- Category: Experimental HCV Drugs
- Published on Thursday, 17 April 2014 00:00
- Written by Liz Highleyman
A combination of 2 direct-acting antivirals, MK-5172 and MK-8742, with or without ribavirin, led to early post-treatment sustained response rates above 90% for genotype 1 hepatitis C patients, including people with cirrhosis or HIV/HCV coinfection, according to a series of presentations last week at the 49th EASL International Liver Congress in London.
The advent of direct-acting antiviral agents than can be used in interferon-free regimens has begun to revolutionize treatment for chronic hepatitis C, but variables such as the optimal duration of therapy, the need for ribavirin, and the best regimens for difficult-to-treat patient groups are not yet fully understood.
The Phase 2 C-WORTHY trial evaluated a regimen of Merck's HCV protease inhibitor MK-5172 and NS5A replication complex inhibitor MK-8742, taken with or without ribavirin, for treatment durations ranging from 8 to 18 weeks.
Researchers at the EASL meeting presented data on sustained virological response at 4 or 8 weeks after finishing treatment (SVR4 or SVR8). This is too soon to declare a cure, as relapse can still happen between then and 12 weeks post-treatment (SVR12), which is considered a cure.
Previously Untreated Patients
Christophe Hézode of Hôpital Henri Mondor in Paris presented findings from previously untreated patients without liver cirrhosis. About half were men, most were white, and the mean age was approximately 48 years. About 20% had the favorable IL28B CC gene variant. HCV genotype distribution varied across arms; some included only people with harder-to-treat 1a, some included only 1b, and some included both.
The investigators first compared regimens containing 100 mg MK-5172 plus either 20 mg or 50 mg MK-8742, both once-daily, with or without ribavirin, for 12 weeks. After seeing promising results, they then tested a shorter 8-week regimen of MK-5172 plus MK-8742 with ribavirin, focusing on subtype 1a.
As reported at last year's AASLD Liver Meeting, Part A of the study showed that triple therapy with MK-5172 plus MK-8742 produced SVR12 rates of 100% using the 20 mg dose and 96% using the 50 mg dose in a comparison of 52 people with HCV subtype 1a or 1b. Dual therapy, tested in 13 subtype 1b patients, also cured 100%.
In Part B, 30 genotype 1a patients were assigned to triple therapy for 8 weeks and 31 were assigned to ribavirin-free dual therapy for 12 weeks. Also, 33 patients with either subtype received triple therapy for 12 weeks.
Hézode presented data from Parts A and B combined, with follow-up durations ranging from 4 to 24 weeks post-treatment. Among participants treated for 12 weeks, 94% in the dual therapy arm and 98% in the triple therapy arm reached SVR4-SVR24. But the response rate was lower in the 8-week arm, at 83%. This was due to a higher proportion of post-treatment relapses (17%) despite the use of ribavirin. Relapse rates in the 12-weeks arms were just 1%-2%.
Cirrhotics and Null Responders
Eric Lawitz from the Texas Liver Institute presented data from a cohort of 123 treatment-naive patients with liver cirrhosis and another of 130 prior null responders to previous treatment with pegylated interferon/ribavirin, either with or without cirrhosis.
These cohorts again included a majority of white men but they were somewhat older (mean approximately 56 years). About 65% had HCV subtype 1a. One-third of treatment naive patients, but hardly any null responders, had the IL28B CC variant. In the null responder arm, about 40% had cirrhosis.
In both cohorts, participants were assigned to take MK-5172 plus MK-8742 (all now using the 50 mg dose), with or without ribavirin, for either 12 or 18 weeks. The rationale was that these traditionally harder-to-treat patients might benefit from longer therapy.
Looking at the treatment-naive cirrhotic group, with 4 to 8 weeks post-treatment follow-up, SVR4-SVR8 rates were 90% in the 12-week triple therapy arm (with 1 viral breakthrough during treatment and 2 relapses), and 97% in the 12-week dual therapy arm and in both the 18-week arms.
97% in the 12-week dual therapy arm (1 relapse), 97% in the 12-week dual therapy arm (1 early discontinuation), and 97% in the 18-week triple therapy arm (1 relapse).
Turning to the prior null responders, again with 4 to 8 weeks post-treatment follow-up, SVR4-SVR8 rates were 94% in the 12-week triple therapy arm (2 early discontinuations), 91% in the 12-week dual therapy arm (3 relapses), 100% in the 18-week triple therapy arm, and 97% in the 12-week dual therapy arm (1 viral breakthrough).
