed.[13] This region became the first therapeutic target for direct-acting antiviral (DAA) therapy, the NS3/NS4 protease inhibitors telaprevir and boceprevir.


Figure 1.

Viral structure and genome demonstrating potential therapeutic targets. Reproduced with permission from.[12] HCV, hepatitis C virus.

The Era of Triple Therapy
The creation of the new standard 'triple therapy' with the DAA medications has led to significant improvements in the response rates for patients with genotype 1 HCV, with SVR rates as high as 63–75% and reduction in duration of therapy by half for many patients based on response-guided therapy (RGT). The first Food and Drug Administration (FDA)-approved protease inhibitors, telaprevir and boceprevir, are designed to mimic the natural NS3/NS4A protease substrate in genotype 1 HCV, therefore inhibiting the onset of the replication process. The successes, failures, and new challenges of triple therapy have become well known. Although the advent of triple therapy has dramatically improved outcomes for many, therapeutic options for HCV are still far from optimal. Many new side effects have been encountered with creative management strategies developed, drug interactions have taken on new importance and issues with resistance and intolerance persist. With the explosion of research and development of newer DAA and additional therapeutic targets, we are at the very beginning of a new era in HCV therapy. A review of the lessons learned from the beginning will be important as we move forward.

First-generation Protease Inhibitors: Lessons From Telaprevir and Boceprevir
Telaprevir efficacy was initially proven in multiple large multicenter trials including protease inhibition for viral evaluation-1 (PROVE-1), PROVE-2, PROVE-3, ADVANCE, REALIZE, and illustrating the effects of combinatherapy with telaprevir (ILLUMINATE).[13–16] The importance of ribavirin was confirmed by demonstration of significant viral breakthrough and relapse after therapy in patients in a pegylated interferon and telaprevir study arm without ribavirin. These early trials developed and confirmed the utility of RGT, suggesting that a shortened duration of therapy was acceptable for patients meeting certain criteria and 24 weeks of telaprevir-based therapy was noninferior to 48 weeks of triple therapy in patients meeting appropriate criteria. Differences have been observed in treatment failure rates between genotypes 1a and 1b and in various difficult-to-treat groups. African–Americans, those with high-viral loads, bridging fibrosis or cirrhosis demonstrated somewhat improved rapid viral response with new agents but responses are still decreased compared with those observed in naive, noncirrhotic patients.[14–17]
                       
Conceptually, the Peg-interferon/ribavirin lead-in was introduced to bring the baseline viral load down prior to starting boceprevir and, in turn, decrease the emergence of drug-resistant mutations. SVR was similar in the 28-week and 48-week groups that demonstrated at least a 1.5 log drop in viral load after the 4-week lead-in therapy phase. Patients in the 28-week triple therapy arm that did not demonstrate the 1.5 log drop after lead-in showed a poor SVR of 30% or less at 28 weeks compared with the corresponding 48-week group. The overall conclusion was that RGT based on 4-week lab values would help predict the best duration of treatment.[18] Serine protease inhibitor therapy trial-2 (SPRINT-2) stratified black and non-black patients into different arms and again demonstrated persistently lower SVR rates for black patients versus non-blacks, suggesting interferon resistance continued to play a role.[19] Additional studies suggest that the use of interleukin (IL)-28 genotyping (rs 12979860) may also identify patients who are more likely to qualify for shorter treatment durations in RGT with boceprevir.[19,20] Thus, interferon responsiveness is important in prediction of response to triple therapy; patients with a poor response to interferon might be best served by waiting for improved future therapies.

Limitations of First-generation Direct-acting Antiviral Therapy
Although the advent of triple therapy with boceprevir and telaprevir has improved response rates and treatment durations for many patients with genotype 1 disease, the phase 3 clinical trials demonstrated that many still do not achieve SVR. In addition, drug–drug interactions limit use, the high pill burden makes compliance difficult and resistance is still a real threat with unclear future implications. New rashes and anorectal symptoms are seen with telaprevir and moderate-to-severe anemia is common in both regimens.[16,19,21] In December 2012, a black box warning was added to telaprevir labeling in light of some rashes resulting in death.[22]

What is Needed: Goals for the Future
Traditionally HCV therapy has been nonspecific in its therapeutic target. Interferon activates the immune system and inhibits viral replication whereas ribavirin is a nonspecific antiviral that may inhibit viral replication but also aid in viral clearance though its true function against HCV is elusive.[23,24] Newer therapies directed against specific viral and host targets appear to have greater potential for success.
Epidemiologists have produced a long list of barriers to HCV treatment including goals for future HCV medications including: improved tolerance, high potency, favorable safety profile, high barrier to resistance, all oral regimen, pan-genotypic, favorable pill burden, short duration, few drug interactions, available for cirrhosis, HIV, mental illness, and affordable.[5,9] For the first time, ongoing research suggests that many of these goals may be realistic.

