AASLD-R E P E A T -- Interim Phase II Data of Merck's Investigational MK-5172

/R E P E A T -- Interim Phase II Data of Merck's Investigational MK-5172 in Combination Therapy in Chronic Hepatitis C Virus Genotype 1 Infection to be Presented at the American Association for the Study of Liver Diseases (AASLD) Annual Meeting/

BOSTON, MA, Nov. 10, 2012 /CNW/ - Merck announced interim results from a Phase II, multi-center, randomized, dose-ranging study (n=332) assessing the safety and antiviral activity of MK-5172, an investigational, once-daily, oral NS3/4A protease inhibitor for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in combination therapy in treatment-naïve patients. These data will be presented this week at The American Association for the Study of Liver Diseases (AASLD) 2012 Annual Meeting.

 

The primary efficacy endpoint of the study was to evaluate the complete early viral response (cEVR) of four regimens of MK-5172 in combination with peginterferon alfa-2b and ribavirin (P/R) compared to the control arm in which patients received a 4-week lead-in of P/R followed by the addition of boceprevir (VICTRELIS^TM). cEVR was assessed by the proportion of patients who achieved undetectable virus (HCV RNA) at week 12 and at week 16 in the control. The MK-5172 regimens had rates of cEVR that ranged from 82.8 to 93 percent, versus the control rate of 74.2 percent.

"These initial results are promising as they show we increased viral eradication rates with MK-5172, said Alnoor Ramji, M.D., Clinical Assistant Professor at the University of British Columbia and a study investigator." At present, we will continue to treat persons with genotype 1 hepatitis C with standard of care triple therapy given the already high eradication rates we can achieve. Future therapies, such as MK-5172, may offer higher eradication rates, be better tolerated and have easier dosing schedules, however, it will be sometime before they will be available in Canada."

In the initial cohort, termed the "Vanguard Cohort," (n=136), 96 percent of patients (25/26) who received a regimen containing 100 mg QD of MK-5172 with P/R achieved sustained virologic response (SVR) 12, defined as having undetectable virus (HCV RNA) 12 weeks after treatment ended, compared to 54 percent of patients (13/24) in the control arm. Currently planned studies evaluating interferon-free regimens with MK-5172 will be dosed at 100 mg QD.

"We are excited by these interim results evaluating MK-5172 in combination therapy," said Eliav Barr, M.D., Vice President of Infectious Disease at Merck Research Laboratories. "Our commitment to chronic hepatitis C remains steadfast. We look forward to continuing our studies of MK-5172, including in interferon-free regimens."

Other data to be presented on MK-5172 at AASLD includes results from a preclinical study evaluating the antiviral activities of MK-5172 in combination with MK-8742, an oral HCV NS5A inhibitor in Phase I development.

Boceprevir in Canada
Boceprevir was approved for use in Canada in July 2011 for the treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alpha and ribavirin, in adult patients (18 years of age and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous therapy.¹

Hepatitis C in Canada
An estimated 250,000 individuals in Canada are infected with HCV and there are 3,200 to 5,000 newly infected individuals each year.² HCV damages the liver and may lead to serious complications, including death, when left untreated.³ It is the leading cause of liver transplants in Canada.⁴

About the Study
This Phase II, multi-center, double blind, randomized, active-controlled, dose ranging, response-guided therapy (RGT) study is designed to examine the safety and antiviral activity of MK-5172 administered with peginterferon alfa-2b (1.5 µg/kg/week) and an investigational, weight-based dose of ribavirin (600-1,400 mg/day) (P/R) in non-cirrhotic, treatment-naïve, adult patients with chronic HCV genotype 1 infection. In the study, 332 patients were enrolled in two cohorts: the Vanguard Cohort of 136 patients, followed by a Second Cohort of 196 patients. In both cohorts, patients were randomized to one of four MK-5172 treatment arms (100mg QD, 200 mg QD, 400 mg QD, 800 mg QD). All patients received MK-5172 in combination with P/R for 12 weeks followed by P/R for 12 or 36 weeks, depending on treatment response at treatment week 4. If the patient's virus (HCV RNA) was target not detected (TND; <10 IU/mL) at treatment week (TW) 4, then the patient was able to stop all therapy at TW 24. If the patient's virus was target detected unquantifiable (TD(u); <25 IU/mL) or target detected quantifiable (TD(q)) at TW 4, then the patient stopped all therapy at TW 48. In the control arm, patients received a 4-week lead-in of P/R followed by the addition of boceprevir, administered as recommended in the prescribing information.

