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EASL 2015: Grazoprevir/ Elbasvir Combo Cures 99% of Hepatitis C Patients with Chronic Kidney Disease

Merck's once-daily combination of grazoprevir and elbasvir cured hepatitis C in almost all people with advanced chronic kidney disease, researchers reported at theEuropean Association for the Study of the Liver (EASL) 50th International Liver Congress last week in Vienna. The findings from the C-SURFER study are the first evidence that people with chronic kidney disease stand a very high chance of being cured using an interferon-free regimen, and will offer hope to a group of people with hepatitis C until now left behind by recent advances in antiviral treatment.

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Hepatitis C is associated with an increased risk of chronic kidney disease, although the mechanisms by which the HCV causes kidney damage are still unclear. People with hepatitis C also face more rapid progression of kidney disease once kidney function begins to decline, and as a consequence they are likely to reach a point where they need dialysis and kidney transplantation sooner. People with hepatitis C also have an increased risk of developing new onset diabetes after developing kidney disease.

If a kidney transplant is necessary, people with hepatitis C have a higher risk of transplant rejection (also known as graft failure) and poorer survival after transplantation. But for many hepatitis C patients who have severe kidney disease, a transplant will remain out of reach; poorer survival among transplant recipients with hepatitis C means that these people are generally assigned a low priority for donor organs.

For all these reasons, curing hepatitis C is an essential part of effective management of chronic kidney disease for people who have the virus. However, available treatments have been unsuitable for people with serious kidney disease. Ribavirin, for instance, exacerbates the anemia experienced by many people with chronic kidney disease.

Sofosbuvir (Gilead Sciences' Sovaldi) must be used with caution in patients with kidney disease because the drug is cleared through the kidneys. Poorer kidney function leads to much higher levels of the drug in the blood, and there are limited safety data on the use of sofosbuvir in people with advanced chronic kidney disease.

A pharmacokinetic study has shown that sofosbuvir metabolite levels increased 5.5-fold in people with severe kidney disease, and 13.8-fold to 21.7-fold in people undergoing dialysis, depending on whether the drug was dosed before or after dialysis. A safety and efficacy study presented at the 2014 AASLD Liver Meeting showed that a 24-week course of sofosbuvir given at a reduced dose of 200 mg plus ribavirin at a reduced dose of 200 mg/day, cured 4 out of 10 people with severe kidney disease. The lower dose of sofosbuvir used in this study is likely to explain the poor efficacy in this population.

Grazoprevir (an HCV NS3/4 protease inhibitor) and elbasvir (an NS5A inhibitor) are evaluated as a once-daily, single-tablet regimen, taken with or without ribavirin. Both drugs are active against multiple genotypes of hepatitis C virus. Results from several other clinical trials of grazoprevir/elbasvir (C-EDGE treatment-naive, C-EDGE treatment-experienced, C-EDGE coinfected, C-SALT for patients with advanced liver disease, and C-SALVAGE for patients with prior treatment failure) were presented at last week's meeting, as Merck prepares to submit the combination for regulatory approval.

Grazoprevir and elbasvir are not excreted through the kidneys, but are broken down in the liver, so these drugs can be used without dose adjustment by people with impaired kidney function.

The Phase 2/3 C-SURFER study recruited people with genotype 1 hepatitis C who had advanced chronic kidney disease (stages 4-5) with reduced creatinine clearance indicated by eGFR <30 mL/min/1.73 m². Three-quarters of participants were dependent on dialysis. The study population was about evenly divided between people with HCV subtypes 1a and 1b (52% vs 48%), and about 80% were previously untreated. Approximately 7% had cirrhosis, defined by non-invasive testing; the study excluded people with decompensated liver disease.

Reflecting the higher prevalence of chronic kidney disease among African Americans, the study population comprised 46% African-Americans, 48% Caucasians, and 6% Asians and other ethnic groups. Approximately 75% of participants were men.

The study population was randomized to immediate treatment with 100 mg grazoprevir plus 50 mg elbasvir for 12 weeks (n=122) or a deferred treatment arm in which participants received placebo for 12 weeks followed by 12 weeks of treatment with grazoprevir/elbasvir (n 113).

In the immediate treatment group, 6 people discontinued treatment for reasons unconnected with the study medication (1 death due to cardiovascular disease, 1 participant withdrew consent, 1 patient was withdrawn from the study due to violent behavior at the dialysis center, 2 participants were lost to follow-up, and 1 was non-adherent).

In the full analysis, which included study discontinuations, the rate of sustained virological response, or continued undetectable HCV viral load at 12 weeks post-treatment (SVR12), was 94%. In the modified on-treatment analysis, the SVR12 rate was 99%, with 1 case of viral relapse after finishing treatment.

Sub-group analyses showed no significant variation in virological response by HCV subtype, ethnicity, treatment experience, stage of chronic kidney disease, diabetes, or dialysis.

Treatment was well tolerated, with no significant difference in reports of headache, nausea, fatigue, insomnia, dizziness, and diarrhea between the placebo group and the active treatment group. Just 1 serious adverse event in the active drug group (lipase elevation) was considered to be related to treatment. Elevations in ALT, AST, and total bilirubin were more frequent in the placebo group than in the active treatment group.

The baseline prevalence of anemia in the study population was not reported, but 23% of participants receiving the active study drug required erythropoietin (EPO) during the study in order to manage anemia, compared to 35% of the placebo group.

Applications for approval of the grazoprevir/elbasvir combination pill will be submitted shortly in the U.S. and European Union, according to Merck, and the product could receive marketing approval by the end of 2015. In the U.S. the Food and Drug Administration has granted "breakthrough status" to the combination for the treatment of people with end-stage renal disease on hemodialysis, which means that the application should be reviewed within 60 days.

4/30/15

References

D Roth, D Nelson, A Bruchfeld, et al. C-SURFER: grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and chronic kidney disease. 2015 International Liver Congress: 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, April 22-26, 2015. Abstract LP02.

E Gane, RA Robson, M Bonacini, et al. Safety, Antiviral Efficacy, and Pharmacokinetics of Sofosbuvir in Patients with Severe Renal Impairment. The Liver Meeting: 65th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). Boston, November 7-12, 2014. Abstract 966.

Other Source

Merck. Merck Announces Results from Phase 2/3 Study of Investigational Chronic Hepatitis C Therapy Grazoprevir/Elbasvir in Patients with Advanced Chronic Kidney Disease. Press release. April 23, 2015.