European Commission Grants Marketing Authorisation for MSD’s ZEPATIER™ (elbasvir/grazoprevir) for the Treatment of Chronic Hepatitis C Infection

MSD (tradename of Merck & Co., Inc., Kenilworth, N.J., USA (NYSE: MRK)) today announced that the European Commission has approved ZEPATIER™ (elbasvir/grazoprevir) with or without ribavirin (RBV) for the treatment of chronic hepatitis C virus (HCV) genotype (GT) 1 or GT4 infection in adults. ZEPATIER is MSD’s once-daily, fixed-dose combination tablet containing the NS5A inhibitor elbasvir (50mg) and the NS3/4A protease inhibitor grazoprevir (100mg). This approval allows marketing of ZEPATIER tablets in the 28 countries that are members of the European Union, as well as European Economic Area members, Iceland, Liechtenstein and Norway. MSD continues to work to supply the EU market, with product launches estimated to begin between the fourth quarter of 2016 and the first quarter of 2017. Product launches are expected to continue across the EU through 2017.

“The approval of ZEPATIER in the European Union, following approvals in the United States and Canada earlier this year, is an important step in offering a new and effective treatment for millions of people infected with hepatitis C virus genotype 1 or 4,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories, a U.S.-based division of Merck & Co., Inc., Kenilworth, N.J., USA. “ZEPATIER is the most recent advance from MSD in our more than 30-year effort to combat the effects of hepatitis C virus infection, and hence, to reduce the burden of this disease around the world.”

Thousands of chronic HCV patients worldwide participated in the ZEPATIER clinical development program, which was designed to include patients with known treatment challenges, such as those with compensated cirrhosis and those for whom treatment with peginterferon plus RBV, with or without an HCV protease inhibitor, has not worked. In the trials, overall sustained virologic response (SVR) 12 weeks after the completion of therapy (SVR12, considered virologic cure based on undetectable HCV RNA levels) was achieved in 96 percent (301/312) of chronic HCV GT1b-infected patients treated with ZEPATIER for 12 weeks. In chronic HCV GT1a-infected patients, 93 percent (483/519) and 95 percent (55/58) achieved cure following treatment with ZEPATIER for 12 weeks or ZEPATIER plus RBV for 16 weeks, respectively. Additionally, 94 percent (61/65) and 100 percent (8/8) of chronic HCV GT4-infected patients achieved cure following treatment with ZEPATIER for 12 weeks or ZEPATIER plus RBV for 16 weeks, respectively.

Chronic HCV infection, caused by a blood-borne virus, is a major public health concern affecting more than 170 million people globally, 15 million of whom are living in Europe. Of the six genotypes of chronic HCV infection, GT1 is the most common in Europe accounting for approximately 66 percent of cases, and GT1b infection is the most prevalent sub-genotype in the majority of European countries. In addition, the prevalence of GT4 infection is increasing in Europe.

“Given the complexities of chronic hepatitis C, it is critical to have a variety of effective treatment options to ensure diverse types of patients have the highest possible chance to achieve cure,” said Professor Rafael Esteban, M.D., chief of the internal medicine and liver unit of the Hospital Universitario Val d’Hebron, Barcelona, Spain, and professor of medicine at the Universidad Autonoma de Barcelona. “In clinical trials, ZEPATIER achieved high cure rates among a broad range of chronic hepatitis C patients with genotype 1 or 4 infection, from patients who are treatment-naïve to many of those whose chronic HCV infection has been historically difficult-to-treat, providing an important new option in the fight against this global public health epidemic.”

A 12-week, once-daily regimen is recommended for patients with chronic HCV GT1 or GT4 infection. For certain patients, a regimen of ZEPATIER plus RBV for 16 weeks should be considered. The recommended regimens and durations for treatment with once-daily ZEPATIER in chronic HCV patients with or without compensated cirrhosis (Child-Pugh A only) are included in the chart below. No dose adjustments are required when using ZEPATIER with acid-reducing agents.

