Merck & Co. Announces Findings For Investigational Triple-Combination Chronic Hepatitis C Therapy Showing High Rates Of Sustained Virologic Response In People With Genotypes 1, 2 Or 3 Infection

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 three Phase 2 clinical trials evaluating MK-3682B (MK-3682/grazoprevir/ruzasvir¹), the company’s investigational all-oral, triple-combination regimen for the treatment of chronic hepatitis C (HCV) infection (informally referred to as MK3). Results from Part B of C-CREST 1 & 2 demonstrated high rates of sustained virologic response² (SVR) 12 weeks after the completion of therapy (SVR12, considered virologic cure) in patients with chronic HCV genotype (GT) 1 or GT3 infection who received eight weeks of treatment with MK-3682B. Findings from C-CREST 1 & 2 Part B also demonstrated high rates of SVR12 in GT1, GT2 and GT3-infected patients who received MK3 for 12 or 16 weeks. Findings from Part C of C-CREST 1 & 2 and interim results from the ongoing C-SURGE study showed high rates of SVR12 and SVR8, respectively, in chronic HCV patients who had failed prior treatment with investigational or approved direct-acting antiviral regimens. These results will be announced in oral presentations at The Liver Meeting^® 2016 today (C-CREST 1 & 2 Parts B and C) and tomorrow (C-SURGE).

“The strong findings observed following treatment with MK-3682B are an encouraging step towards Merck’s goal of developing and delivering a shorter-duration, pan-genotypic next-generation treatment regimen for more patients with chronic hepatitis C infection.”

“Across the chronic hepatitis C treatment landscape, incredible progress has been made in a remarkably short amount of time, but there remains a need for more options, particularly for patients who do not achieve sustained virologic response with treatment regimens available today,” said Dr. Eliav Barr, senior vice president, global clinical development, infectious diseases and vaccines, Merck Research Laboratories. “The strong findings observed following treatment with MK-3682B are an encouraging step towards Merck’s goal of developing and delivering a shorter-duration, pan-genotypic next-generation treatment regimen for more patients with chronic hepatitis C infection.”

C-CREST 1 & 2 Part B Overview and Findings

Part B of C-CREST 1 & 2 – ongoing, open-label Phase 2 clinical trials – was designed to evaluate the safety and efficacy of MK-3682B in patients with chronic HCV GT1, GT2 or GT3 infection, with or without cirrhosis. Patients with GT2 or GT3 infection received MK-3682B with or without RBV. All patients with GT1 or GT2 infection were treatment-naïve. Fifty six percent (189/337) of patients with GT3 infection were treatment naïve and 44 percent (148/337) were previously treated with peginterferon/ribavirin (RBV). The primary endpoint of the study was the proportion of patients in each treatment arm who achieved SVR12.

Eight weeks of treatment with MK-3682B resulted in SVR12 rates of 95 percent, 86 percent and 95 percent in GT1, GT2 and GT3 patients, respectively. A 12-week treatment duration resulted in high SVR12 rates in all genotypes (GT1, 99%; GT2, 97%; GT3, 97%). Efficacy was comparable in patients with and without cirrhosis. There were no virologic failures in the patients with GT1 or GT2 infection who received 12 weeks of MK-3682B. Efficacy results are presented in the table below. Results from Part A of C-CREST 1 & 2 were previously reported at The Liver Meeting^® in November 2015.

Among patients who received at least one dose of MK-3682B with or without RBV, the overall most common adverse events (AEs) reported (greater than 10% incidence in either treatment arm) were headache (22%), fatigue (19%) and nausea (13%). There were two drug-related serious AEs, both considered related to RBV only. Nine patients discontinued study drug due to AEs, four of whom discontinued RBV only. One patient died due to AEs not related to the study drug.

“As a scientist and physician who regularly treats patients with chronic hepatitis C, the importance of continuing to research this complex disease and its many complications is evident,” 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. “The virologic cure rates observed in Part B of C-CREST 1 & 2 clearly demonstrate the potential for MK3 and support further study of this investigational regimen.”

C-SURGE Overview and Preliminary Findings

C-SURGE is an ongoing, open-label Phase 2 clinical trial designed to evaluate MK-3682B with or without RBV in chronic HCV GT1 patients who previously failed therapy with either ledipasvir/sofosbuvir (LDV/SOF) or ZEPATIER™ (elbasvir and grazoprevir). The study enrolled 94 patients randomized to receive 16 weeks of MK-3682B plus RBV (n=45) or 24 weeks of MK-3682B without ribavirin (n=49); one patient in the 16 week arm withdrew prior to starting treatment. Of the 93 patients who received treatment in this study, 61 percent (57/93) had previously received 12 to 24 weeks of treatment with LDV/SOF; 15 percent (14/93) had received 8 weeks of LDV/SOF; and 24 percent (22/93) had received 12 weeks of ZEPATIER. A majority of patients (84%, 78/93) had at least one baseline NS5A resistance-associated variant (RAV) at positions 28, 30, 31 or 93.