Understanding Direct-acting Antiviral Resistance is Important for the Future
Drug resistance was noted in some form with both telaprevir and boceprevir in the early protease inhibitor trials, impacting the final structure of treatment protocols. Specifically, ribavirin use is required by all protocols and genotypic subtypes 1a and 1b demonstrate a recognizable difference in rates of SVR. The findings are explained by the very low genetic barrier to resistance of protease inhibitors as a class, defined as the number of amino acid substitutions required to confer full resistance to a drug.[25,26] In general, DAAs with a low genetic barrier to resistance require only 1–2 amino acid substitutions for high resistance and DAAs with a high barrier to resistance usually require 3–4 amino acid substitutions in the same region. Telaprevir resistance is recognized to most frequently be represented by mutation R155K. The R-K change requires only one nucleotide change in genotype 1a, whereas genotype 1b requires two nucleotide changes. The amino acid target sequence of the NS3 region differs significantly between HCV genotypes (explaining why telaprevir and boceprevir have efficacy limited to genotype 1) and resistance can develop easily with few mutations.[25] The barrier to genetic resistance of DAA in development will be a critical factor in the success of future regimens.

Resistance-associated amino acid variants (RAVs) have been found in treatment-naive HCV as well as after drug exposure, thought to result from genetic variation inherent in the virus itself and selective pressure from drugs. Given as monotherapy, most DAAs rapidly select for HCV variants with reduced drug susceptibility resulting in virological failure and treatment rebound.[27] Although protocols instruct against monotherapy, reaffirmation of the mandate that these drugs not be used alone is important. Cross-reactivity has been shown in RAV between telaprevir and boceprevir and there is the theoretical risk for development of resistance to several protease inhibitors with injudicious use of one of the current regimens. Careful monitoring of stopping rules is essential in current therapies, particularly in the setting of treatment of prior null responders.[28] Fortunately, there are multiple different targets for therapy with differing genetic barriers to resistance. On the basis of what we have learned to this point, combination therapy will be the rule in the future.

New Drugs in Development
In addition to boceprevir and telaprevir, many new DAA and host-targeted drugs are in development


Table 1.  New hepatitis C drugs in development
 
NS3/4A protease inhibitorsNS5ANS5B polymerase nucleos(t)ideNS5BNNI Host targets
AsunaprevirDaclatasvirMericitabineTegobuvirAlisporovir
VaniprevirABT-267SofasbuvirFilibuvirMirvirsen
DanoprevirGS-5885IDX184BI-207127
MK-5172PPI-461PSI-938VX-222lambda IFN
BI-201335BMS791325Setrobuvir
Simeprevir
ABT-333
TibotecINX-189
ABT-450


Protease Inhibitors: The Next Generation
Despite their limitations, protease inhibitors have high antiviral efficacy and will play an important role in future therapies. Newer protease inhibitors in development: asunaprevir, danoprevir, vaniprevir, MK-5172, BI-201335, and simeprevir are expected to have improved tolerance and safety profiles and will likely be used in combination with pegylated interferon and ribavirin or in newer DAA combination regimens in the future.

Polymerase Inhibitors: NS5B
Polymerase inhibitors interfere with viral replication by binding to the NS5B RNA-dependent RNA polymerase. Their success has been demonstrated extensively in phase 1 and 2 trials, and they are expected to play an important role in newer DAA combination therapy regimens. The class comprises two types – nucleos(t)ide inhibitors and non-nucleotide inhibitors (NNIs). Nucleos(t)ide analogue inhibitors are active site inhibitors that mimic the natural substrates of the polymerase, being incorporated into the RNA chain and causing direct chain termination. As the active site of NS5B is highly conserved, these are potentially active against all the different genotypes. In addition, as amino acid substitutions in every position of the active site may result in loss of function, resistance to nucleos(t)ide analogue inhibitors is usually low. Mericitabine and sofosbuvir both have demonstrated convincing data in clinical trials.
Non-nucleoside inhibitors, on the contrary, bind to several discrete sites outside of the polymerase active center, which results in a conformational protein change before the elongation complex is formed – essentially inhibiting the polymerase from a distance. Resistance is more frequent with NNIs as NS5B is structurally organized into multiple different domains with at least four different binding sites. Mutations at the individual binding sites do not necessarily cause loss of function of the polymerase.[25] Drugs in this category are tegobuvir, filibuvir, BI-207127, VX-222, ANA598, ABT-333.