HCV Genotype		Treatment and Duration
GT1a		ZEPATIER for 12 weeks   ZEPATIER for 16 weeks plus RBV* should be considered in patients with baseline HCV RNA level >800,000 IU/ml and/or the presence of specific NS5A polymorphisms‡ to minimise the risk of treatment failure.
GT1b		ZEPATIER for 12 weeks
GT4		ZEPATIER for 12 weeks   ZEPATIER for 16 weeks plus RBV* should be considered in patients with baseline HCV RNA level >800,000 IU/ml to minimise the risk of treatment failure.
*In the clinical studies, the dose of RBV was weight-based (<66 kg = 800 mg/day, 66 to 80 kg = 1,000 mg/day, 81 to 105 kg = 1,200 mg/day, >105 kg = 1,400 mg/day) administered in two divided doses with food.
‡NS5A polymorphisms, causing at least a 5-fold reduction in activity of elbasvir, included L/M28T/A, R/Q30E/H/R/G/K/L/D, L31M/V/F, H58D and Y93C/H/N.

“Expanding the treatment landscape is always meaningful for the patient community as we continue to build upon the strides made in recent years to raise awareness of and treat chronic hepatitis C worldwide,” said Charles Gore, president, World Hepatitis Alliance. “Competition helps fuel dialogue and ensure people know chronic hepatitis C is treatable. With new treatment options, more patients may be able to achieve cure, and hopefully share their stories to inspire others to get treated.”

ZEPATIER Clinical Trial Program

The efficacy and safety of ZEPATIER were evaluated in eight clinical studies in approximately 2,000 patients. The development program was designed to investigate ZEPATIER across diverse chronic HCV patients, including those on opioid agonist therapy, with chronic kidney disease or with HCV/HIV-1 co-infection. The primary efficacy endpoint in all studies was SVR12. An overview of the studies is provided below. For full study details, see the Summary of Product Characteristics at http://ec.europa.eu/health/documents/community-register/2016/20160722135308/anx_135308_en.pdf.

Study		Patient Population		Study Arms and Duration
C-EDGE TN (double-blind)		GT1, GT4 or GT6 TN +/- cirrhosis		ZEPATIER for 12 weeks (N=316) Placebo for 12 weeks (N=105)
C-EDGE COINFECTION (open-label)		GT1, GT4 or GT6 TN with HCV/HIV-1 co-infection +/- cirrhosis		ZEPATIER for 12 weeks (N=218)
C-SURFER (double-blind)		GT1 TN or TE with Stage 4 or Stage 5 chronic kidney disease +/- cirrhosis		ZEPATIER* for 12 weeks (N=122, including 11 patients in open-label intensive PK arm) Placebo for 12 weeks (N=113)
C-WORTHY (open-label)		GT1 or GT3 TN +/- cirrhosis, TE null responders +/- cirrhosis, TN with HCV/HIV-1 co-infection without cirrhosis		ZEPATIER* for 8, 12 or 18 weeks (N=31, 136 and 63, respectively) ZEPATIER* + RBV† for 8, 12 or 18 weeks (N=60, 152 and 65, respectively)
C-SCAPE (open-label)		GT4 or GT6 TN without cirrhosis		ZEPATIER* for 12 weeks (N=14) ZEPATIER* + RBV† for 12 weeks (N=14)
C-EDGE TE (open-label)		GT1, GT4 or GT6 TE +/- cirrhosis, and +/- HCV/HIV-1 co-infection		ZEPATIER for 12 or 16 weeks (N=105 and 105, respectively) ZEPATIER + RBV† for 12 or 16 weeks (N=104 and 106, respectively)
C-SALVAGE (open-label)		GT1 TE with HCV protease inhibitor regimen‡ +/- cirrhosis		ZEPATIER* + RBV† for 12 weeks (N=79)
C-EDGE CO-STAR (double-blind)		GT1, GT4 or GT6 TN on opioid agonist therapy, +/- cirrhosis		ZEPATIER for 12 weeks (N=201) Placebo for 12 weeks (N=100)
GT = Genotype
TN = Treatment-Naïve
TE = Treatment-Experienced (failed prior treatment with interferon [IFN] or peginterferon alfa [pegIFN] with or without RBV or were intolerant to prior therapy)
PK = pharmacokinetic
*Elbasvir 50mg + grazoprevir 100mg co-administered as single agents
†RBV was administered at a total daily dose of 800mg to 1,400mg based on weight
‡Failed prior treatment with boceprevir, telaprevir, or simeprevir in combination with pegIFN + RBV

Important Safety Information about ZEPATIER (elbasvir/grazoprevir)

ZEPATIER is contraindicated in patients with hypersensitivity to the active substances or to any of the excipients and in patients with moderate or severe hepatic impairment (Child-Pugh B or C). Co-administration of ZEPATIER with inhibitors of organic anion transporting polypeptide 1B (OATP1B) or with inducers of cytochrome P450 3A (CYP3A) or p-glycoprotein (P-gp) is also contraindicated.

