Merck Announces Results from C-SURFER Phase 2/3 Study of Investigational Chronic Hepatitis C Therapy Grazoprevir/Elbasvir in Patients with Advanced Chronic Kidney Disease

As well as results from its Pivotal Phase 3 C-EDGE Programme Evaluating Grazoprevir/Elbasvir Showing High Sustained Virologic Responses Across Broad Range of Patients with Chronic Hepatitis C Virus Infection

KIRKLAND, QC, April 24, 2015 /CNW Telbec/ - Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced the first presentation of data from C-SURFER, as well as the C-EDGE  trials at the 50th annual congress of the European Association for the Study of the Liver (EASL) – held this April 22 to 25th in Vienna, Austria.

"HCV affects approximately 130-170 million people worldwide, and 350,000 to 500,000 people die each year from HCV-related liver diseases. In Canada this translates to approximately 242,500 individuals infected with HCV," explains Dr. Rejean Thomas, CEO and cofounder of the L'Actuel, Centre of Excellence for HIV and Hepatitis, located in Montreal. "The results from these studies provide hope for the patients with cirrhosis and advanced chronic kidney diseases. CKD represent an unmet clinical need especially for those on hemodialysis.  There is a need for more effective treatment options in Canada for these patients."

C-SURFER Trial is First to Investigate an All-Oral Ribavirin-Free Hepatitis C Treatment Regimen in Treatment-Naïve and Treatment-Experienced Patients with Advanced Chronic Kidney Disease Infected with Hepatitis C Virus Genotype 1
The C-SURFER trial is 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 (CKD) infected with chronic hepatitis C virus (HCV) genotype 1 (GT1).1 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.2 Following 12 weeks of treatment with grazoprevir and elbasvir, 99 percent (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). 3 These data will be 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, Houston, Texas, U.S.A. "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 (ITG), 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 percent were treatment-naïve, 36 percent had diabetes, 18 percent had stage 4 CKD, 82 percent had stage 5 CKD, 75 percent were receiving haemodialysis and 45 percent were African-American. Among those patients who received at least one dose of grazoprevir plus elbasvir, five percent (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 percent (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 percent (115/122) of patients achieved SVR12.

"The  broad clinical development program of Merck 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 ITG arm died from cardiac arrest (not considered related to study medicine) and three patients (3%) in the placebo group died from aortic aneurysm, pneumonia and an unknown cause..

About C-SURFER

C-SURFER is a Phase 2/3 clinical trial evaluating Merck investigational grazoprevir plus elbasvir in patients infected with chronic HCV GT1 and with advanced chronic kidney disease (stages 4 and 5, including patients on haemodialysis) with or without liver cirrhosis, which are among those with HCV infection who are most difficult to treat, over 12 weeks.

C-EDGE Data Sets Include Treatment-Naïve, Treatment-Experienced and HIV Co-Infected Patients with Chronic Hepatitis C Virus Genotypes 1, 4 or 6 Infection
The company's ongoing C-EDGE pivotal Phase 3 clinical trial programme is evaluating the investigational once-daily tablet grazoprevir/elbasvir (100mg/50mg) in patients with or without cirrhosis who are infected with chronic hepatitis C virus (HCV) genotypes 1, 4 or 6 (GT1, 4 or 6).[4] Patients in both the HCV infected, treatment-naïve (C-EDGE TN), and HIV/HCV co-infected, treatment-naïve (C-EDGE CO-INFXN) trials treated for 12 weeks achieved rates of sustained virologic response 12 weeks after the completion of treatment (SVR12) of 95 percent (299/316 and 207/218, respectively). In addition, HCV infected, treatment-experienced patients (C-EDGE TE) treated with or without ribavirin (RBV) for 12 weeks achieved SVR12 rates of 94 percent (98/104) and 92 percent (97/105), respectively, and those treated for 16 weeks achieved SVR12 rates of 97 percent (103/106) and 92 percent (97/105), respectively. These data were presented at The International Liver CongressTM 2015 – the 50th annual congress of the European Association for the Study of the Liver (Abstract #G07, E-Poster P0886 and E-Poster P0887). A paper detailing the findings of C-EDGE TN was published online in the Annals of Internal Medicine today. 

"Patients with co-morbidities and varying treatment experiences represent important segments of the chronic hepatitis C population in need of additional innovative treatment options," said Dr. Eric Lawitz, Vice President, Scientific and Research Development, The Texas Liver Institute and Clinical Professor of Medicine, The University of Texas Health Science Center, San Antonio, Texas, U.S.A. "These findings are important because they demonstrate that a single pill of grazoprevir/elbasvir taken once-daily achieved consistently high rates of SVR12 in the patient populations studied."

"At Merck, we continue to build upon our clinical experience using grazoprevir/elbasvir across diverse populations of patients infected with chronic hepatitis C virus," said Dr. Eliav Barr."We remain on track to submit a New Drug Application with the U.S. Food and Drug Administration in the first half of 2015."

