Clinical Findings Support Advancement into Phase 3 Trials
Thursday, April 10, 2014 1:00 am EDT
WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside of the United States and Canada, today announced additional data from the ongoing C-WORTHy study, a multi-arm Phase 2 clinical trial evaluating the efficacy and safety of a once-daily, all-oral regimen combining MK-5172, an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor, and MK-8742, an investigational HCV NS5A replication complex inhibitor, among patients with chronic HCV Genotype 1 infection (GT1). In an interim analysis of treatment-naïve, non-cirrhotic patients administered a 12-week regimen of MK-5172/MK-8742, with and without ribavirin (RBV), a sustained viral response1 (SVR) was observed in 98 percent (42/43) of patients administered MK-5172/MK-8742 alone and 94 percent (75/80) in those administered MK-5172/MK-8742 plus RBV. These data were presented, along with data on an 8-week regimen, at the 49th Annual Meeting of the European Association for the Study of the Liver (EASL), also known as The International Liver Congress™ 2014, in London, UK.
“These Phase 2 results add to growing evidence for the potential efficacy of MK-5172 and MK-8742 for treatment of chronic HCV infection,” said Dr. Eliav Barr, vice president, Infectious Diseases, Merck Research Laboratories. “These findings are integral to advancing our research of these investigational candidates into C-EDGE, the Phase 3 clinical program that will seek to more broadly evaluate the potential of MK-5172/MK-8742 in diverse patient populations.”
C-WORTHy Study Design
C-WORTHy is a two-part, parallel-group, randomized (within group) clinical trial evaluating a range of subpopulations of patients with HCV GT1 infection. The study evaluated different treatment durations of MK-5172 (100 mg once daily) plus MK-8742 (50 mg once daily), with or without RBV. A total of 471 patients with HCV GT1 RNA levels of ≥10,000 IU/mL were enrolled in C-WORTHy across 16 arms.
Key Findings for MK-5172/MK-8742
The interim results presented were from treatment-naïve, non-cirrhotic patients who received one of 3 regimens: A) MK-5172/MK-8742 + RBV for 8 weeks (N=30), B) MK-5172/MK-8742 + RBV for 12 weeks (N=85), and C) MK-5172/MK-8742 (without RBV) for 12 weeks (N=44), (see table 1).
Table 1 – Interim Results from the C-WORTHy Trial Showing Treatment-Naïve, Non-Cirrhotic Patients with HCV GT1 Infection (Intention-to-Treat (ITT) Analysis)
|Parameter||MK-5172 + MK-8742 |
|MK-5172 + MK-8742 + RBV |
(N = 85)
|MK-5172 + MK-8742 + |
|SVR4-24†, % (n)||98% (43)||94% (80)||83% (25)|
|No SVR, % (n)|
|Relapse||2% (1)||1% (1)||17% (5)|
|Non-virologic Discontinuation||0||4% (3)||0|
|GT1a||97% (29)||94% (49)||83% (25)|
|GT1b§||100% (14)||94% (31)||--|
† Part A: 100% of patients completed Follow-up week (FU)24; Part B: 8 week arm: 93% have completed FU8; 12 week arm: 100% of patients have completed FU4; 2 patients (Part A) and 1 patient (Part B) discontinued early and are counted as failures.
§ Two patients with GT1 (non-a, non-b) were enrolled; these are analyzed with GT1b.
Among the five patients who relapsed in the eight-week regimen arm of PN035B, two patients had very low MK-5172 and MK-8742 levels during the course of therapy. The relationship between this finding and the relapse is being investigated.
The most common adverse events recorded in the RBV and RBV-free treatment groups, respectively, were fatigue (32%, 23%), headache (20%, 33%), nausea (21%, 16%), diarrhea (13%, 9%) and insomnia (13%, 7%). There were no early discontinuations due to drug-related adverse events and no clinically significant abnormalities detected in routine laboratory analysis of hematologic markers.
PN038 Study Design and Findings
Additionally, new data from PN038, a Phase 2 dose-ranging clinical trial evaluating MK-5172 once-daily with peginterferon alfa-2b and ribavirin (PR, weekly), were presented, evaluating SVR24 in treatment-naïve, non-cirrhotic patients with GT1 infection. PN038 is a Phase 2 clinical trial investigating the efficacy and safety of MK-5172 doses (25 mg, 50 mg, and 100 mg) once-daily with PR over a 12-week treatment cycle in GT1 treatment-naïve, non-cirrhotic patients (n=87). The analysis presented was ITT, in which all patients who did not achieve SVR (including those who dropped out for non-virologic reasons), were recorded as failures.
MK-5172 at doses of 50 mg and 100 mg with PR for 12 weeks of treatment achieved SVR24 rates of 75.0 percent (21/28) and 83.3 percent (25/30), respectively, supporting use of MK-5172 below 100 mg dose (see table 2).
Table 2: PN038 Virologic Responses – (ITT Analysis)
|Patients with HCV RNA <25 IU/mL / total # of patients (%)|
|MK-5172 25 mg |
|MK-5172 50 mg |
|MK-5172 100 mg |
|TW*4||93.1% (27/29)||96.4% (27/28)||100.0% (30/30)|
|TW12||93.1% (27/29)||96.4% (27/28)||96.7% (29/30)|
|SVR12||48.3% (14/29)||75.0% (21/28)||86.7% (26/30)|
|SVR24||48.3% (14/29)||75.0% (21/28)||83.3% (25/30)|
The most common recorded adverse experiences recorded across all treatment arms were: fatigue (61%), headache (46%), nausea (43%), and decreased appetite (43%). These adverse experiences did not appear to be dose-related.
One patient discontinued therapy after seven days of dosing with MK-5172 100 mg, plus PR and experienced muscle inflammation (creatine kinase >5x upper limits of normal [ULN]), elevated transaminases to >3x ULN, and total bilirubin >2x ULN, associated with a positive toxicology screen for ethanol. There were no other clinically significant transaminase elevations recorded in this study.
About Merck’s Phase 3 HCV Program: C-EDGE
Based on the results of the Phase 2 clinical program, Merck has initiated Phase 3 clinical trials for MK-5172/MK-8742. The Phase 3 program, called C-EDGE, will evaluate the safety and efficacy of MK-5172/MK-8742 with and without ribavirin in various genotypes and across a broad range of patient populations with chronic HCV. Study cohorts will include: C-EDGE TN (GT1, GT4-6; treatment-naive ± cirrhosis), C-EDGE CO-INFXN (GT1, GT4-6; treatment-naive ± cirrhosis with HIV/HCV co-infection), C-EDGE RECOVERY (GT1, GT4-6; treatment-naive ± cirrhosis; ± HIV/HCV co-infection on opiate substitution therapy), and C-EDGE TE (GT1, GT4-6; prior failed treatment with peginterferon/ribavirin; ± HIV/HCV co-infection). Study information can be found at www.clinicaltrials.gov.
Merck’s Commitment to HCV
For more than 25 years, Merck has been at the forefront of the response to the HCV epidemic. Merck employees are dedicated to applying their scientific expertise, resources and global reach to deliver healthcare solutions that support people living with HCV worldwide.
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1 Defined as HCV RNA below the limit of quantification or below the limit of detection at the last visit on record – 4, 8, 12, or 24 weeks after the completion of therapy
Caroline Lappetito, 267-305-7639
Sarra Herzog, 201-669-6570
Carol Ferguson, 908-500-1101
Justin Holko, 908-423-5088