In November 2015, at the AASLD Liver Meeting, researchers unveiled promising findings from the phase 2 C-CREST trial. They tested an 8-week, interferon-free regimen combining Merck’s grazoprevir, the NS5A inhibitors elbasvir or MK-8408, and the experimental nucleotide polymerase inhibitor MK-3682. This treatment achieved cure rates exceeding 90% in hepatitis C patients without cirrhosis across genotypes 1, 2, and 3.
The advent of direct-acting antiviral agents (DAAs) has revolutionized hepatitis C treatment, with most studies showing cure rates of 90% or better for combination therapy taken for 12 or 24 weeks. However, there remains room for more effective drugs for difficult-to-treat patients, including those with HCV genotype 3. Shorter therapy durations would also be less expensive and improve convenience and potentially adherence.
Dr. Edward Gane from Auckland Clinical Studies in New Zealand and colleagues conducted the C-CREST study to evaluate the safety and efficacy of all-oral regimens consisting of three DAAs: the NS3/4A HCV protease inhibitor grazoprevir (formerly MK-5172), the HCV NS5B polymerase inhibitor MK-3682, and an NS5A inhibitor—either elbasvir (formerly MK-8742) or MK-8408.
Grazoprevir plus elbasvir taken for 12 weeks has demonstrated good efficacy in phase 3 trials for previously untreated people and prior non-responders to interferon-based therapy. A co-formulation of these drugs, marketed as Zepatier, has been approved for use in the US and Europe. Dr. Gane’s team assessed whether adding a third antiviral targeting a different step in the HCV lifecycle might allow treatment to be shortened to 8 weeks without reducing effectiveness.
C-CREST 1 and 2 Part A included a total of 240 previously untreated chronic hepatitis C patients without cirrhosis. C-CREST 1 enrolled 93 people with HCV genotype 1 (46 with subtype 1a and 47 with 1b) and 61 with genotype 2, while C-CREST 2 enrolled 86 patients with genotype 3. About half of the participants were men, more than 90% were white, and the median age was approximately 48 years. Most had absent to moderate liver fibrosis (stage F0-F2), but about 7% had advanced fibrosis (stage F3). People with HIV or hepatitis B co-infection, significant laboratory abnormalities, or liver cancer were excluded.
Participants in this open-label study were randomly allocated to four once-daily 8-week regimens containing 100mg grazoprevir, 300 or 450mg MK-3682, and either 50mg elbasvir or 60mg MK-8408. None of the regimens included ribavirin. The primary endpoint was sustained virological response, or continued undetectable HCV viral load at 12 weeks after completing treatment (SVR12).
Among participants with HCV genotype 1, the SVR12 rate was 98% for both subtype 1a and 1b, with two relapses in the arm assigned to grazoprevir, 450mg MK-3682, and MK-8408. Among people with HCV genotype 2, the regimen containing grazoprevir, 450mg MK-3682, and MK-8408 was highly effective, with an SVR12 rate of 94%. However, regimens containing 300mg MK-3682 or elbasvir were less effective, with SVR12 rates ranging from 60 to 71%. Among people with HCV genotype 3, the overall SVR12 rate was 91%, with no significant differences across treatment arms (86 to 95%).
No treatment-emergent NS5A resistance-associated variants (RAVs) were detected in the two relapsers with genotype 1. Genotype 3 patients with NS5A RAVs at baseline had a lower response rate (85%), and one of the three relapsers had a treatment-emergent Y93H variant.
All regimens were generally well tolerated, and all study participants completed the full 8 weeks of treatment. There were no drug-related serious adverse events, and no participants discontinued therapy due to adverse events. The most common drug-related adverse events were headache (23%), fatigue (20%), and nausea (13%). There were no consistent treatment-related differences in laboratory tests, vital signs, ECG (cardiac), or kidney safety parameters.
“An 8-week regimen of grazoprevir/MK-8408/MK-3682 (450mg) was highly effective, with SVR12 >90% in treatment-naive, non-cirrhotic patients with HCV genotype 1, 2, or 3 infection,” the researchers concluded. “[Treatment] was generally safe and well tolerated, with no discontinuations due to adverse events and no cardiac or renal signals.” They added that the results of Part A “support further evaluation of this pan-genotypic three-drug combination among a diverse population of HCV-infected patients, including those with additional HCV genotypes, cirrhosis, prior treatment, and HIV/HCV co-infection.”
Based on the results from this initial trial, Merck indicated in a press release that it has initiated a further study of grazoprevir (100mg), MK-3682 (450mg), and MK-8408 (60mg) in Part B of the C-CREST phase 2 clinical development program.