Summary of SVR12 findings: C-EDGE TN, C-EDGE CO-INFXN, C-EDGE TE

 


C-EDGE
TN

C-EDGE

CO-INFXN

C-EDGE TE

Without
RBV
(n=316)

Without
RBV

(n=218)

Without
RBV
(n=105)

With

RBV

(n=104)

Without
RBV
(n=105)

With

RBV

(n=106)

Duration

12 weeks

12 weeks

12 weeks

12 weeks

16 weeks

16 weeks

All Patients:
SVR12

95%

(299/316)

95%

(207/218)

92%

(97/105)

94%

(98/104)

92%

(97/105)

97%

(103/106)

Cirrhotic

97%

(68/70)

100%

(35/35)

89%

(33/37)

89%

(31/35)

92%

(35/38)

100%

(37/37)

Non-
cirrhotic

94%

(231/246)

94%

(172/183)

94%

(64/68)

97%

(67/69)

93%

(62/67)

96%

(66/69)

Genotype 1a

92%

(144/157)

94%

(136/144)

90%

(55/61)

93%

(56/60)

94%

(45/48)

95%

(55/58)

Genotype 1b
or other
Genotype 1

99%

(129/131)

96%

(43/45)

100%

(35/35)

97%

(28/29)

96%

(46/48)

100%

(38/38)

Genotype 4

100%

(18/18)

96%
(27/28)

78%

(7/9)

93%

(14/15)

60%

(3/5)

100%

(8/8)

Genotype 6

80%

(8/10)

100%

(1/1)

N/A

N/A

75%

(3/4)

100%

(2/2)

 

C-EDGE TN Overview and Additional Findings

C-EDGE TN is a randomised, blinded, placebo-controlled trial evaluating the efficacy and safety of grazoprevir/elbasvir in treatment-naïve patients with or without cirrhosis infected with chronic HCV GT1, 4 or 6 who received therapy for 12 weeks. Patients were randomised to an immediate treatment group that received grazoprevir/elbasvir for 12 weeks or to a deferred treatment group that received placebo for 12 weeks, were followed for an additional four weeks, and then received open label grazoprevir/elbasvir for the next 12 weeks. The primary efficacy analysis included those patients who received immediate treatment with grazoprevir/elbasvir or placebo. Of the 316 patients who received immediate treatment with grazoprevir/elbasvir, 50 percent were infected with GT1a, 42 percent with GT1b, six percent with GT4 and three percent with GT6. Overall, 22 percent of patients had liver cirrhosis.

In this study, virologic failure occurred in 13 patients (4%) in the immediate treatment group, including one virologic breakthrough and 12 virologic relapses. Serious adverse events occurred in nine (3%) and three (3%) patients in the immediate treatment and corresponding placebo arms, respectively; none were considered drug-related. The most common adverse events reported (greater than 5% incidence) in the immediate treatment and corresponding placebo groups, were headache (17%, 18%), fatigue (16%, 17%), nausea (9%, 8%) and arthralgia (6%, 6%), respectively.         

C-EDGE CO-INFXN Overview and Additional Findings

C-EDGE CO-INFXN is an open label, single-arm study evaluating the efficacy, safety  and tolerability of grazoprevir/elbasvir in treatment-naïve patients with or without cirrhosis infected with chronic HCV GT1, 4 or 6 and HIV who received treatment for 12 weeks. Of the 218 patients enrolled in the trial, 66 percent were infected with HCV GT1a, 21 percent with GT1b or other GT1, 13 percent with GT4, and one percent with GT6. Overall, 16 percent of patients had liver cirrhosis.

In this study, virologic failure occurred in seven patients (3%), including six virologic relapses and one reinfection. There were no reported drug-related serious adverse events. The most common (greater than 5% incidence) adverse events reported were fatigue (13%), headache (12%) and nausea (9%).

C-EDGE TE Overview and Additional Findings

C-EDGE TE is a randomised study evaluating the efficacy and safety of once-daily grazoprevir/elbasvir with or without twice-daily RBV in treatment-experienced (prior null response, partial response or relapse with peg-interferon/RBV) patients with or without cirrhosis infected with chronic HCV GT1, 4 or 6 who received therapy for 12 weeks or 16 weeks.

12 week arms     

Of the 209 patients randomised to the 12 week arms, 105 patients received grazoprevir/elbasvir only and 104 patients received grazoprevir/elbasvir plus RBV. Patients in the grazoprevir/elbasvir only arm comprised 58 percent GT1a, 33 percent GT1b or other GT1 and nine percent GT4. Overall, 35 percent had liver cirrhosis. Among the 104 patients receiving grazoprevir/elbasvir plus RBV, 58 percent were infected with chronic HCV GT1a, 28 percent GT1b or other GT1, and 14 percent GT4. Overall, 34 percent had liver cirrhosis.      

