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.


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.

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.”

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.
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
2 MK-5172 (100 mg) + MK-8742 (50 mg) + ribavirin 24 70% / 30% 23/24
3 MK-5172 (100 mg) + MK-8742 (50 mg) 12 0% / 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

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  1. Thank you Merck and my study staff for this opportunity !!! I am 79, genotype 1a with cirrhosis, treatment naive in week 8 of new trial with riba. Was <25 weeks 1 and 2 UND week 4 .Week 8 labs being done Nov 6th.. No side effects so far.

  2. Wishing you a safe and successful journey.