NS5A Inhibitors
NS5A is a membrane-associated phosphoprotein involved in HCV virion production and the viral life cycle. Daclatasvir, the first in its class NS5A inhibitor, exhibits high potency and is expected to have a broad range of genotypic coverage; it is synergistic with other DAAs. Several others are in development including ABT-267, GS-5885, PPI-461.[25,28]

Host-targeted Therapies
Several drugs are in development against host targets. Cyclophilin inhibitors such as the cyclophilin A binding molecule alisporivir appear to have potent anti-HCV activity and have broad genotype activity for types 1–4. Alisporivir appears to inhibit HCV viral replication by interfering with the interaction between cyclophilin A and NS5A. In early trials with pegylated interferon and ribavirin, an SVR rate into the 70% range was seen with 24 weeks of once daily therapy and benefits have been confirmed in genotypes 2 and 3, with particular success against genotype 3 and a very high barrier to resistance.[23] An additional host-targeted agent is the subcutaneously administered drug, mirvirsen, which specifically targets the liver-specific micro-RNA miR-122 that is involved in gene expression and HCV viral replication, producing dramatic suppression of HCV viremia without evidence of RAV or significant side effects in early trials. New interferons have also been explored. Native human interferon lambda proteins are generated by the immune system in response to viral infection. This interferon family has been found to have antiviral activity against HCV. The interferon and its receptor are both expressed at high levels by hepatocytes but not all tissues suggesting that this reagent could have tissue specific effects, potentially equating to reduced toxicity compared to current experience with α-interferon.[23] This could be a better tolerated alternative to interferon α until oral regimens are available.

What About Interferon-free Regimens?
Interferon-free regimens are widely being tested in clinical trials with encouraging results. The following selected trials demonstrate how rapidly progress is being made. Beginning in 2010, studies demonstrated the potential for antiviral efficacy of an all-oral regimen using combinations of drugs with different targets.

Interferon-free regimen for the management of HCV-1 (INFORM-1) was a phase 1 proof of concept study from 2010 using combination DAA without interferon.[27] Danoprevir, an NS3/4A protease inhibitor, and RG7128 (later named mericitabine), a NS5B nucleoside polymerase inhibitor, were given for up to 13 days in multiple different dosing arms to assess the ability of an interferon-free regimen to suppress viral load. After the treatment period, all patients subsequently were given standard of care pegylated interferon and ribavirin for 48 weeks. Overall, the DAA combination therapy was well tolerated, and there were no treatment-related study withdrawals or dose reductions during the treatment period. Most common adverse event was headache. The DAA combination regimen showed very potent activity against HCV in all participants, including previous null responders giving encouragement that interferon-free all DAA regimens are possible. Of note, patients with cirrhosis were excluded.

SOUND-1 and SOUND-2 trials included an NS3/4A protease inhibitor (BI-201335) and an NNI NS5B polymerase inhibitor (BI-207127) and ribavirin to demonstrate proof of potent antiviral activity against HCV with rapid viral response rates of 73–100% dependent on dosing. Genotype 1b responded more favorably than 1a and the ribavirin-sparing arm in the later trial showed reasonable but substantially lower response rates. Final results were presented in abstract form at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting 2012.[29] Patient results were randomized by genotype 1a versus 1b and by IL-28 genotype CC/CT/TT. Ribavirin arms with variable DAA dosing demonstrated a range in SVR12 (SVR after only 12 weeks off therapy), of 52–69% but only 39% in ribavirin-free arms. Genotype 1b responded better than 1a and IL-28 appeared to be an independent predictor of SVR. All IL-28 genotype of 1b and IL-28 CC 1a patients demonstrated SVR 12 rates as high as 84% with the all-oral regimen.

