Real-World Observational Study in the U.S. Veterans Affairs System Evaluating Use of Merck’s ZEPATIER® (Elbasvir and Grazoprevir) Shows High Sustained Virologic Response Rates in Patients with Chronic Hepatitis C

Study Evaluated VA Population with High Incidence of Co-Morbidities

KENILWORTH, N.J. April 21, 2017 –(BUSINESS WIRE)–Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the presentation of findings from a retrospective database analysis of patients with chronic hepatitis C virus (HCV) infection who were administered ZEPATIER® in the U.S. Department of Veterans Affairs (VA) healthcare system. For the evaluable population (n=2,436), 95.6 percent of veterans treated with ZEPATIER achieved the primary outcome of sustained virologic response (SVR), defined as undetectable HCV RNA at least twelve weeks after the end of treatment. For patients with no HCV RNA measurements at or after 12 weeks (19% of the study cohort), the analysis used HCV RNA measurements available at least four and less than 12 weeks after the end of treatment. The response rates in the real-world setting of the VA supplement the overall findings from the controlled clinical studies of ZEPATIER. These findings will be presented today in an oral session (abstract #PS-095) at The International Liver Congress™ 2017 being held in Amsterdam, the Netherlands.

In the United States, ZEPATIER is indicated for the treatment of chronic HCV GT1 or GT4 infection in adults. ZEPATIER is indicated for use with ribavirin (RBV) in certain patient populations. The U.S. Prescribing Information for ZEPATIER includes a Boxed Warning about the risk of hepatitis B virus (HBV) reactivation in patients co-infected with HCV and HBV. In controlled clinical studies of ZEPATIER, SVR was the primary endpoint defined as HCV RNA less than lower limit of quantification (LLOQ) at 12 weeks after the cessation of treatment (SVR12).

“U.S. veterans are three times more likely to have chronic hepatitis C compared to the general U.S. population and a high proportion suffer co-morbid conditions that can make treatment challenging,” said Jennifer Kramer, investigator, Michael E. DeBakey VA Medical Center, Houston, Texas, and assistant professor of medicine, department of medicine, Baylor College of Medicine. “This study shows that chronic hepatitis C antiviral treatment can result in a high rate of sustained virologic response in U.S. veterans.”

This retrospective database analysis included patients with chronic HCV treated with ZEPATIER (elbasvir and grazoprevir) in the VA healthcare system between February 1, 2016 and August 1, 2016. Study outcomes include real-world utilization and SVR rates. Please see additional information about the design, methodology and limitations of this observational study below.

After applying study exclusion criteria, 2,436 patients were included in the evaluable population cohort. The mean age of subjects was 63.5 years. The prevalence of co-morbidities as determined by ICD-9 and CPT codes as recorded in the VA database was as follows: cirrhosis (33.2%), diabetes (53.2%), depression (57.2%) and HIV co-infection (3%). Additionally, more than half of the patients had a history of drug (53.9%) or alcohol (60.5%) abuse. The population included 1,988 previously untreated patients and 448 treatment-experienced patients (322 of whom previously received an interferon-based regimen with or without an NS3/4A HCV protease inhibitor, and 126 of whom previously received an interferon-free direct-acting antiviral regimen).

A total of 95.6 percent (2,328/2,436) of patients in the evaluable population achieved SVR following treatment with ZEPATIER. The SVR rates by genotype (GT) were as follows: all GT1, 95.4 percent (2218/2324); GT1a, 93.4 percent (788/844); GT1b, 96.6 percent (1379/1428); and GT4, 96.9 percent (62/64). The SVR rates by baseline viral load (BVL) were as follows: BVL greater than 800,000 IU/ml, 94.7 percent (1497/1580); and BVL less than or equal to 800,000 IU/ml, 97.3 percent (726/746).

The SVR rates by baseline patient characteristics were as follows: male, 95.5 percent (2,245/2,350); female, 96.5 percent (83/86); African American, 95.9 percent (1,342/1,400); Hispanic, 95.1 percent (77/81); White, 95.0 percent (783/824); previously untreated, 96.1 percent (1,910/1,988); treatment-experienced, 93.3 percent (418/448); cirrhosis, 95.5 percent (772/808); without cirrhosis, 95.6 percent (1556/1628); stage 3 chronic kidney disease (CKD) (eGFR 30 to 59 mL/min/1.73m2), 96.7 percent (380/393); stage 4-5 CKD (eGFR less than 30 mL/min/1.73m2), 96.3 percent (392/407); HIV positive, 98.6 percent (73/74); HIV negative, 95.5 percent (2255/2362); history of alcohol abuse, 95.9 percent (1412/1473); no history of alcohol abuse, 95.1 percent (916/963); history of drug abuse, 95.3 percent (1251/1313); no history of drug abuse, 95.9 percent (1077/1123).

