Monday, November 10, 2014

UPDATED: Merck's hepatitis C cocktail drug fails a 4-week challenge

UPDATED: Merck's hepatitis C cocktail drug fails a 4-week challenge

November 10, 2014 | By John Carroll

After sending out signals that it might be running into trouble with a short-duration study of a new triple combination drug for its hepatitis C regimen, Merck ($MRK) investigators hailed the clear success of an 8-week test but confirmed analysts' fears in a batch of 4-week data released at the meeting of the American Association for the Study of Liver Diseases.
A mix of grazoprevir/elbasvir (MK-5172/MK-8742, MK-5172A)--the company's investigational NS3/4A protease inhibitor and NS5A inhibitor, in combination with Gilead's Sovaldi (sofosbuvir), an NS5B nuc inhibitor, clearly hit the mark with a 94.7% cure rate for treatment naïve cirrhotic patients at 8 weeks. But the combination fell well short of the goal line on efficacy at 4 weeks, with a cure rate of 38.7%. At 6 weeks the triple hit an 80% cure rate in the treatment-naïve group of cirrhotic patients while the non-cirrhotic cohort hit 86.7%--shy of the 90% level some analysts believe Merck is likely to face as a competitive hurdle cleared by rivals. All the patients in the study were genotype 1.
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Merck’s Four-Week Hepatitis C Regimen Fails to Top Gilead
Merck & Co. (MRK) won’t move forward with an ultra-short hepatitis C regimen that attempted to cut treatment durations in half by combining two of its drugs with another from Gilead Sciences Inc.

Patients in the mid-stage, 102-person trial got Merck’s experimental drugs grazoprevir and elbasvir, along with Gilead’s Sovaldi, for as little as four weeks, with the length of treatment based partly on how severe their infection was.

In patients whose livers weren’t already badly damaged by the virus, 38.7 percent were cured in four weeks and 86.7 percent were cured in six weeks, according to data to be presented at the American Association for the Study of Liver Diseases conference in Boston.

That’s well below the 90 percent-plus cure rates seen with longer treatments. Merck won’t take the four-week course into a new round of testing, said Eliav Barr, the company’s vice president of infectious diseases...

Merck's hepatitis C regimen is only disappointing because improvements in treatments for the viral liver disease have progressed at a rapid and remarkable rate. Five years ago, the best treatment for hepatitis C required weekly injections and twice-daily pills for one year. At best, about half of hepatitis C patients were cured but only after enduring debilitating side effects, including flu-like symptoms and anemia.

Merck 4-week hep C regimen with Gilead's Sovaldi comes up short

Nov 9 (Reuters) - An attempt by Merck & Co to shorten hepatitis C treatment to just four weeks by adding Gilead Sciences Inc's huge selling Sovaldi to its own oral two-drug combination came nowhere near the desired efficacy due to a high rate of relapses, according to interim data from a midstage study.

Several companies have been working to find ways to further reduce the number of weeks of treatment needed, while keeping cure rates above 90 percent.

A just approved pill called Harvoni that combines Sovaldi with another Gilead drug requires eight weeks of treatment for many patients, and longer for tougher to treat patients.

In the ongoing Merck trial of previously untreated patients, only 38.7 percent had no detectable sign of the liver destroying virus after four weeks of treatment with Sovaldi and Merck's grazoprevir/elbasvir combination. Nineteen of the 31 patients in the four-week treatment arm relapsed prior to the planned end of the study, which is 12 weeks after completion of dosing.

The preliminary data was set to be presented on Monday at the American Association for the Study of Liver Diseases (AASLD) meeting in Boston.

The best result so far in the multi-arm, three-drug study called C-Swift was observed with eight weeks of treatment of patients with cirrhosis in which 94.7 percent had no detectable virus. They will be deemed cured if the virus has not reappeared 12 weeks after stopping treatment.

With a six-week regimen in non-cirrhotics, 86.7 percent of patients had no sign of virus up to 8 weeks after completing treatment, according to the interim results.

"These findings will inform the design of larger studies aimed at understanding the potential of short-duration triple therapy across multiple patient types," Dr. Eric Lawitz, the study's lead investigator, said in a statement.

The three drugs each work in a different way to help prevent the virus from replicating. But following failure of the 4-week experiment, Merck said it will turn its attention to studying a combination of three of its own drugs in development rather than involving the Gilead medicine in future studies.

The hepatitis C field has been moving at a lightning pace. Only a handful of years ago, patients needed 48 weeks of treatment with drugs that had harsh side effects and only cured about 40 percent of patients.

The new all-oral treatments eliminate the need for injectable interferon and its flu-like side effects, as well as another older drug called ribavirin that caused anemia and other problems, while dramatically increasing cure rates and reducing treatment duration.
(Reporting by Bill Berkrot; Editing by Chris Reese)

Interim Data from Proof-of-Concept Study of Merck’s Investigational Hepatitis C Treatment Grazoprevir/Elbasvir in Combination with a Nucleotide Inhibitor (C-SWIFT study) Presented at The Liver Meeting®
BOSTON--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the presentation of interim data from the C-SWIFT study exploring the potential of a candidate triple-therapy regimen consisting of the fixed-dose combination of grazoprevir/elbasvir (MK-5172/MK-8742, MK-5172A), the company’s investigational NS3/4A protease inhibitor and NS5A inhibitor, in combination with sofosbuvir, a nucleotide (NS5B) inhibitor for the treatment of chronic hepatitis C virus (HCV) infection. Preliminary findings in treatment-naïve HCV genotype 1- (GT1) infected non-cirrhotic patients, following six and four weeks of treatment, and patients with cirrhotic disease, following eight and six weeks of treatment, will be presented by Dr. Eric Lawitz, vice president, scientific and research development, The Texas Liver Institute, San Antonio, TX and C-SWIFT lead investigator. This poster presentation is part of a late-breaking abstract session at the 65th American Association for the Study of Liver Diseases (AASLD) Annual Meeting, also known as The Liver Meeting®.

