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Merck Announces Results From Phase 3 Studies of ZEPATIER™ (Elbasvir and Grazoprevir) in Chronic Hepatitis C Patient Populations at The International Liver Congress™

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KENILWORTH, N.J.--(BUSINESS WIRE)--

Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the presentation of results from two Phase 3 clinical trials evaluating ZEPATIER™ (elbasvir and grazoprevir) 50mg/100mg tablets in chronic hepatitis C (HCV) patients with inherited blood disorders (C-EDGE IBLD) and in patients with a history of intravenous drug use who are receiving opioid agonist therapy (C-EDGE CO-STAR), respectively. Results from C-EDGE IBLD demonstrated high rates of sustained virologic response (SVR) 12 weeks after the completion of treatment (SVR12, considered virologic cure) and a safety profile consistent with that observed in prior studies (abstract #SAT-128). Findings from C-EDGE CO-STAR showed a high rate of SVR 24 weeks after completion of treatment (SVR24) for the baseline chronic HCV infection and provided insights into the incidence of reinfection in this high risk population (abstract #SAT-163). The SVR24 data confirm the C-EDGE CO-STAR SVR12 results unveiled at The Liver Meeting® in November 2015. ZEPATIER Merck's once-daily, fixed-dose combination tablet indicated with or without ribavirin (RBV) for the treatment of chronic HCV genotype (GT) 1 or GT4 infection in adults was approved by the U.S. Food and Drug Administration in January 2016, based in part on prior studies from the Phase 3 program. Data from these additional Phase 3 studies were presented today at The International Liver CongressTM 2016 (ILC).

"To reduce the global burden and potential spread of chronic hepatitis C, it is important that we develop evidence about meaningful options for those patients for whom treatment may be challenging," said Dr. Eliav Barr, vice president, infectious diseases, Merck Research Laboratories. "These data from Merck's broad clinical development program underscore the company's commitment to evaluating ZEPATIER in historically underserved and understudied chronic hepatitis C populations, such as patients with inherited blood disorders or those receiving opioid agonist therapy."

C-EDGE IBLD Overview and Findings

C-EDGE IBLD is a Phase 3 randomized, double-blind, placebo-controlled study evaluating treatment with ZEPATIER (elbasvir and grazoprevir) in patients with chronic HCV GT1, GT4 or GT6 infection and inherited blood disorders, including hemophilia A/B, von Willebrand disease, beta thalassemia and sickle cell anemia. Patients were randomized in a 2:1 ratio to either an immediate treatment group (ITG; 12 weeks of ZEPATIER) or deferred treatment group (DTG; 12 weeks of placebo as control arm, followed by 12 weeks of open-label ZEPATIER). The primary efficacy endpoint for the study was the proportion of patients in the ITG who achieved SVR12. Safety and tolerability were evaluated by comparing subjects receiving ZEPATIER in the ITG (n=107) to those receiving placebo in the DTG (n=52).

Following 12 weeks of treatment with ZEPATIER, 93 percent of patients in the ITG (100/107) achieved SVR12 (virologic cure). Six patients relapsed following twelve weeks of treatment; five of these patients (3 GT1a, 1 GT1b and 1 GT4) had detectable NS5A resistance-associated polymorphisms at baseline.1 The study did not evaluate other ZEPATIER-based dosage regimens or durations.

The most common (greater than 10%) adverse events (AEs) among patients receiving ZEPATIER for 12 weeks in C-EDGE IBLD, compared with those receiving placebo, were headache (21%, 12%) and fatigue (17%, 8%). No patient receiving ZEPATIER discontinued due to AEs, compared with one patient receiving placebo. Three patients (3%) receiving ZEPATIER and six patients (12%) receiving placebo reported a total of 12 serious AEs. Treatment did not affect pre-defined hematological parameters and did not interfere with the management of underlying blood disorders.

C-EDGE CO-STAR Overview and Findings

C-EDGE CO-STAR is a Phase 3 double-blind, placebo-controlled study evaluating treatment with ZEPATIER in patients with chronic HCV GT1, GT4 and/or GT6 infection who are on opioid agonist therapy (i.e., methadone, buprenorphine). Efficacy (SVR12) and safety results from the trial were previously presented at The Liver Meeting® in November 2015. Results presented at ILC this week included secondary efficacy endpoint (SVR24) and reinfection analyses. A separate analysis of health-related quality of life data from C-EDGE CO-STAR was also presented this week at ILC.

The study included an immediate treatment group (ITG) that received blinded ZEPATIER (elbasvir and grazoprevir) for 12 weeks (n=201) and a deferred treatment group (DTG) that received 12 weeks of placebo (control arm) (n=100), followed by 12 weeks of open-label ZEPATIER (n=95). The secondary efficacy analysis evaluated SVR24 in the modified full analysis set (n=271), which included patients from both treatment groups who received ZEPATIER for 12 weeks and completed 24 weeks of follow up, excluding those who discontinued for non-treatment related reasons. An additional analysis evaluated the reinfection incidence among all patients who completed active study therapy (n=296).