Comparing subgroups in the 2 cohorts combined, SVR4-SVR8 rates were 94% for HCV subtype 1a vs 99% for 1b. The response rate was 94% for cirrhotic subtype 1a patients (both treatment-naive and null responders) and 100% for cirrhotics with subtype 1b.
Finally, Mark Sulkowski from Johns Hopkins School of Medicine presented data from a cohort of 59 patients with HIV/HCV coinfection who were previously not treated for hepatitis C and did not have cirrhosis.
The coinfected group was 80% men and mostly white, with a mean age of 45 years. About 75% had HCV subtype 1a, 35% had the IL28B CC variant, and 10% had advanced liver fibrosis. They were on antiretroviral therapy containing raltegravir (Isentress) plus 2 NRTIs -- shown not to interact with the HCV drugs -- and had undetectable HIV viral load and a mean CD4 T-cell count above 600 cells/mm3.
Participants were randomized to received MK-5172 plus MK-8742 (50 mg), with or without ribavirin, all for 12 weeks.
SVR4 rates were 97% for the triple regimen and 90% for MK-5172 plus MK-8742 alone. There was 1 relapse in the ribavirin arm, and 2 HCV viral breakthroughs plus 1 loss to follow-up in the dual therapy arm. The 2 patients with HCV breakthrough had low blood drug levels suggesting poor adherence. There were no cases of HIV breakthrough. CD4 counts declined (-62 cells/mm3) in the ribavirin arm -- a known side effect -- but increased (+47 cells/mm3) in the dual therapy arm.
Across all cohorts, treatment with MK-5172 plus MK-8742 was generally safe and well-tolerated. Frequency of serious adverse events ranged from none to 7%, and there were few or no discontinuations due to adverse events. The most common side effects were fatigue, headache, nausea, diarrhea, insomnia and weakness. Anemia occurred in about 5%-10% of ribavirin recipients, but not in people taking the dual regimen.
Hezode's team concluded, "A 12-week regimen of MK-5172 + MK-8742 with or without ribavirin is a highly efficacious, safe, well tolerated, all-oral regimen with once-daily dosing." Hezode added that "ribavirin is not needed regardless of HCV genotype 1 subtype."
"MK-5172 + MK-8742 +/- ribavirin demonstrated high efficacy," Lawitz's team summarized. "In treatment-naive patients with cirrhosis, high efficacy was achieved regardless of use of ribavirin or extended treatment duration. In prior null responder patients, a 12-week ribavirin-free regimen resulted in >90% SVR4-SVR8."
Sulkowski's group concluded that, "Safety, tolerability, and efficacy in coinfected patients was similar to other patient populations in C-WORTHY."
Good response rates for people with HIV in several studies of direct-acting antivirals have led experts to suggest that coinfected patients should no longer be considered a "special" or difficult-to-treat population, as long as drug interactions with antiretrovirals are taken into account.
These results "support the hypothesis that HIV coinfection is not associated with poorer response to all-oral regimens," Sulkowski said. In fact, people with HIV on suppressive ART are known to have good adherence, which may predict future adherence to hepatitis C treatment as well. He added, however, that MK-5172 affects the CYP3A4 enzyme, so it could be "potentially problematic" with regard to interactions with certain antiretrovirals and other medication classes.
These findings support ongoing Phase 3 clinical trials testing MK-5172 + MK-8742 with or without ribavirin in various patient populations. Lawitz noted that a coformulation of the two Merck drugs is being developed.
C Hézode, L Serfaty, JM Vierling, et al. Safety and efficacy of the all-oral regimen of MK-5172/MK-8742 +/- ribavirin in treatment-naive, non-cirrhotic, patients with hepatitis C virus genotype 1 infection: the C-WORTHY study. 49th European Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract O10.
E Lawitz, C Hézode, E Gane, et al. Efficacy and safety of MK-5172 and MK-8742 +/- ribavirin in hepatitis C genotype 1 infected patients with cirrhosis or previous null-repsonse: the C-WORTHY study. 49th European Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract O61.
M Sulkowski, J Mallolas, S Pol, et al. Efficacy and safety of the all-oral regimen, MK-5172/MK-8742 +/- RBV for 12 weeks in GT1 HCV/HIV co-infected patients: the C-WORTHY study. 49th European Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract O63.
Merck. Merck Announces Results from Studies Evaluating Investigational Hepatitis C Treatments, MK-5172 and MK-8742, in Treatment-Naive Patients with Genotype 1 Infection. Press release. April 10, 2014.
Merck. Merck’s Investigational Chronic Hepatitis C Combination Therapy MK-5172/MK-8742 Demonstrates Antiviral Activity in Hard-to-Cure Patients with HCV Genotype 1 Infection. Press release. April 11, 2014.