More recently, exciting results from the phase 2 ELECTRON trial were reported.[30] Sofosbuvir (formerly known as GS-7977) NS5B polymerase inhibitor in a once daily dose was combined with ribavirin for 12 weeks, pegylated interferon and ribavirin for 4, 8, or 12 weeks in naive patients with genotypes 2 or 3 or sofosbuvir monotherapy for 12 weeks in naive patients with genotypes 2 or 3. An additional group of 35 genotype 1 patients was enrolled, 25 naive patients and 10 prior nonresponders who were also treated with sofosbuvir and ribavirin for 12 weeks. After 24 weeks of therapy, all naive genotype 2 and 3 patients on combination therapy had an SVR at 24 weeks (100%). SVR was seen in only 60% of the genotype 2 and 3 patients on monotherapy. Among genotype 1, treatment-naive patients demonstrated 84% SVR and prior nonresponders fared less well with an SVR of only 10%. Sofosbuvir appears to be well tolerated and to have a high barrier to resistance. This study suggests a new DAA option may soon be available for naive patients with genotype 1, 2, and 3; however, ribavirin still plays a role in maintenance of an antiviral response.[30]
                       
Another new phase 2 clinical trial was found to show even better responses in genotype 1 patients. ABT-450 (an NS3 protease inhibitor) combined with low-dose ritonavir, ABT-333 (a non-nucleoside NS5B polymerase inhibitor), and ribavirin were used in varying doses in treatment-naive and experienced patients excluding those with cirrhosis for 12 weeks. Treatment-naive patients demonstrated an SVR12 of 93–95% depending on dose and treatment experienced patients an SVR12 of 47%. Some viral breakthrough and resistance was noted during treatment in the prior nonresponder population and the study suggests this population will need a modified DAA regimen as extending duration would not have changed outcome. Overall, this 12-week combination therapy may be an effective future therapy for HCV genotype 1.[31]

Conclusion
We are once again preparing for a dramatic paradigm shift in approach to HCV infection. Worldwide, the epidemic proportions of HCV are coming to light both in the efforts of healthcare workers and governments in the underdeveloped world and in the burden from untreated and undiagnosed disease in the developed world. Numerous new drugs targeting various aspects of the HCV life cycle and the host are in development and clinical trials. Overall, combination therapies will be the rule. New combinations of DAA have synergistic effects, decrease the risk of resistance, and improve antiviral efficacy, are effective in different genotypes and have a favorable safety profile. Despite universal hope for all-oral regimens, pegylated-IFN is still in the literature. Many phase 1 and 2 clinical trials are still designed to demonstrate the safety of new DAA in combination with a pegylated interferon and ribavirin backbone and though the best response rates in interferon containing regimens still tend to be in favorable genotypes or IL-28 CC patients, the important benefit in these combinations is much shorter treatment duration of 12 weeks. Interferon-free combination regimens appear to be on the horizon, providing a new option in particular for patients with non-genotype 1 HCV, but there will still be treatment failures and resistance issues to be overcome, particularly in the treatment experienced population.

http://www.medscape.com/viewarticle/802844_1

Sunday, April 28, 2013

EASL- MK-5172 : New Drug Holds Promise in Hepatitis C


New Drug Holds Promise in Hepatitis C

By Michael Smith, North American Correspondent, MedPage Today
Published: April 28, 2013

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

AMSTERDAM -- An investigational protease inhibitor for hepatitis C (HCV) achieved high response rates in treatment-naive patients when given in what one expert called an "old-fashioned" regimen.

Action Points
  • This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • An investigational protease inhibitor (MK-5172) for hepatitis C achieved higher response rates than treatment with an approved protease inhibitor, boceprevir, in treatment-naive patients who also received pegylated interferon and ribavirin.
  • Point out that only 7% of patients stopped therapy owing to adverse events in the combined MK-5172 arms compared with 14% in the boceprevir arm.

    The drug (MK-5172) rendered the virus undetectable 24 weeks after the end of therapy in almost 90% of patients with the difficult-to-treat HCV genotype 1, according to Michael Manns, MD, of Hannover Medical School in Hannover, Germany.

    In contrast, treatment with an approved protease inhibitor, boceprevir (Victrelis), led to an SVR24 in just 54%, Manns reported at the meeting of the European Association for the Study of the Liver (EASL).

    But both drugs were combined with pegylated interferon and ribavirin, medications that are widely regarded as likely to fade from practice as a range of investigational direct-acting agents reaches the clinic.

