Summary/Abstract

People who inject drugs (PWID) are at risk for Hepatitis C virus (HCV) infection through the sharing of needles and drug-preparation equipment.  The U.S. Food and Drug Administration today approved Zepatier (elbasvir and grazoprevir) with or without ribavirin for the treatment of chronic hepatitis C virus (HCV) genotypes 1 and 4 infections in adult patients. Merc is offering Zepatier for as little as $5.00 for those that need assistance.

Content

Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved ZEPATIER^™ (elbasvir and grazoprevir) for the treatment of adult patients with chronic hepatitis C virus (HCV) genotype (GT) 1 or GT4 infection, with or without ribavirin (RBV), following priority review by the FDA. ZEPATIER (pronounced ZEP-ah-teer) is a once-daily, fixed-dose combination tablet containing the NS5A inhibitor elbasvir (50 mg) and the NS3/4A protease inhibitor grazoprevir (100 mg). The FDA previously granted two Breakthrough Therapy designations to ZEPATIER, for the treatment of chronic HCV GT1 infection in patients with end stage renal disease on hemodialysis, and for the treatment of patients with chronic HCV GT4 infection. Breakthrough Therapy designation is given to investigational medicines for serious or life-threatening conditions that may offer substantial improvement over existing therapies. Across multiple clinical studies, ZEPATIER achieved high rates of sustained virologic response ranging from 94 to 97 percent in GT1-infected patients, and 97 to 100 percent in GT4-infected patients. Sustained virologic response is defined as HCV RNA levels measuring less than the lower limit of quantification at 12 weeks after the cessation of treatment (SVR12), indicating that a patient’s HCV infection has been cured.

“We are embracing this opportunity to partner with payers and physicians to enable as many appropriate patients to be treated as possible, as quickly as possible.”

 ZEPATIER is not for use in patients with moderate or severe hepatic impairment (Child-Pugh B or C). ZEPATIER also is not for use with organic anion transporting polypeptides 1B1/3 (OATP1B1/3) inhibitors (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 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.

“Continued innovation is needed to help address the worldwide epidemic of chronic hepatitis C virus infection,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. “Our clinical program was designed to study a broad range of patients infected with the hepatitis C virus, including difficult-to-treat patients such as those with stage 4 or 5 chronic kidney disease. The approval of ZEPATIER is a testament to Merck’s unwavering commitment to improving therapy for patients with hepatitis C virus infection, and we are eager to bring this innovation to patients and physicians in the United States.”

ZEPATIER was approved with a treatment duration of 12 or 16 weeks, depending on HCV genotype, prior treatment history and, for patients with GT1a infection, the presence of certain baseline NS5A polymorphisms. A 12-week, once-daily regimen is recommended for the vast majority of patients for whom ZEPATIER is indicated.

Merck’s broad clinical trial program supporting the efficacy of ZEPATIER included six studies in 1,373 patients with chronic HCV GT1 or GT4 infection. These studies assessed the rate of sustained virologic response 12 weeks after the completion of treatment with ZEPATIER (SVR12). The clinical development program for ZEPATIER enrolled diverse groups of HCV GT1- and GT4-infected patients, including treatment-naïve patients and those who had failed prior therapy with peginterferon alfa (PegIFN) and RBV, as well as patients suffering with meaningful co-morbidities and health complications, such as compensated cirrhosis and HIV-1 co-infection. GT1-infected patients with severe renal impairment on hemodialysis and those who previously failed therapy with PegIFN and RBV in combination with an HCV NS3/4A protease inhibitor (boceprevir, simeprevir or telaprevir) also were studied.

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 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.

Recommended Dosage Regimens and Durations for ZEPATIER (elbasvir and grazoprevir)

In patients with GT1a infection, some hepatitis C viruses may contain mutations that can confer resistance to treatment. These are called resistance-associated polymorphisms, also referred to as resistance-associated variants (RAVs). GT1a infection accounts for 46 percent of U.S. HCV cases. To help as many patients as possible to achieve SVR12, testing for NS5A resistance-associated polymorphisms (positions 28, 30, 31 or 93) is recommended for GT1a-infected patients prior to starting treatment with ZEPATIER to determine the optimal dosage regimen and duration. In clinical trials of ZEPATIER, 12 percent (37/309) of GT1a-infected U.S. study participants had these NS5A resistance-associated polymorphisms at baseline. A 16-week regimen of ZEPATIER with RBV is recommended for GT1a-infected patients with these baseline NS5A polymorphisms as described in the above table.

“This approval provides patients and physicians with an additional treatment option that has the potential to cure many patients with chronic hepatitis C in the United States,” said Dr. Ira Jacobson, site chair, department of medicine, Mount Sinai Beth Israel, New York. “ZEPATIER is a once-daily, single-tablet direct-acting antiviral that has demonstrated high cure rates in genotype 1 and in genotype 4, including treatment-naïve and treatment-experienced patients with or without compensated cirrhosis and those with chronic kidney disease.”

