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EASL 2015: Grazoprevir/ Elbasvir Is Highly Effective for Previously Untreated Hepatitis C


A 12-week course of the combination of grazoprevir and elbasvir cured 95% of previously untreated people with hepatitis C virus gentoypes 1, 4, or 6, according to results of the C-EDGE trial presented at the European Association for the Study of the Liver (EASL) 50th International Liver Congress last week in Vienna. However, the study also showed that people with higher baseline HCV viral load and genotype 1a may have a poorer response to this combination, particularly if they have naturally occurring HCV variants that are less sensitive to drugs from the NS5A inhibitor class.

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Grazoprevir (an HCV NS3/4 protease inhibitor) and elbasvir (a NS5A inhibitor) are being developed by Merck. The combination is being studied as a once-daily single-tablet regimen, with or without ribavirin. The 2 drugs are active against multiple genotypes of HCV.

The study, presented Stefan Zeuzem of Goethe University Hospital in Frankfurt and published online in Annals of Internal Medicine, is known as C-EDGE, and forms part of a suite of studies that include previously untreated, treatment-experienced, and HIV/HCV coinfected patients. Results from the treatment-experienced and coinfection C-EDGE studies are reported in a separate article.

C-EDGE was an international Phase 3 clinical trial in which participants were randomly assigned to receive immediate treatment with a fixed-dose combination of grazoprevir (100 mg) and elbasvir (50 mg) once-daily for 12 weeks (n=316), or to receive a placebo for 12 weeks followed by active open-label grazoprevir/elbasvir treatment for 12 weeks (n=105). No one received ribavirin in this study. The study arms were stratified by genotype and by cirrhosis status to ensure equal distribution.

The study population was predominantly white (63%), 46% were women, and 91% had genotype 1 infection. 22% had cirrhosis and 70% had HCV RNA above 800,000 IU/mL.

Overall, 95% of patients in the immediate-treatment arm achieved SVR12, or sustained undetectable viral load 12 weeks after completion of therapy. When broken down by genotype, 99% of the genotype 1b participants achieved SVR12, compared to 92% of genotype 1a participants, 100% of genotype 4 participants, and 80% of genotype 6 participants. Virological failure was almost entirely due to post-treatment relapse (12 cases), with only 1 case of viral breakthrough during therapy.

The only baseline factor significantly associated with achieving sustained virological response was baseline viral load: participants with baseline HCV RNA below 800,000 IU/mL were significantly more likely to achieve SVR12 than those with higher levels (100% vs 92%).

Analysis of outcomes by baseline resistance-associated variants (RAVs) showed that the presence of NS3 (protease) RAVs made no difference to response in genotype 1a or genotype 1b patients. In fact, genotype 1a participants without RAVs showed a non-significant trend towards worse response than participants with RAVs, when compared to genotype 1b: 89% (1a) vs 100% (1b) in those without, compared to 97% vs 96% in those with RAVs.

However, when participants were compared according to baseline RAVS in the NS5A region, genotype 1a participants with baseline RAVs had significantly poorer responses than those without (58% vs 99%). Where baseline RAVs conferred a greater than 5-fold loss of sensitivity to elbasvir, 22% of participants achieved SVR12, compared to 100% in those with less than 5-fold loss of sensitivity.

In ION-3, the Phase 3 study of sofosbuvir/ledipasvir, viral load only became a factor affecting response when baseline viral load was above 6 million IU/mL, according to an ad hoc analysis presented at the ID Week 2014 conferencelast October. Otherwise, virological outcomes were very similar to those reported in the ION-3 study, across genotypes 1a and 1b and between cirrhotic and non-cirrhotic patients.

The grazoprevir/elbasvir combination was well tolerated, with no significant difference in reports of the most common adverse events -- headache, fatigue, nausea, and arthralgia -- between the active treatment and placebo arms. There was also no difference in reports of serious adverse events between the 2 arms (2.8% and 2.9%). Patients with cirrhosis were no more likely to experience adverse events.

The grazoprevir/elbasvir combination pill is due to be submitted for regulatory approval in the U.S., Europe, and other countries shortly, and may be approved by the end of 2015. It will be the third all-oral, interferon-free combination to be marketed exclusively by one company, and will enter a market where AbbVie’s 3D combination treatment (Viekira Pak in the U.S., Viekirax and Exviera in the European Union) is trailing behind Gilead Sciences' sofosbuvir/ledipasvir (Harvoni).

Merck is seeking to demonstrate that its combination addresses unmet needs and provides benefit for specific populations. A number of studies at the International Liver Congress have reported on the use of the combination in people with chronic kidney disease, advanced cirrhosis, highly treatment-experienced patients, and people with HIV/HCV coinfection.

Merck is also seeking to reduce the duration of hepatitis C treatment and to prove that their combination is active across as many genotypes as possible, in order to simplify the delivery of treatment and to make it practical for primary care physicians to treat people with hepatitis C who do not have major complications such as decompensated cirrhosis or post-transplant patients, company spokesman Eliav Barr said at a Merck press conference on Friday.

Asked about the place of the grazoprevir/elbasvir combination pill in clinical practice, Zeuzem said, "I love competition, so we should have as many regimens with excellent virological response as possible. There is still space for treatment individualization, and still only 2 combinations in a single pill."

Rajender Reddy of University of Pennsylvania School of Medicine, speaking at an EASL press conference, agreed that choice of regimens would be important for physicians and patients, and pointed to the strong performance of the Merck combination in patients with genotype 4 infection.



S Zeuzem, R Ghalib, KR Reddy, et al. The phase 3 EDGE treatment-naïve study of a 12-week oral regimen of grazoprevir (GZR / MK-5172) / elbasvir (EBR, MK-8742) in patients with chronic HCV genotype (GT) 1, 4 or 6 infection. 2015 International Liver Congress: 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, April 22-26, 2015. Abstract G07.

S Zeuzem, R Ghalib, KR Reddy, et al. Grazoprevir–Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic HCV Genotype 1, 4, or 6 Infection: A Randomized Trial. Annals of Internal Medicine. April 24, 2015 (Epub ahead of print).

Other Source

Merck. Merck’s Pivotal Phase 3 C-EDGE Program Evaluating Grazoprevir/Elbasvir Shows High Sustained Virologic Responses Across Broad Range of Patients with Chronic Hepatitis C Virus Infection. Press release. April 24, 2015.