In the grazoprevir/elbasvir only and grazoprevir/elbasvir plus RBV arms, six patients in each arm (6%) were reported to have virologic relapse. No patients were reported to have virologic breakthrough or rebound. Serious adverse events were reported in four patients in the grazoprevir/elbasvir only arm (4%) and three patients in the grazoprevir/elbasvir plus RBV arm (3%). The most common (greater than 10% incidence) adverse events reported in the grazoprevir/elbasvir and grazoprevir/elbasvir plus RBV arms, respectively, were fatigue (19%, 27%), headache (21%, 20%) and nausea (9%, 14%).

16 week arms

Of the 211 patients enrolled in the 16 week arms, 105 patients received grazoprevir/elbasvir only and 106 patients received grazoprevir/elbasvir plus RBV. In the grazoprevir/elbasvir only arm, 46 percent were infected with chronic HCV GT1a, 46 percent with GT1b or other GT1, five percent with GT4 and four percent with GT6. Overall, 36 percent of patients had liver cirrhosis. Among those in the grazoprevir/elbasvir plus RBV arm, 55 percent were infected with chronic HCV GT1a, 36 percent with GT1b or other GT1, eight percent with GT4, and two percent with GT6. Overall, 35 percent had liver cirrhosis. 

Among the patients receiving grazoprevir/elbasvir only, three patients (3%) were reported to have virologic breakthrough or rebound and four patients (4%) were reported to have virologic relapse. No virologic failures occurred in patients receiving grazoprevir/elbasvir plus RBV. Serious adverse events were reported in three patients in the grazoprevir/elbasvir only arm (3%) and four patients in the grazoprevir/elbasvir plus RBV arm (4%). The most common (greater than 10% incidence) adverse events reported in the grazoprevir/elbasvir and grazoprevir/elbasvir plus RBV arms, respectively, were fatigue (16%, 30%), headache (19%, 19%) and nausea (4%,17%).

About the C-EDGE Programme

C-EDGE is the Phase 3 clinical development programme for the investigational HCV treatment grazoprevir/elbasvir of Merck comprising five studies with more than 1,700 patients across more than 25 countries. These studies are evaluating grazoprevir/elbasvir in multiple genotypes (GT1, 4 and 6) and diverse patient populations, including difficult-to-treat patients such as: treatment-experienced, patients with cirrhosis, HIV/HCV co-infection, advanced chronic kidney disease, inherited blood disorders, and those receiving opiate substitution therapies.

About Grazoprevir/Elbasvir

Grazoprevir/elbasvir is an investigational, once-daily single tablet regimen consisting of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A replication complex inhibitor). As part of the broad clinical trials programme of Merck, grazoprevir/elbasvir is being studied in multiple HCV genotypes and in patients with difficult-to-treat conditions such as HIV/HCV co-infection, advanced chronic kidney disease, inherited blood disorders, liver cirrhosis and those on opiate substitution therapy.

About Hepatitis C

Hepatitis C is a chronic liver disease caused by the hepatitis C virus (HCV). HCV affects approximately 130-170 million people worldwide, and 350,000 to 500,000 people die each year from HCV-related liver diseases . Approximately 15-30 percent of persons with chronic HCV will develop cirrhosis within 20 years. Approximately 40 percent of people with HIV are co-infected with HCV and approximately 40-50 percent of injection drug users are infected with HCV

In  Canada, an estimated 242,500 individuals are infected with HCV. Approximately 21% of those individuals don't know they are infected and remain undiagnosed. Many people infected with HCV have no symptoms and are unaware of their infection, but they are still infectious.

About Chronic HCV Infection and Chronic Kidney Disease

Chronic HCV infection is both a cause and complication of the treatment of CKD. In patients with CKD, chronic HCV infection is associated with an increased risk of accelerated loss of remaining kidney function, kidney transplant failure and death. Furthermore, patients with chronic HCV infection and advanced CKD represent an unmet need due to a lack of demonstrated HCV treatment options for this group.

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 deliver innovative healthcare solutions that support people living with HCV worldwide.

About Merck

Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside Canada and the United States. Through our prescription medicines, vaccines, biologic therapies, and consumer care 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. For more information about our operations in Canada, visit www.merck.ca.

Forward-Looking Statement

This news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck'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; Merck'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 Merck's patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

Merck 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 Merck's 2014 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).

________________________________

1 In Phase 2 studies, grazoprevir/elbasvir are administered as two separate tablets
2 Stages 4 and 5 chronic kidney disease are defined as severely or very severely reduced kidney function, based on estimated glomerular filtration rate <30 mL/min/1.73m2
3 Includes patients who received ≥1 dose of study drug and excluded those with missing data because of death or early discontinuation for reasons unrelated to study drug
4 Grazoprevir is an HCV NS3/4A protease inhibitor and elbasvir is an HCV NS5A replication complex inhibitor

 

SOURCE Merck Canada Inc.

For further information: Media Contact: Annick Robinson, (438) 837-2550; Investor Contact: Justin Holko, (908) 740-1879

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