The company anticipates that ZEPATIER will be available for shipping to wholesalers within seven business days.

“Chronic hepatitis C is a potentially devastating illness that can cause serious long-term health consequences for patients, including reduced liver function, liver failure or liver cancer,” said Michael Ninburg, executive director, Hepatitis Education Project, Seattle. "Today, chronic hepatitis C is a curable condition for many patients, and we are fortunate to have multiple therapeutic tools that can mitigate its impact.”

Selected Safety Information about ZEPATIER (elbasvir and grazoprevir) (continued)

The concomitant use of ZEPATIER with certain drugs may lead to possible clinically significant adverse reactions from greater exposure to ZEPATIER or concomitant drugs. Coadministration of ZEPATIER is not recommended with certain strong CYP3A inhibitors (e.g., ketoconazole or the cobicistat-containing regimens of elvitegravir/cobicistat/emtricitabine/tenofovir [disoproxil fumarate or alafenamide]). Healthcare professionals should not exceed atorvastatin 20mg/daily or rosuvastatin 10mg/daily when given with ZEPATIER. If ZEPATIER is given with fluvastatin, lovastatin or simvastatin, healthcare professionals should give the lowest statin dose necessary and closely monitor for statin-associated adverse events. If ZEPATIER and tacrolimus are coadministered, frequent monitoring of tacrolimus whole blood concentrations, changes in renal function and tacrolimus-associated adverse events is recommended.

The concomitant use of ZEPATIER and certain drugs may cause significant decrease of elbasvir and grazoprevir plasma concentrations, which may lead to reduced therapeutic effect of ZEPATIER and possible development of resistance. Coadministration of ZEPATIER is not recommended with moderate CYP3A inducers (e.g., nafcillin, bosentan, etravirine, modafinil).

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.

Pricing Designed to Enable Broad Patient Access to ZEPATIER (elbasvir and grazoprevir)

The latest innovations in chronic HCV treatment that have become available over the past three years, now including ZEPATIER, provide the U.S. with an unprecedented opportunity to significantly reduce the burden of HCV. The scientific community believes that control of HCV infection may be possible and is actively working to achieve that goal by 2030. A significant medical need remains: it is estimated that less than one in five patients with chronic HCV infection are currently treated, with thousands of new cases each year.

ZEPATIER, which received two Breakthrough Therapy designations (for GT1 patients with end stage renal disease on hemodialysis and for GT4 patients) and was thereafter approved by the FDA following priority review, offers a highly effective option for a broad range of adult patients with chronic HCV GT1 or GT4 infection. Public reports indicate that net prices for the most commonly used direct-acting antiviral regimens are substantially lower than the list prices. However, the majority of patients with chronic HCV have not yet been treated, in some cases due to cost constraints. After considering these factors, Merck has established a list price of $54,600 for a 12-week regimen, which the company believes to be in the range of net prices for other commonly used HCV direct-acting antiviral regimens at 12 weeks of therapy. Merck anticipates that this price, as well as our comprehensive access strategy to seek broad coverage across commercial and public segments, will help broaden and accelerate patient access to treatment and move us closer to our shared goal of reducing the burden of chronic HCV in the U.S.

“Merck’s decades-long commitment in chronic hepatitis C -- and infectious diseases overall -- has been to both scientific innovation and access,” said Robert McMahon, president, U.S. Market, Global Human Health, Merck. “We are embracing this opportunity to partner with payers and physicians to enable as many appropriate patients to be treated as possible, as quickly as possible.”

Financial Assistance Programs for Those Who Need Help With the Cost of Their Medicine

Merck also anticipates that the list price of ZEPATIER will result in lower out-of-pocket medication costs for some patients. Lower out-of-pocket costs alone do not necessarily reflect a cost advantage in the outcome of the condition treated, because there are other variables that affect relative costs. The direct out-of-pocket costs to patients will vary, depending on an individual’s insurance plan.

Privately insured patients who have difficulty affording the co-pay set by their insurance plan may be eligible for significant co-pay assistance and may pay as little as $5 for each prescription. Maximum savings are limited and terms and conditions apply. Information is available at www.merckaccessprogram-ZEPATIER.com. Merck anticipates that the website for ZEPATIER will be accessible within 24 hours of FDA approval.

Merck also offers assistance to patients who cannot afford ZEPATIER through Merck’s 50-year-old Patient Assistance Program. The Merck PAP provides certain Merck medicines free of charge to eligible patients. The Merck PAP for ZEPATIER is designed primarily for the uninsured who, without our assistance, could not afford their medication. Additionally, for those patients whose insurance plan covers ZEPATIER, but who still cannot afford their medication, a request for an exception may be made if they meet certain financial, medical, and/or insurance criteria. For more information about the Merck PAP, please visit www.merckhelps.com or call the Merck Patient Assistance Program at 1-800-405-5810.