Following 12 weeks of treatment with ZEPATIER, 94 percent (175/186) and 96 percent (82/85) of patients achieved SVR24 in the ITG (blinded) and DTG (open-label), respectively. The analysis of 296 patients showed six probable HCV reinfections occurred,2 including five through follow up week 12 (FU12) in the ITG and one additional by FU24 in the DTG. These results represent a reinfection incidence of 8.4 cases (95% CI: 3.1, 18.5) per 100 person years after 24 weeks of follow up. Patients in the trial will be evaluated regularly for three years following the 24-week period.

An analysis of AEs during the initial treatment period and first two weeks of follow-up showed the most common AEs among patients receiving blinded ZEPATIER or placebo were fatigue (16%, 20%), headache (13%, 14%), nausea (11%, 9%) and diarrhea (10%, 9%), respectively. Reported AEs in the open-label treatment group were similar to the blinded group (fatigue, 14%; headache, 13%; nausea, 7%; diarrhea, 8%). One patient receiving ZEPATIER and one patient receiving placebo reported serious treatment-related AEs. In addition, one patient receiving ZEPATIER and one patient receiving placebo discontinued due to AEs.

"Injection drug use is one of the leading contributors to the spread of hepatitis C infection around the world. Many current or former injection drug users with chronic hepatitis C infection are on opioid agonist therapy, but historically there has been reluctance to treat these patients due to concerns about reinfection and compliance with treatment," said Dr. Barr. "These results from C-EDGE CO-STAR help contribute to our understanding of the incidence of hepatitis C reinfection in these patients following treatment with ZEPATIER."

Selected Safety Information about ZEPATIER (elbasvir and grazoprevir)

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 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 ribavirin (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 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 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 (elbasvir and grazoprevir) 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.

About ZEPATIER™ (elbasvir and grazoprevir) 50mg/100 mg Tablets

ZEPATIER is a fixed-dose combination product containing elbasvir, a hepatitis C virus (HCV) NS5A inhibitor, and grazoprevir, an HCV NS3/4A protease inhibitor, and is indicated with or without ribavirin (RBV) for treatment of chronic HCV genotype (GT) 1 or GT4 infection in adults. The dosing regimens and durations for treatment with once-daily ZEPATIER for chronic HCV GT1 or GT4 infection in patients with or without cirrhosis, HIV-1 co-infection or renal impairment are as follows:

  • Twelve weeks of treatment with ZEPATIER is recommended for: GT1a-infected patients who are treatment-naïve or who failed prior treatment with peginterferon alfa plus RBV (PegIFN/RBV-experienced) without baseline NS5A resistance-associated polymorphisms (amino acid positions 28, 30, 31 or 93); GT1b-infected patients who are treatment-naïve or PegIFN/RBV-experienced; and GT4-infected patients who are treatment-naïve.
  • Twelve weeks of treatment with ZEPATIER in combination with RBV is recommended for GT1a- or GT1b-infected patients who failed prior treatment with PegIFN/RBV + a HCV NS3/4A protease inhibitor (PI) (boceprevir, simeprevir or telaprevir). For GT1a-infected PegIFN/RBV/PI-experienced patients with one or more baseline NS5A resistance-associated polymorphisms, the optimal ZEPATIER-based treatment regimen and duration of therapy has not been established.
  • Sixteen weeks of treatment with ZEPATIER in combination with RBV is recommended for: GT1a-infected patients who are treatment-naïve or PegIFN/RBV-experienced with baseline NS5A resistance-associated polymorphisms; and GT4-infected patients who are PegIFN/RBV-experienced.

For patients with chronic HCV GT1a infection, testing for the presence of NS5A resistance-associated polymorphisms is recommended prior to starting treatment with ZEPATIER (elbasvir and grazoprevir) to determine the optimal dosage regimen and duration.

Merck's Commitment to HCV

For nearly 30 years, Merck has been at the forefront of the response to the HCV epidemic. Merck employees are dedicated to applying their scientific expertise, resources and global reach to develop and deliver innovative healthcare solutions to support people living with chronic HCV worldwide.

About Merck

For 125 years, Merck has been a global health care leader working to help the world be well. Merck is known as MSD outside the United States and Canada. 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. For more information, visit www.merck.com and connect with us on Twitter, Facebook, YouTube and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA

This news release of Merck & Co., Inc., Kenilworth, N.J., USA (the "company") includes "forward-looking statements" within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company's management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company's ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company's patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company's 2015 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).

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

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1 Any variant at amino acid position 28, 30, 31 or 93, as determined by population sequencing.

2 Reinfection determined by virologic failure with a different genotype, subtype or viral strain compared to baseline virus.

Merck
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Sarra Herzog, 201-669-6570
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