Merck has released the first presentation of data from C-SURFER, the company’s Phase 2/3 clinical trial evaluating the investigational once-daily treatment regimen of grazoprevir (100mg) and elbasvir (50mg) in patients with advanced chronic kidney disease infected with chronic hepatitis C virus (HCV) genotype 1 (GT1).
Treatment-naïve patients and patients who failed prior pegylated interferon HCV therapy, with or without cirrhosis, all of whom had CKD stages 4 or 5, were enrolled. Following 12 weeks of treatment with grazoprevir and elbasvir, 99% (115/116) of patients in the pre-specified primary population for analysis of efficacy data achieved a sustained virologic response 12 weeks after the completion of treatment (SVR12).These data were presented today at The International Liver CongressTM 2015 – the 50th annual congress of the European Association for the Study of the Liver (late breaking E-Poster #LP02).
“There is an unmet medical need to treat chronic hepatitis C virus infection in patients with advanced chronic kidney disease,” said Dr. Howard Monsour, Jr., chief of hepatology, Houston Methodist Hospital. “In this trial, the first to investigate an all-oral ribavirin-free treatment regimen in treatment-naïve and treatment-experienced CKD patients, treatment with grazoprevir and elbasvir for 12 weeks was effective in this study population with HCV genotype 1 infection.”
The ongoing C-SURFER Phase 2/3 clinical trial is a randomized, parallel-group, placebo-controlled study evaluating patients infected with chronic HCV GT1 with advanced CKD with or without liver cirrhosis. Patients were randomised to one of two study arms:
- Immediate treatment group, grazoprevir plus elbasvir (blinded) once-daily for 12 weeks (n=111);
- Deferred treatment group (DTG), initially placebo (control arm) for 12 weeks followed by a four week follow-up period and then treatment with grazoprevir plus elbasvir (open label) once-daily for 12 weeks (n=113).
In addition, 11 patients received grazoprevir plus elbasvir (open label) once-daily for 12 weeks with intensive pharmacokinetic sampling.
Of the 122 patients who received grazoprevir plus elbasvir, 83% were treatment-naïve, 36% had diabetes, 18% had stage 4 CKD, 82%had stage 5 CKD, 75% were receiving haemodialysis and 45% were African-American. Among those patients who received at least one dose of grazoprevir plus elbasvir, 5% (6/122) were excluded from the pre-specified primary efficacy analysis population, or modified full analysis set, due to missing data caused by death or early discontinuation for reasons unrelated to study drug.
In the modified full analysis set, 99% (115/116) of patients receiving grazoprevir plus elbasvir achieved SVR12. One GT1b infected, non-cirrhotic, interferon-intolerant patient showed a viral relapse at follow-up week 12. Within the modified full analysis set, efficacy was consistent across the patient sub-populations assessed. In a supportive analysis of all 122 patients who received at least one dose of grazoprevir plus elbasvir in the ITG arms, including patients who did not complete the study for reasons not related to study drug, 94% (115/122) of patients achieved SVR12.
“MSD’s broad clinical development program includes studies dedicated to bringing a once-daily regimen to diverse populations of patients infected with chronic HCV, including certain types of patients with co-morbidities, such as advanced chronic kidney disease,” said Dr. Eliav Barr, vice president, infectious diseases, Merck Research Laboratories, a U.S.-based division of Merck & Co., Inc., Kenilworth, N.J., U.S.A. “These data highlight how emerging innovations in chronic hepatitis C treatment may lead to new options for patient populations in which it historically has been difficult to achieve high rates of sustained viral clearance.”
No patients in the ITG arms discontinued treatment due to adverse events (AEs), while four percent (5/113) of patients in the comparator placebo phase of the DTG arm discontinued treatment due to AEs. The rates of serious AEs reported were 14 percent (16/111) in the ITG arms and 17 percent (19/113) in the placebo control DTG arm. The most common treatment-related AEs in the ITG arms and DTG arm (placebo) were headache (17%, 17%), nausea (15%, 16%) and fatigue (10%, 15%), respectively. There were four deaths reported during the initial treatment phase and the first 14 days of study follow-up. One patient (1%) in the open label arm died from cardiac arrest (not considered related to study medicine) and three patients (2%) in the placebo group died from aortic aneurysm, pneumonia and an unknown cause.
On April 8, 2015, the company announced that the U.S. Food and Drug Administration (FDA) had granted Breakthrough Therapy designation to grazoprevir/elbasvir for the treatment of patients infected with chronic HCV GT1 with end-stage renal disease on hemodialysis and patients infected with chronic HCV GT4. Breakthrough Therapy designation is intended to expedite the development and review of a candidate that is planned for use, alone or in combination, to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.