    The direct-acting agents, such as boceprevir and MK-5172, attack elements of the virus, in contrast to interferon and ribavirin, which respectively boost the immune system and target general viral replication.

    Both have a range of unpleasant side effects and interferon in particular is seen as both difficult to tolerate and dangerous to use.

    MK-5172 "is a very good drug," commented Alessio Aghemo, MD, of the University of Milan in Italy, who was not involved with the study but who moderated the EASL session at which it was presented.

    But he told MedPage Today that clinicians and researchers are withholding judgment until it is tested without interferon and perhaps without ribavirin.

    "The SVR rates are high with (interferon and ribavirin) but it's an old-fashioned regimen," he said. "It needs to go into an interferon-free regimen."

    The study, Manns reported, included 332 treatment-naïve patients with genotype 1 virus and without cirrhosis. They were randomly assigned to one of four doses (100, 200, 400, or 800 mg) of MK-5172 or to boceprevir as a control. All patients also received pegylated interferon, and ribavirin for durations that varied according to early treatment response.

    Manns presented data on the proportion of patients in each arm who reached SVR24 or who had undetectable virus at their last visit if that occurred before they completed 24 weeks after the end of therapy.

    When the data were compiled in March, 311 patients had either reached the 24-week mark or had dropped out of the study before then, but all patients had completed treatment.

    Analysis showed that the SVR24 rates in the MK-5172 arms ranged from 86% to 92%, compared with 54% in the boceprevir arm.

    When the researcher added those who had not reached the 24-week mark, but who had undetectable virus at their last study visit, the rates ranged from 92% to 99% for MK-5172 and rose to 67% in the boceprevir arm.

    Interestingly, there was little variation when the researchers stratified patients by polymorphisms of the IL28B gene, which predicts response to interferon, although the favorable CC allele tended to yield slightly better response rates numerically.

    Manns noted that some patients getting higher doses of MK-5172 (400 and 800 mg ) were "down-dosed" to 100 mg daily, which will be the dose used in future studies.

    There were no deaths on the study and the rates of serious adverse events were similar – 9% in the combined MK-5172 arms and 8% in the boceprevir arm, Manns said. Adverse events included gastrointestinal problems, rash, and anemia.

    Only 7% of patients stopped therapy owing to adverse events in the combined MK-5172 arms compared with 14% in the boceprevir arm.

    A total of 26 patients had bilirubin elevations, possibly because MK-5172 inhibitors some transporter molecules and enzymes, he said. The elevations mostly occurred early and were not associated with decreases in hemoglobin.

    In general, the drug was well tolerated but the investigators noted dose-related elevations in liver enzymes, he said.

    The study was supported by Merck. Manns reported financial links with the company, as well as with Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Novartis, Roche, Idenix, and Valeant.

    Aghemo reported financial links with Roche, Gilead, Jannsen, and Merck.

    Primary source: EASL 2013
    Source reference:
    Manns M, et al. "High Sustained Viral Response at 12- and 24-Week Follow-Up of MK-5172 with Pegylated Interferon Alfa-2B and Ribavirin (PR) in HCV Genotype Treatment-Naive Non-Cirrhotic Patients" EASL 2013;abstract 66.

  • EASL Coverage @ MedPage Today

    Updates

    Triple Therapy Can Help in Advanced Hep C
    4/28/2013   
    AMSTERDAM -- About 40% of people with advanced hepatitis C (HCV) can benefit from triple therapy even if they have cirrhosis and previous treatment failures, a researcher said here.
    more

    4/28/2013
    AMSTERDAM -- Elimination of spontaneous liver shunts, or reducing the size of surgically placed shunts, is an effective treatment for hepatic encephalopathy in cirrhotic patients, researchers said here. 
     