The rate of late alanine transaminase (ALT) elevations during treatment is directly related to the plasma exposure to grazoprevir. During clinical studies with ZEPATIER with or without RBV, < 1 % of subjects experienced elevations of ALT from normal levels to greater than 5 times the upper limit of normal (ULN). Higher rates of late ALT elevations occurred in females (2 % [11/652]), Asians (2 % [4/165]), and subjects aged ≥ 65 years (2 % [3/187]). These late ALT elevations generally occurred at or after treatment week 8.

Hepatic laboratory testing should be performed prior to therapy, at treatment week 8, and as clinically indicated. For patients receiving 16 weeks of therapy, additional hepatic laboratory 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 discoloured faeces. Discontinuation of ZEPATIER should be considered if ALT levels are confirmed to be greater than 10 times the 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 normalised ratio (INR).

ZEPATIER contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product. ZEPATIER contains 3.04 mmol (or 69.85 mg) sodium per dose. To be taken into consideration by patients on a controlled sodium diet.

In clinical studies, the most commonly reported adverse reactions (greater than 10%) were fatigue and headache. Less than 1 % of subjects treated with ZEPATIER with or without RBV had serious adverse reactions (abdominal pain, transient ischaemic attack and anaemia). Less than 1 % of subjects treated with ZEPATIER with or without RBV permanently discontinued treatment due to adverse reactions. The frequency of serious adverse reactions and discontinuations due to adverse reactions in subjects with compensated cirrhosis were comparable to those seen in subjects without cirrhosis.

When ZEPATIER was studied with RBV, the most frequent adverse reactions to ZEPATIER + RBV combination therapy were consistent with the known safety profile of RBV.

Very common (≥ 1/10) adverse reactions identified with ZEPATIER, based on pooled data from patients treated for 12 weeks without RBV, include headache and fatigue. Common (≥ 1/100 to < 1/10) adverse reactions include decreased appetite, insomnia, anxiety, depression, dizziness, nausea, diarrhea, constipation, upper abdominal pain, abdominal pain, dry mouth, vomiting, pruritus, alopecia, arthralgia, myalgia, asthenia, irritability.

Common adverse reactions of fatigue, headache, and nausea occurred at a similar frequency in patients treated with ZEPATIER or placebo.

For detailed information, please visit http://ec.europa.eu/health/documents/community-register/2016/20160722135308/anx_135308_en.pdf.

MSD’s Commitment to HCV and Treatment Access

For more than 30 years, MSD has been at the forefront of the response to chronic HCV infection, and we continue to work to advance scientific understanding of this significant global public health epidemic. MSD’s chronic HCV clinical development programs have included more than 135 clinical trials in approximately 40 countries and have enrolled nearly 10,000 participants.

MSD believes scientific advancements must be supported by a commitment to access to make a meaningful difference in the lives of patients. While the latest innovations in chronic HCV treatment that have become available over recent years provide Europe with an unprecedented opportunity to significantly reduce the burden of HCV, an urgent medical need remains. It is estimated that less than one in five diagnosed chronic HCV patients are currently treated in the largest countries within Europe (France, Germany, Italy, Spain and United Kingdom), with thousands of new cases each year. As part of our longstanding leadership in infectious disease and experience in delivering market-defined access programs, MSD will continue to collaborate with stakeholders to ensure ZEPATIER is an option for all patients for whom it is indicated. Together, we believe we can facilitate the collective goal of addressing the global burden of chronic HCV.

About MSD

For 125 years, MSD has been a global health care leader working to help the world be well. MSD is a tradename of Merck & Co., Inc., Kenilworth, N.J., USA. 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 healthcare through far-reaching policies, programs and partnerships.

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Please see European Summary of Product Characteristics for ZEPATIER (elbasvir/grazoprevir) at http://ec.europa.eu/health/documents/community-register/2016/20160722135308/anx_135308_en.pdf .

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