Grazoprevir / elbasvir highly effective in previously untreated hepatitis C

A 12-week course of the combination of grazoprevir and elbasvir cured 95% of previously untreated people with genotypes 1, 4 or 6 hepatitis C virus (HCV), according to results of the C-EDGE trial, presented on Friday at the International Liver Congress in Vienna, Austria.

However, the study also showed that people with higher baseline HCV viral load and genotype 1a infection may have a poorer response to this combination, particularly if they have naturally occurring HCV variants that are less sensitive to suppression by drugs from the NS5A inhibitor class.

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

Glossary

cirrhosis

Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. 

sustained virological response (SVR)

The continued, long-term suppression of a virus as a result of treatment. In hepatitis C, refers to undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 12 or 24 weeks after ending treatment and is considered to be a cure (SVR12 or SVR24).

ribonucleic acid (RNA)

The chemical structure that carries genetic instructions for protein synthesis. Although DNA is the primary genetic material of cells, RNA is the genetic material for some viruses like HIV.

 

phase III

The third and most definitive stage in the clinical evaluation of a new drug or intervention, typically a randomised control trial with the new intervention compared to an existing therapy or a placebo, in large numbers of participants (typically hundreds or thousands). Trial results are used to evaluate the overall risks and benefits of the drug and provide the information needed for regulatory approval.

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

The study presented at the International Liver Congress by Dr Stefan Zeuzem of the Goethe University Hospital, Frankfurt, Germany, and published online today in Annals of Internal Medicine, is known as C-EDGE, and forms part of a suite of studies involving people who have not previously taken hepatitis C treatment, people who do have previous experience of treatment, and people with HCV and HIV co-infection. Results from the treatment-experienced C-EDGE study are reported in a separate article.

C-EDGE was an international phase III randomised trial, in which participants were randomly assigned to receive immediate treatment with a fixed-dose combination of grazoprevir (100mg) and elbasvir (50mg) once daily for 12 weeks (n = 316), or to receive a placebo for 12 weeks followed by active open-label 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. Twenty-two per cent had cirrhosis. Seventy per cent had HCV RNA (viral load) above 800,000 IU/ml.

Overall, 95% of the immediate-treatment arm achieved sustained virological response twelve weeks post-treatment, known as SVR12 (95% confidence interval 92-97%). When broken down by genotype, 99% of the participants with genotype 1b achieved SVR12 (n = 131), compared to 92% of participants with genotype 1a (n = 157), 100% of participants with genotype 4 (n = 10) and 80% of participants with genotype 6 (n = 70). Virological failure was almost entirely due to post-treatment relapse (12 cases), with only one case of viral breakthrough during therapy.

The only baseline factor significantly associated with achieving a sustained virological response was baseline HCV RNA: participants with baseline HCV RNA below 800,000 iu/ml were significantly more likely to achieve SVR12 (100% vs 92.3%).

Analysis of outcomes by baseline resistance-associated variants (RAVs) showed that presence of NS3 (protease) RAVs made no difference to response in participants with genotype 1a or genotype 1b. In fact, participants with genotype 1a 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 fivefold loss of sensitivity to elbasvir, SVR was achieved in 22% of participants, compared to an SVR rate of 100% in those with less than fivefold loss of sensitivity.

In ION-3, the phase III study of sofosbuvir/ledipasvir (Harvoni), 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 conference in October 2014. Otherwise, virological outcomes were very similar to those reported in the ION-3 study, across genotypes 1a and 1b and between people with and without cirrhosis.

The combination was well tolerated, with no significant difference in reports of the most common adverse events – headache, fatigue, nausea and arthralgia (joint pain) – between the active treatment and placebo arms. There was no difference in reports of serious adverse events between the two study arms (2.8% and 2.9%). People 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 United States, 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 combination treatment (Viekira Pak in the United States, Viekirax and Exviera in the European Union) is trailing badly in competition with Gilead’s Harvoni (sofosbuvir/ledipasvir).

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

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 Dr Eliav Barr said at a press conference on Friday.

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

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

References

Zeuzem S 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. J Hepatology 62 (50th International Liver Congress, Vienna), abstract G07, 2015.

Zeuzem S 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, online advance publication, 24 April 2015.