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AASLD 2013: Merck Interferon-free Regimen Shows High Hepatitis C Cure Rate in Early Study

A 2-drug combination of direct-acting antivirals developed by Merck, MK-5172 and MK-8742, with or without ribavirin, achieved very high cure rates in patients with genotype 1 hepatitis C in a small study presented this week at the 64th AASLD Liver Meeting in Washington, DC.

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The C-WORTHY study compared a combination of 2 drugs with and without ribavirin in patients with genotype 1a and 1b hepatitis C virus (HCV) infection. Merck is slightly behind several other pharmaceutical companies in its progress towards the development of interferon-free drug combinations for treatment of chronic hepatitis C.

Current hepatitis C treatment is based on the use of a first-generation direct-acting antiviral in combination with pegylated interferon and ribavirin. Both interferon and ribavirin are poorly tolerated by many people, especially in extended courses of treatment that may last more than a year in some cases. Numerous pharmaceutical companies are working to develop interferon-free regimens that can cure hepatitis C within 12 to 24 weeks.

The role of ribavirin in future treatment is less clear. Phase 2 studies of other direct-acting antivirals have indicated that, for HCV subtype 1a at least, ribavirin improves the cure rate. Ribavirin may not be necessary for patients with genotype 1b infection. Subtype 1b has a higher barrier to the development of drug resistance than 1a. This raises the possibility that patients with genotype 1b may be able to use 2 highly potent direct-acting antivirals without ribavirin to achieve a cure with 12 weeks of treatment, potentially reducing the risk of side effects.

C-WORTHY tested a combination of the HCV protease inhibitor MK-5172 and the NS5A inhibitor MK-8742, with or without ribavirin, for 12 weeks. The study recruited patients with less advanced liver disease (stage F0 to F2, or absent to moderate fibrosis) and no previous treatment experience, a population with a higher prospect of responding to treatment than patients with cirrhosis.

The study compared 3 regimens, all given for 12 weeks:

• Arm 1: MK-5172 (100 mg once-daily) + MK-8742 (20 mg once-daily) + ribavirin (600-1400 mg/day) (stratified by genotype 1a vs 1b);
• Arm 2: MK-5172 (100 mg once-daily) + MK-8742 (50 mg once-daily) + ribavirin (stratified by genotype 1a vs 1b);
• Arm 3: MK-5172 (100 mg once-daily) and MK-8742 (50 mg once-daily) (genotype 1b only).

The study enrolled 65 participants, but 7 patients were excluded from the primary analysis because they received incorrect doses of ribavirin (4) or because they discontinued study medication for protocol violations or due to withdrawal of study consent. Primary results are detailed in the table below:

A single case of virological relapse occurred within 4 weeks of completion of treatment. Drug level testing revealed that despite achieving an undetectable viral load at week 2 of treatment, the patient had low drug levels, resulting in viral rebound.

Presenter Eric Lawitz from the Texas Liver Institute noted that the addition of ribavirin made little difference to the speed at which virus levels declined after starting treatment.

Almost 1 in 5 patients (19%) in the ribavirin-containing arms developed anemia (hemoglobin <10 mg/dL) in this 12-week study, but no trial participants stopped treatment as a consequence of developing anemia. There were 7 cases of rash observed in the ribavirin-containing arms, but not all were attributable to ribavirin, said the investigators.

Other common side effects included fatigue (26%), headache (22%), nausea (18%), diarrhea (12%), and dizziness (11%).

The C-WORTHY study is also testing the 2 Merck drugs, with and without ribavirin, in cirrhotic and HIV/HCV coinfected people, as well as in previous non-responders to pegylated interferon and ribavirin. Results from these study arms will be presented at future scientific conferences in 2014.

11/6/13

Reference

E Lawitz, JM Vierling, A Murillo, et al. 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.64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. Abstract76.