“These interim data provide a compelling proof-of-concept for the potential of an eight- or six-week triple therapy course in treatment-naive patients with genotype 1 disease, including cirrhotic patients,” said Dr. Lawitz. “These findings will inform the design of larger studies aimed at understanding the potential of short-duration triple therapy across multiple patient types.”

To date, the investigational triple therapy has shown response rates (sustained virologic response1 [SVR] at 4/8 weeks following therapy) ranging from 80 percent to 94.7 percent in cirrhotic and non-cirrhotic patients following six and eight weeks of treatment in this study, as shown in table 1. The four-week regimen resulted in sub-optimal efficacy.
Table 1
duration (weeks)
Virologic Failure*14419
*All treatment failures were due to relapses.
**21 patients enrolled; two patients discontinued; 18/19 (modified intent-to-treat).
Data includes week 8 follow up data for 99/102 patients (excludes 2 cirrhotic patients who discontinued).
All 28 patients not achieving SVR4/8 relapsed following the end of therapy. Of these patients, 25 (89%) were genotype 1a (GT1a) and three (11%) were genotype 1b (GT1b) [82% of enrolled subjects were infected with HCV GT1a at baseline]. Sequence analysis of virologic failures is so far available for 23 patients. Wild type virus was determined to be the cause in 12 of the relapsed patients. In the other relapsed patients, 10 had elbasvir-resistant viral variants and one had a variant resistant to both grazoprevir and elbasvir.

In this study, the co-administration of grazoprevir/elbasvir and sofosbuvir was generally well-tolerated. The most common adverse events associated with the triple regimen were: headache (4%), fatigue (2%) and nausea (2%). One patient withdrew from the study for reasons unrelated to treatment.

“Our goal is to establish a simple, effective, well-tolerated regimen that is applicable across the diverse population of patients with HCV,” said Dr. Eliav Barr, vice president, infectious diseases, Merck Research Laboratories. “The preliminary data provide us with the confidence to initiate our C-CREST study to evaluate a triple combination comprising Merck’s investigational candidates from three major therapeutic classes of HCV medicines.”


The C-SWIFT study enrolled a total of 102 treatment-naïve patients with HCV genotype 1 (GT1a and GT1b) infection at The Texas Liver Institute, San Antonio, TX. Treatment-naïve, non-cirrhotic patients were randomized to receive the fixed-dose combination of grazoprevir/ elbasvir (one pill containing 100 mg, 50 mg respectively) plus the nucleotide inhibitor sofosbuvir (400 mg) once daily for eight, six or four weeks. Similarly, treatment-naïve, cirrhotic patients were randomized to receive the investigational combination for either eight or six weeks. The primary endpoint of the study is the percentage of patients achieving sustained virologic response 12 weeks after the completion of therapy (SVR12). An additional analysis of patients with genotype 3 (GT3) HCV enrolled in the C-SWIFT study will be presented at a future scientific congress.


Based upon the interim findings from C-SWIFT and data from the Phase 1 clinical trial for MK-3682, also presented at The Liver Meeting®, Merck plans to initiate Phase 2 clinical trials evaluating the efficacy and safety of two short-duration triple therapy regimens: MK-3682 in combination with grazoprevir/elbasvir; and MK-3682 in combination with grazoprevir and Merck’s investigational early-stage NS5A inhibitor MK-8408, in non-cirrhotic HCV patients. Part A of the Phase 2 studies is planned to evaluate eight weeks of therapy among non-cirrhotic HCV-infected patients, and Part B studies may evaluate shorter courses of treatment based on findings from Part A.

MK-3682 (formerly IDX21437) Data Presentation at AASLD Annual Meeting

MK-3682 is an investigational oral prodrug HCV nucleotide analogue NS5B polymerase inhibitor. Phase 1/2a clinical trial results for MK-3682 are scheduled to be presented in a poster session (Abstract #1974) at The Liver Meeting®. HCV infected subjects (24 GT1 and 20 GT2/3) were randomized to receive placebo or 50, 150 or 300 mg of MK-3682 daily for seven days. Following initial pharmacokinetic and pharmacodynamic analysis, enrollment into the 50 mg and 150 mg treatment groups was discontinued due to a small reduction in viral load. In the 300 mg arms, the mean maximum viral load reductions from baseline for 7-day dosing were 4.6 and 4.1 log10 IU/mL in GT 2 (n=3) and GT 3 subjects (n=7), respectively. In GT1a (n=3) and GT1b subjects (n=5), the mean maximum viral load reductions from baseline for 7-day dosing were 4.8 and 3.9 log10 IU/mL respectively.

To date, no discontinuations due to an adverse event and no drug-related serious adverse events have been reported. Most adverse events were mild or moderate in intensity, with no apparent dose effect. There were no clinically significant abnormalities reported in routine blood and urine biomarker panels and physical examinations. Initial results from this study were previously announced by Idenix Pharmaceuticals in April 2014.

About Grazoprevir/Elbasvir

Grazoprevir/elbasvir (MK-5172/MK-8742, MK-5172A) is an investigational, oral, once-daily, fixed-dose combination chronic HCV treatment, consisting of grazoprevir, an investigational oral, once-daily HCV NS3/4A protease inhibitor, and elbasvir, an investigational oral, once-daily HCV NS5A replication complex inhibitor. In October 2013, Merck announced that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to grazoprevir/elbasvir for treatment of chronic HCV infection. Breakthrough therapy designation 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.

AASLD - Media Updates

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