Interim results from the modified full analysis set (mFAS), which excludes one patient in the 16-week arm who withdrew due to administrative reasons after receiving three doses of study medication, show all patients (43/43) who have completed treatment with MK-3862B plus RBV for 16 weeks achieved SVR8. All patients (49/49) in the mFAS who received MK-3682B for 24 weeks have completed treatment and remain subject to follow-up; the interim results show of those in the 24-week arm who have reached follow-up weeks four and eight, 100 percent have achieved SVR4 (38/38) and SVR8 (30/30), respectively. SVR12 is the primary outcome measure of this ongoing trial. Final results will be presented at a future scientific congress.

Among patients who received at least one dose of MK-3682B with or without RBV, the overall most common AEs reported were fatigue (35%), headache (13%), diarrhea (9%), rash (9%) and pruritus (5%). There were no drug-related serious AEs, and no patients discontinued due to a drug-related AE.

C-CREST 1 & 2 Part C Overview and Findings

Part C of C-CREST 1 & 2 was designed to evaluate retreatment with MK-3682B plus RBV for 16 weeks among patients who previously failed an investigational triple-therapy regimen (MK-3682/grazoprevir/ruzasvir or MK-3682/grazoprevir/elbasvir). The study enrolled 24 patients with GT1 (n=2), GT2 (n=14) or GT3 (n=8) infection. All patients (23/23) who completed treatment achieved SVR12. One GT2 patient discontinued treatment after a single dose due to drug-related serious AEs. Among patients who received at least one dose of MK-3682B plus RBV, the most common AEs reported (greater than 20% incidence) were headache (33%), fatigue (25%), nausea (25%), rash (21%) and insomnia (21%).

About MK-3682B

MK-3682B (informally referred to as MK3) is Merck’s investigational triple-combination therapy in Phase 2 development for the treatment of chronic HCV infection. MK-3682B combines an HCV nucleotide analogue NS5B polymerase inhibitor (MK-3682), an HCV NS3/4A protease inhibitor (grazoprevir, MK-5172) and an HCV NS5A inhibitor (ruzasvir, MK-8408).

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

ZEPATIER is a fixed-dose combination product containing elbasvir, an HCV NS5A inhibitor, and grazoprevir, an HCV NS3/4A protease inhibitor. ZEPATIER is indicated with or without ribavirin (RBV) for treatment of chronic HCV genotypes 1 or 4 infection in adults.

Selected Safety Information about ZEPATIER

ZEPATIER 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 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 adverse reactions or reduced therapeutic effect due to drug interactions. Certain strong CYP3A inhibitors may increase the plasma concentration of ZEPATIER, leading to possibly clinically significant adverse reactions. Moderate CYP3A inducers may decrease the plasma concentration of ZEPATIER, leading to reduced therapeutic effect and possible development of resistance. Coadministration of ZEPATIER with these drugs is not recommended. Physicians should consult the Prescribing Information for potential drug interactions.

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.

Selected Dosage and Administration Information for ZEPATIER (elbasvir and grazoprevir)

ZEPATIER is a single tablet taken once daily. The recommended dosing is 12 or 16 weeks with or without RBV, depending on HCV genotype, prior treatment history and, for patients with genotype 1a infection, presence of certain baseline NS5A resistance-associated polymorphisms. See Prescribing Information for ZEPATIER for specific dosage regimens and durations. Refer to RBV prescribing information for RBV dosing and dosage modifications when ZEPATIER is given with RBV. To determine dosage regimen and duration of ZEPATIER for genotype 1a patients, testing for the presence of virus with one or more baseline NS5A resistance-associated polymorphisms at positions 28, 30, 31, or 93 is recommended prior to initiating treatment.

Merck’s Commitment to HCV

For more than 30 years, Merck has been at the forefront of the response to the HCV epidemic. Merck’s chronic HCV clinical development programs have included more than 135 clinical trials in approximately 40 countries and have enrolled nearly 10,000 participants. As part of our longstanding leadership in infectious diseases, Merck collaborates with the scientific and patient communities to develop and deliver innovative 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

¹ MK-3682 is an HCV nucleotide analogue NS5B polymerase inhibitor. Grazoprevir (MK-5172) is an HCV NS3/4A protease inhibitor. Ruzasvir (MK-8408) is an HCV NS5A inhibitor.

² Measured as HCV RNA less than 15 IU/mL.