MK-5172 boosts interferon/ribavirin response regardless of IL28B status

The experimental HCV protease inhibitor MK-5172 increased sustained response rates to over 90% when added to pegylated interferon/ribavirin in a study of previously untreated genotype 1 hepatitis C patients, researchers reported this week at the 48^th International Liver Congress (EASL 2013) in Amsterdam.

The advent of direct-acting antiviral agents (DAAs) has changed the treatment paradigm for chronic hepatitis C. While many patients and clinicians await all-oral regimens, pegylated interferon remains a mainstay of therapy for those with progressive liver disease who cannot afford to wait.

Michael Manns from Hannover Medical School and colleagues conducted a multicentre, phase II dose-ranging trial to evaluate MK-5172 as an add-on to pegylated interferon plus ribavirin for treatment-naive chronic hepatitis C patients without cirrhosis.

The analysis included 332 participants. Nearly 60% were men, a majority were white and the median age was 51 years. Regarding predictors of response, 75% had high baseline viral load, 61% had harder-to-treat HCV subtype 1a and 73% had unfavourable (non-CC) IL28B gene patterns.

Participants were randomly assigned to receive once-daily oral MK-5172 at doses of 100, 200, 400 or 800mg, along with standard doses of pegylated interferon and ribavirin for 12 weeks. At that point, using a response-guide therapy algorithm, those who had undetectable HCV RNA at week 4 continued pegylated interferon/ribavirin through week 24, while those with poorer response continued through week 48. A control group received the latest standard-of-care, the approved HCV protease inhibitor boceprevir (Victrelis) plus pegylated interferon/ribavirin.

Dr Manns presented results for sustained virological response, or continued undetectable HCV RNA at 24 weeks post-treatment (SVR24). At the time of analysis 311 of 332 patients (94%) had either reached 24 weeks of follow-up or discontinued before that point. The primary efficacy analysis included all randomised patients who received at least one dose of study drugs.

SVR24 rates were 86, 92, 91 and 87%, respectively, in the 100, 200, 400 and 800mg MK-5172 dose groups, indicating no clear dose-response effect. The response rate in the control arm was 54%; this was higher than control group response in most DAA trials – which typically compare to pegylated interferon/ribavirin alone – but lower than expected because many patients were still undergoing follow-up. Some patients who did not achieve SVR were found to have low blood drug concentrations, suggesting poor adherence.

Dr Mann also reported 'target not detectable at last visit', meaning rates of undetectable viral load at the last measurement among people who discontinued therapy for reasons other than virological failure, were still undergoing follow-up, or did not return for the 24-week post-treatment visit. These rates were a bit higher, 92, 99, 96 and 98% for the respective MK-5172 dose groups and 67% for the control arm.

Looking at the 100mg dose – the one Merck has decided test further – 91% of recipients had undetectable HCV RNA at week 4 and were eligible for the shorter 24-week course of response-guided therapy. Within this group, 90% achieved SVR24. Among those who did not qualify, 25% treated with the 48-week course were sustained responders.

Stratifying by response predictors, IL28B genotype had a minimal effect. SVR24 rates across MK-5172 doses ranged from 82 to 95% for people with favourable CC genotypes and from 85 to 91% for those with non-CC patterns. HCV subtype had a small influence on outcomes, with SVR24 rates ranging from 81 to 90% for genotype 1a compared with 92 to 100% for genotype 1b.

Turning to safety and tolerability, rates of serious adverse events were similar in the combined MK-5172 arms and the boceprevir arm (9 vs 8%), but there were half as many discontinuations due to adverse events among MK-5172 recipients (7 vs 14%). Rash (20 vs 27%) and anaemia (22 vs 36%) occurred more often in the boceprevir arm.

Some patients taking MK-5172 developed elevated bilirubin or transaminase (ALT or AST) liver enzyme levels, mostly in the higher-dose arms. In fact, a data safety monitoring board recommended that people in the 400mg and 800mg MK-5172 cohorts reduce their dose to 100mg due to transaminase elevations, which only occurred in one person taking the lowest dose. In most cases, bilirubin elevations occurred early and were moderate and transient, likely to be attributable to the drug's effect on transporters.

The researchers concluded that MK-5172 in combination with 24 or 48 weeks of pegylated interferon/ribavirin was "highly efficacious in inducing SVR24 in treatment-naive, non-cirrhotic patients with [genotype] 1 HCV infection".