Adverse event data were not collected as part of this real-world data analysis.

“Analysis of data from real-world medical settings can provide useful insights to supplement knowledge gained from randomized clinical trials,” said Susan Shiff, senior vice president, center for observational and real-world evidence, Merck. “These data from a real-world VA setting add to the body of evidence on ZEPATIER (elbasvir and grazoprevir) and help deepen scientific understanding of the treatment of this complex disease affecting diverse, sometimes difficult to treat, patient populations.”

Study Methodology
Patients with chronic HCV treated with ZEPATIER from February 1 to August 1, 2016 were identified from the VA Corporate Data Warehouse, a national repository of VA electronic medical records. Inclusion criteria specified initiation of ZEPATIER therapy, at least 18 years of age, positive HCV RNA, and at least one inpatient or outpatient visit within a one-year period prior to treatment initiation (n=2,985). Patients were excluded if they had RBV added greater than one month after treatment initiation (n=23). Patients without SVR data or on-treatment HCV RNA data (n=494), or those treated with ZEPATIER for greater than seventeen weeks (n=32), were excluded as well. The total number of patients in the evaluable population was 2,436.

SVR was assessed based on undetectable HCV RNA at least twelve weeks after the end of treatment. For patients with no HCV RNA measurements at or after 12 weeks, the analysis used HCV RNA measurements available at least four and less than 12 weeks after the end of treatment. SVR was evaluated based on HCV RNA measurement at least 12 weeks post treatment in 81 percent of the study population.

About Real-World Data Analyses and Associated Limitations
Real-world studies analyze data generated outside of randomized clinical trials, such as through analyses of electronic medical records or claims databases, to provide insight into how medicines perform or are used from a clinical and economic viewpoint in real-world clinical settings. Information from real-world analyses alone does not provide sufficient evidence to validate efficacy or safety of a therapeutic regimen and does not provide a substitute for evidence obtained from randomized controlled clinical trials.

This study is subject to certain limitations. The VA population may not be generalizable to the entire U.S. population, due in part to the potential for a differing demographic make-up and/or risk factors. Bias may exist as diagnoses and co-morbidities were identified through ICD-9 and CPT codes. Treatment completion was identified through prescription records which may not reflect adherence. Database analyses are also prone to errors in coding and missing data, including unavailable SVR data at or after the 12-week post-treatment time point. Additionally, some laboratory data including data on the presence of baseline NS5A resistance associated substitutions was not available at the time of this analysis.

About the VA Corporate Data Warehouse (CDW)
The Department of Veterans Affairs Veterans Healthcare Administration (VHA) is supported by one of the largest integrated healthcare information systems in the United States. The VHA’s Corporate Data Warehouse (CDW) was developed in 2006 to accommodate the massive amounts of data being generated from more than 20 years of use and to streamline the process of knowledge discovery to application.

About ZEPATIER ® (elbasvir and grazoprevir) 50mg/100mg Tablets
ZEPATIER is a fixed-dose combination product containing elbasvir, a HCV NS5A inhibitor, and grazoprevir, an HCV NS3/4A protease inhibitor. In the United States, ZEPATIER is indicated for the treatment of chronic HCV GT1 or 4 infection in adults. ZEPATIER is indicated for use with ribavirin (RBV) in certain patient populations. The efficacy of ZEPATIER has not been established in patients who have previously failed treatment with other regimens that included an NS5A inhibitor.

Selected Safety Information about ZEPATIER
The US Prescribing Information for ZEPATIER contains a Boxed Warning about the risk of hepatitis B virus (HBV) reactivation in patients coinfected with HCV and HBV. Healthcare professionals should test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating treatment with ZEPATIER. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Healthcare professionals should monitor HCV/HBV coinfected patients for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Healthcare professionals should initiate appropriate patient management for HBV infection as clinically indicated.