 

After the primary TW 12 analysis of the MK-5172 arms in the Vanguard cohort, patients receiving the 400 mg and 800 mg doses in the Second Cohort were down-dosed due to elevated liver transaminases and began to receive 100 mg in an open-label fashion between weeks 3 and 12 of MK-5172 therapy.

All patients in both cohorts of the study (termed the Combined Cohort when analyzed together) have reached the primary endpoint of the study, cEVR, or have discontinued early. cEVR values reflect both those patients with both undetectable (TND) and detectable unquantifiable (TD(u)) HCV RNA. In the Second Cohort, 134 of 156 patients randomized into the MK-5172 arms are receiving P/R (n=17) or are in the follow-up phase (n=117) of the study. All patients in the Vanguard Cohort who received MK-5172 are in the follow-up phase of the study or have discontinued early.

Of the patients randomized to the MK-5172 arms, 2.3 percent (6/266) met the protocol-defined criteria for virologic failure: one (1) patient was re-infected with genotype 3 infection; and four patients had no detectable (n=3) or low (n=1) levels of MK-5172 at time of failure and for a period of time prior. The primary efficacy analysis included the full analysis set (FAS) of all randomized patients who received at least one dose of study treatment.

SVR12 Results in the Vanguard Cohort
In the Vanguard Cohort, higher SVR12 rates were achieved across all MK-5172 arms compared to control (FAS) - 96.2 percent (25/26) in the MK-5172 100 mg arm; 86.7 percent (26/30) in the MK-5172 200 mg arm; 87.0 percent (20/23) in the MK-5172 400 mg arm; and 81.5 percent (22/27) in the MK-5172 800 mg arm; versus 54.2 percent (13/24) in the control arm. All patients achieving SVR12 had undetectable (TND) HCV RNA.

Safety Findings
In the MK-5172 arms of the study, there were two transient liver abnormalities observed - elevations in bilirubin before TW4, associated with normalization of ALT/AST levels, and elevations in liver transaminases (ALT/AST) occurring after TW4.

Of those patients with bilirubin elevation, 92 percent (22/24) occurred within the first seven to 23 days of therapy, and their bilirubin levels decreased from peak levels despite continued dosing.
The frequency and severity of ALT/AST elevations were dose dependent. The frequencies of ALT/AST elevations in the MK-5172 100 mg arm and the control arm after TW4 were comparable at 2 percent each, (1/66) and (1/66), respectively. The frequency of ALT/AST elevations observed in the MK-5172 200 mg, MK-5172 400 mg and MK-5172 800 mg arms after TW 4 were higher. One patient in the MK-5172 800 mg arm experienced a serious adverse event due to elevated ALT and bilirubin levels, which returned to normal after stopping therapy.

About MK-5172
MK-5172 is an investigational, once-daily, oral HCV NS3/4A protease inhibitor currently in Phase II development that has demonstrated potent in vitro antiviral activity. Early data on MK-5172 has shown a broad HCV genotypic activity spectrum and in vitro activity against genotype 1a and 1b viral variants that have been associated with resistance to other HCV protease inhibitors, including those in development. Given the clinical experience of MK-5172 to date, including its potentially high barrier to resistance and antiviral activity across HCV genotypes, Merck will evaluate MK-5172 in treatment regimens in a broad spectrum of patients with chronic HCV infection.
Merck recently announced plans to initiate two new clinical trials designed to assess the efficacy and safety of MK-5172 in all-oral, interferon-free combination regimens in non-cirrhotic, treatment-naïve patients with chronic HCV genotype 1 infection. More information is available at http://clinicaltrials.gov using identifiers, NCT01717326 and NCT01716156.

Merck's Global Commitment to Advancing Hepatitis Therapy
Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. In hepatitis C, company researchers developed the first approved therapy for chronic HCV in 1991 and the first combination therapy in 1998. In addition to ongoing studies with VICTRELIS^TM, extensive research efforts are underway to develop additional innovative oral therapies for viral hepatitis treatment.

About Merck
Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our medicines, vaccines, biologic therapies, and consumer and animal 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. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company's plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that all of the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; and the exposure to 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 2011 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).

^TM Trademark of Schering Corporation, a subsidiary of Merck & Co., Inc. Used under license.

References
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1 VICTRELISTM Product Monograph, July 27, 2011, p. 3.

2 Canadian Institutes of Health Research. About the Hep C Research Initiative. http://www.cihr-irsc.gc.ca/e/38855.html. Accessed October 31, 2012.

3 Public Health Agency of Canada. http://www.phac-aspc.gc.ca/hepc/pubs/multiling-hepc/index-eng.php. Accessed October 31, 2012.

4 Canadian Liver Foundation. http://www.liver.ca/Liver_Disease/. Accessed October 31, 2012.

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