    Tuesday, April 23, 2013

    EASL: Merck to Present Interim Data on MK-5172 from Phase II Trial

    Bloomberg:

    Merck's Experimental Hepatitis C Drug Beats Victrelis

    Merck & Co. (MRK) said an experimental drug against hepatitis C was more effective than its Victrelis pill in a patient study. 
    The virus was undetectable in the blood of as many as 92 percent of patients six months after they stopped the 12-week course of treatment with the drug, known as MK-5172, compared with 54 percent of those who received Victrelis, Whitehouse Station, New Jersey-based Merck said in a statement today. The trial included 332 people with the most common form of hepatitis C in the U.S., and all received standard therapy ribavirin in addition to either MK-5172 or Victrelis.  
    Merck said yesterday that it’s entered a non-exclusive agreement with Bristol-Myers Squibb Co. (BMY) to test MK-5172 in combination with Bristol’s daclatasvir.   
    “The interim findings from this study provide clear direction for future larger trials designed to evaluate MK-5172 in novel, all-oral regimens for HCV,” Eliav Barr, Merck’s vice president of infectious diseases, said in today’s statement.  
    The drug caused increased levels of potentially harmful liver enzymes in some patients on the highest doses, who had their doses reduced as a result, Merck said.  
    Victrelis was approved by the U.S. Food and Drug Administration in May 2011, the first hepatitis C drug in almost a decade. 
     
    Source - Bloomberg
    To contact the reporter on this story: Simeon Bennett in Geneva at sbennett9@bloomberg.net
    To contact the editor responsible for this story: Phil Serafino at pserafino@bloomberg.net

    Press Release:

    Merck to Present Updated Interim Data from Phase II Trial Evaluating Investigational NS3/4A Protease Inhibitor MK-5172 for Chronic Hepatitis C Virus Genotype 1 Infection at the International Liver Congress™
              
    Tuesday, April 23, 2013 6:39 am EDT

    WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced the presentation of the latest interim data from a Phase II, multi-center, randomized, dose-ranging clinical trial evaluating the safety and antiviral activity of MK-5172, for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection. MK-5172 is an investigational, once-daily, oral HCV NS3/4A protease inhibitor that in preclinical evaluations has demonstrated a high barrier to resistance. These data will be presented at the International Liver Congress™ during the 48th meeting of the European Association for the Study of the Liver being held in Amsterdam on Friday, April 26, from 4-6 p.m. local time. Earlier interim data from this study was previously presented at the American Association for the Study of Liver Diseases Annual Meeting in November 2012.

    MK-5172 in combination with peginterferon alfa-2b and ribavirin (PR) was evaluated versus VICTRELIS® (boceprevir), 200 mg Capsules, in combination with PR in treatment-naïve, non-cirrhotic patients with HCV genotype 1. A total of 332 patients were enrolled and randomized to receive MK-5172 at 100, 200, 400 or 800-mg in combination with PR or boceprevir with PR. MK-5172 was administered for 12 weeks with PR, followed by an additional 12 or 36 weeks of PR therapy (depending on the HCV RNA levels at Treatment Week 4). Boceprevir was administered according to the U.S. product circular.

    For those patients evaluated to date, the rates of sustained viral response (SVR) at week 24 follow-up (SVR24) were 86 percent (55/64) and 92 percent (61/66) for the MK-5172 100 mg plus PR and MK-5172 200 mg plus PR arms, respectively, versus 54 percent (31/57) in the boceprevir plus PR active control arm. Patients who discontinued the study for reasons other than virologic failure and were either in follow-up or did not return for week 24 follow-up were, per protocol, formally counted as ‘failures’ in the SVR24 analysis, regardless of their HCV RNA status at the last visit on record. An analysis combining such patients with those who were evaluable for the SVR24 endpoint showed that undetectable HCV RNA, (HCV RNA negative), at last visit on record was achieved for 92 percent (61/66), 99 percent (67/68), and 67 percent (44/66) for MK-5172 100 mg plus PR, MK-5172 200 mg plus PR, and boceprevir plus PR groups respectively.

    “We continue to build upon our clinical experience of MK-5172 in chronic hepatitis C,” said Eliav Barr, M.D., vice president, Infectious Diseases, Project Leadership and Management, Merck Research Laboratories. “The interim findings from this study provide clear direction for future larger trials designed to evaluate MK-5172 in novel all oral regimens for HCV.”

    Following a review of safety data, an increased incidence of elevated liver transaminases (ALT/AST), a marker of liver toxicity, was observed in patients receiving the highest doses (400 mg and 800 mg) of MK-5172 and consequently the dose of MK-5172 was reduced to 100 mg in these patients. In the patients administered higher doses of 400 mg and 800 mg MK-5172, 91 percent (58/64) and 87 percent (52/60) of patients respectively achieved SVR24.