HBV reactivation has been reported in HBsAg positive patients and also in patients with serologic evidence of resolved HBV infection (ie, HBsAg negative and anti-HBc positive). The risk of HBV reactivation may be increased in patients receiving some immunosuppressant or chemotherapeutic agents. HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection, reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, ie, increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.

ZEPATIER (elbasvir and grazoprevir) is not for use in patients with moderate or severe hepatic impairment (Child Pugh B or C). ZEPATIER is also not for use with inhibitors of organic anion transporting polypeptides 1B1/3 (OATP1B1/3) that are known or expected to significantly increase grazoprevir plasma concentrations (e.g., atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cyclosporine), strong cytochrome P450 3A (CYP3A) inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s Wort), and efavirenz. If ZEPATIER (elbasvir and grazoprevir) is administered with RBV, healthcare professionals should refer to the prescribing information for RBV as the contraindications, warnings and precautions, adverse reactions and dosing for RBV also apply to this combination regimen.

Elevations of alanine transaminase (ALT) to greater than 5 times the upper limit of normal (ULN) occurred in 1% of subjects, generally at or after treatment week 8. These late ALT elevations were typically asymptomatic and most resolved with ongoing or completion of therapy. Healthcare professionals should perform hepatic lab testing on patients prior to therapy, at treatment week 8, and as clinically indicated. For patients receiving 16 weeks of therapy, additional hepatic lab testing should be performed at treatment week 12.

Patients should be instructed to consult their healthcare professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces. Healthcare providers should consider discontinuing ZEPATIER (elbasvir and grazoprevir) if ALT levels remain persistently greater than 10 times ULN. ZEPATIER should be discontinued if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or international normalized ratio.

The concomitant use of ZEPATIER with certain drugs may lead to adverse reactions or reduced therapeutic effect due to drug interactions. Certain strong CYP3A inhibitors may increase the plasma concentration of ZEPATIER, leading to possibly clinically significant adverse reactions. Moderate CYP3A inducers may decrease the plasma concentration of ZEPATIER, leading to reduced therapeutic effect and possible development of resistance. Coadministration of ZEPATIER with these drugs is not recommended. Physicians should consult the Prescribing Information for potential drug interactions.

In subjects receiving ZEPATIER for 12 weeks, the most commonly reported adverse reactions of all intensity (greater than or equal to 5% in placebo-controlled trials) were fatigue, headache and nausea. In subjects receiving ZEPATIER with RBV for 16 weeks, the most commonly reported adverse reactions of moderate or severe intensity (greater than or equal to 5%) were anemia and headache.

Selected Dosage and Administration Information for ZEPATIER ® (elbasvir and grazoprevir)
ZEPATIER is a single tablet taken once daily. The recommended dosing is 12 or 16 weeks with or without RBV, depending on HCV genotype, prior treatment history and, for patients with genotype 1a infection, presence of certain baseline NS5A resistance-associated polymorphisms. See Prescribing Information for ZEPATIER for specific dosage regimens and durations. Refer to RBV prescribing information for RBV dosing and dosage modifications when ZEPATIER is given with RBV. To determine dosage regimen and duration of ZEPATIER for genotype 1a patients, testing for the presence of virus with one or more baseline NS5A resistance-associated polymorphisms at positions 28, 30, 31, or 93 is recommended prior to initiating treatment.

Merck’s Commitment to HCV
For more than 30 years, Merck has been at the forefront of the response to the HCV epidemic. Merck’s chronic HCV clinical development programs have included more than 135 clinical trials in approximately 40 countries and have enrolled nearly 10,000 participants. As part of our longstanding leadership in infectious diseases, Merck collaborates with the scientific and patient communities to develop and deliver innovative solutions to support people living with chronic HCV worldwide.

About Merck
For more than a century, Merck, a leading global biopharmaceutical company known as MSD outside of the United States and Canada, has been bringing forward medicines and vaccines for many of the world’s most challenging diseases. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world – including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease and infectious diseases including HIV and Ebola. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA
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Please see Prescribing Information for ZEPATIER (elbasvir and grazoprevir) at http://www.merck.com/product/usa/pi_circulars/z/zepatier/zepatier_pi.pdf and the Patient Information for ZEPATIER at http://www.merck.com/product/usa/pi_circulars/z/zepatier/zepatier_ppi.pdf

SOURCE: Merck