Merck interferon-free combination shows high hepatitis C cure rate in early study

A two-drug combination of direct-acting antivirals developed by Merck achieved very high cure rates, with and without ribavirin, in patients with genotype 1 hepatitis C infection in a small study presented on Sunday at the 64th Meeting of the American Association for the Study of Liver Diseases (the Liver Meeting) in Washington DC.

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

Current hepatitis C treatment is based on the use of a direct-acting antiviral in combination with pegylated interferon and ribavirin. Both pegylated interferon and ribavirin are poorly tolerated by many people, especially in extended courses of treatment that may last more than one 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 II studies of other direct-acting antivirals have indicated that, for genotype 1a at least, ribavirin improves the cure rate. It is less clear that ribavirin treatment will be necessary for patients with genotype 1b infection.

Genotype 1b HCV has a higher barrier to the development of drug resistance than genotype 1a. This raises the possibility that patients with genotype 1b infection may be able to use two highly potent direct-acting antivirals without ribavirin to achieve a cure with 12 weeks of treatment, potentially reducing the risk of side-effects.

The C-WORTHY study 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 (F0 to F2 fibrosis) and no previous experience of treatment, a population with a higher prospect of responding to treatment than patients with cirrhosis.

The study compared three 12-week regimens:

• Arm 1: MK-5172 (100 mg once daily), MK-8742 (20 mg once daily) plus ribavirin (600-1400 mg/d) (stratified by genotype 1a vs 1b)
• Arm 2: MK-5172 (100 mg once daily), MK-8742 (50 mg once daily) plus 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).

All treatment was given for 12 weeks.

The study enrolled 65 patients, but seven 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.

One case of virological relapse occurred within four 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.

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

Almost one-in-five patients in the ribavirin-containing arms developed anaemia (haemoglobin < 10mg/dL) (19%) in this 12-week study, but no trial participants either stopped treatment or required treatment as a consequence of developing anaemia. Seven cases of rash were 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%), diarrhoea (12%), dizziness (11%) and rash (11%).

The C-WORTHY study is also testing the two drugs, with and without ribavirin, in cirrhotic and HIV co-infected 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.