    Of the patients evaluated so far in this study, the incidence of bilirubin increase and/or a late transaminase increase in the 100 mg dose of MK-5172 was comparable to control. In 124 patients receiving a higher dose of MK-5172 (67 on 400 mg and 65 on 800 mg), transaminase levels normalized by week 4 on therapy but increased to more than twice the upper limit of normal thereafter; in the majority of these patients levels declined with continued MK-5172 treatment at the 100 mg level and normalized by week 16. Overall, rates of serious adverse events were 9 percent (25/266) and 8 percent (5/66) for MK-5172 plus PR arms and control group respectively. The incidence of rash was 20 percent (54 /266) and 27 percent (18/66) for MK-5172 plus PR arms and control group respectively. Rates of anemia in MK-5172 plus PR arms, 18 percent (48/266), were lower than those observed in the control group, 27 percent (18/66).

    In a separate poster, (#403), Merck scientists presented data from the analysis of blood samples from patients in this Phase II study evaluating MK-5172 plus PR. They evaluated the relationship between MK-5172 plasma levels and elevated liver transaminase activity. A dose dependent, non-linear relationship was determined between exposure to high levels of MK-5172 and the probability of liver toxicity. Based on this data and the SVR data with MK-5172, the 100 mg dose level is being evaluated in trials of interferon-containing and interferon-free regimens.

    About MK-5172

    MK-5172 is an investigational orally available HCV NS3/4A protease inhibitor currently being evaluated in combination with other approved and investigational medications in Phase II clinical trials. This includes an all oral combination with MK-8742, Merck’s investigational orally available HCV NS5A inhibitor.

    Indications and Usage for VICTRELIS

    VICTRELIS® (boceprevir) is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 (G1) infection, in combination with peginterferon alfa and ribavirin (PR), in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy, including prior null responders, partial responders, and relapsers.

    The following points should be considered when initiating VICTRELIS for treatment of chronic HCV infection:
    VICTRELIS must not be used as monotherapy and should only be used in combination with PR.
    The efficacy of VICTRELIS has not been studied in patients who have previously failed therapy with a treatment regimen that includes VICTRELIS or other HCV NS3/4A protease inhibitors.
    Poorly interferon responsive patients who were treated with VICTRELIS in combination with PR have a lower likelihood of achieving a sustained virologic response (SVR), and a higher rate of detection of resistance-associated substitutions upon treatment failure, compared to patients with a greater response to PR.

    Important Safety Information about VICTRELIS

    All contraindications to PR also apply since VICTRELIS must be administered with PR. Because ribavirin may cause birth defects and fetal death, VICTRELIS in combination with PR is contraindicated in pregnant women and in men whose female partners are pregnant. Avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to therapy; have monthly pregnancy tests; and use 2 or more forms of effective contraception during treatment and for at least 6 months after treatment has concluded. One of these forms of contraception can be a combined oral contraceptive product containing at least 1 mg of norethindrone. Oral contraceptives containing lower doses of norethindrone and other forms of hormonal contraception have not been studied or are contraindicated.

    VICTRELIS is contraindicated in patients with a history of a hypersensitivity reaction to VICTRELIS. VICTRELIS is contraindicated in coadministration with drugs that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events. VICTRELIS is also contraindicated in coadministration with potent CYP3A4/5 inducers, where significantly reduced VICTRELIS plasma concentrations may be associated with reduced efficacy. Drugs that are contraindicated with VICTRELIS include: alfuzosin, carbamazepine, phenobarbital, phenytoin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John’s Wort (hypericum perforatum), lovastatin, simvastatin, drospirenone, Revatio® (sildenafil) or Adcirca® (tadalafil) (when used for the treatment of pulmonary arterial hypertension), pimozide, triazolam, and orally administered midazolam.

    Anemia and/or Neutropenia – The addition of VICTRELIS to PR is associated with an additional decrease in hemoglobin concentrations compared with PR alone and/or may result in worsening of neutropenia associated with PR therapy alone. Dose reduction or discontinuation of peginterferon alfa and/or ribavirin may be required. If peginterferon alfa or ribavirin is permanently discontinued, VICTRELIS must also be discontinued. Dose reduction of VICTRELIS is not recommended. VICTRELIS must not be administered in the absence of PR.

    Complete blood count (with white blood cell differential counts) must be conducted in all patients prior to initiating combination therapy with VICTRELIS. Complete blood counts should be obtained at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. Serious acute hypersensitivity reactions (eg, urticaria, angioedema) have been observed during combination therapy with VICTRELIS and PR. If such an acute reaction occurs, combination therapy should be discontinued and appropriate medical therapy immediately instituted.

    The most commonly reported adverse reactions (>35%) in clinical trials in adult patients receiving the combination of VICTRELIS with PR were: fatigue, anemia, nausea, headache, and dysgeusia. Of these commonly reported adverse reactions, fatigue, anemia, nausea, and dysgeusia occurred at rates ≥5% above the rates for PR alone in either clinical study. The incidence of these adverse reactions in previously untreated subjects that were treated with combination therapy with VICTRELIS compared with PR alone were: fatigue (58% vs 59%), anemia (50% vs 30%), nausea (46% vs 42%), and dysgeusia (35% vs 16%), respectively. The incidence of these adverse reactions in previous treatment failure patients that were treated with combination therapy with VICTRELIS compared with PR alone were: fatigue (55% vs 50%), anemia (45% vs 20%), nausea (43% vs 38%), and dysgeusia (44% vs 11%), respectively.

    VICTRELIS is a strong inhibitor of CYP3A4/5 and is partly metabolized by CYP3A4/5. The potential for drug-drug interactions must be considered prior to and during therapy.

    Please see U.S. prescribing information at: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf

    Merck's Global Commitment to Development of Hepatitis Therapies

    Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. In hepatitis C, company researchers developed the first approved therapy for chronic HCV in 1991 and the first combination therapy in 1998. In addition to ongoing studies for our marketed and investigational medicines for the treatment of chronic HCV, extensive research efforts are underway to develop additional oral therapies for viral hepatitis treatment.

    About Merck

    Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside of the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

    Merck forward-Looking Statement

    This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

    Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

    Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2012 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

    Monday, April 22, 2013

    MK-5172 and Daclatasvir-Merck Enters Agreement with Bristol-Myers Squibb to Conduct a Phase II Clinical Trial

    Merck Enters Agreement with Bristol-Myers Squibb to Conduct a Phase II Clinical Trial Evaluating Combination of Investigational Oral Candidates MK-5172 and Daclatasvir for Chronic Hepatitis C

     "In HCV, agreements like this that combine novel investigational candidates are important to evaluate the potential of novel oral regimens early in the development cycle,"

    WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK) today announced it has entered into a non-exclusive agreement with Bristol-Myers Squibb to conduct a Phase II clinical trial to evaluate the safety and efficacy of a once-daily oral combination regimen consisting of Bristol-Myers Squibb’s investigational NS5A replication complex inhibitor daclatasvir and Merck's investigational NS3/4A protease inhibitor MK-5172 for the treatment of chronic hepatitis C virus (HCV) infection, genotype 1.

    “In HCV, agreements like this that combine novel investigational candidates are important to evaluate the potential of novel oral regimens early in the development cycle,” said Eliav Barr M.D., vice president, Infectious Diseases, Project Leadership and Management, Merck Research Laboratories. “We are pleased to collaborate with Bristol-Myers Squibb to advance this potential all-oral combination.”

    The planned initiation of the Phase II clinical trial follows the completion of a Phase I safety evaluation of the investigational combination regimen. Under the agreement, Merck will conduct the Phase II clinical trial. Further clinical development activities beyond the Phase II study are not covered as part of this agreement. Additional details of the collaboration were not disclosed.

    About MK-5172

    MK-5172 is an investigational orally available HCV NS3/4A protease inhibitor currently being evaluated in combination with other approved and investigational medications in Phase II clinical trials. This includes an all oral combination with MK-8742, Merck’s investigational orally available HCV NS5A protease inhibitor.

    Merck's Global Commitment to Development of Hepatitis Therapies

    Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. In hepatitis C, company researchers developed the first approved therapy for chronic HCV in 1991 and the first combination therapy in 1998. In addition to ongoing studies for our marketed and investigational medicines for the treatment of chronic HCV, extensive research efforts are underway to develop additional oral therapies for viral hepatitis treatment.

    About Daclatasvir

    Daclatasvir is an NS5A replication complex inhibitor that is being extensively studied as a key component of potential direct-acting antiviral (DAA) based hepatitis C treatment regimens. Studied in more than 4,100 patients to date, daclatasvir is in Phase III development.

    About Merck

    Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside of the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

    Merck forward-Looking Statement

    This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

    Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

    Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2012 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

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