New England Journal of Medicine Publishes Phase 3 Clinical Study of PREVYMIS™ (Letermovir), Merck's New CMV Prophylaxis Medicine

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck & Co., Inc. (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the New England Journal of Medicine has published online the main results from the pivotal Phase 3 clinical study of PREVYMIS™ (letermovir), the company’s new medicine for prophylaxis (prevention) of...

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck & Co., Inc. (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the New England Journal of Medicine has published online the main results from the pivotal Phase 3 clinical study of PREVYMIS™ (letermovir), the company’s new medicine for prophylaxis (prevention) of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). The paper will also appear in a forthcoming print issue of the journal.

CMV-seropositive patients who undergo allogeneic hematopoietic-cell transplantation are at high risk for CMV reactivation. CMV infection is a common clinically significant complication in these patients and early CMV reactivation after transplant is associated with increased mortality. PREVYMIS is a first-in-class antiviral drug that inhibits CMV replication.

“This study culminates more than a decade of efforts to identify new, highly effective antiviral medicines for patients that can be prescribed prophylactically after hematopoietic-cell transplantation,” said Dr. Francisco M. Marty, associate professor of medicine at Harvard Medical School and attending physician in transplant and oncology infectious diseases at Dana-Farber Cancer Institute and Brigham and Women’s Hospital.

In the study, significantly fewer patients in the PREVYMIS arm (37.5%, n=122/325) compared to the placebo arm (60.6%, n=103/170) developed clinically significant CMV infection, discontinued treatment or had missing data through Week 24 post-transplant (p<0.001), the primary efficacy endpoint. The treatment effect for PREVYMIS in preventing clinically significant CMV infection was consistent across pre-specified high- and low-risk strata for CMV reactivation both at Week 14 (end of treatment) and at Week 24 post-transplant. All-cause mortality in patients receiving PREVYMIS was lower compared to placebo at Week 24 post-transplant and at Week 48 post-transplant.

PREVYMIS is contraindicated in patients receiving pimozide or ergot alkaloids. Increased pimozide concentrations may lead to QT prolongation and torsades de pointes. Increased ergot alkaloids concentrations may lead to ergotism. PREVYMIS is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Significantly increased pitavastatin or simvastatin concentrations may lead to myopathy or rhabdomyolysis.

“Merck has been working to bring PREVYMIS forward to address the significant unmet medical need for hematopoietic stem cell transplant recipients – a vulnerable patient population at risk from CMV infection and disease,” said Dr. Nicholas Kartsonis, vice president, infectious disease clinical research, Merck Research Laboratories. “Based on the results of this study, in addition to the recent U.S. approval of PREVYMIS, Merck has regulatory applications pending in other markets, including in the European Union and Japan.”

PREVYMIS will be available for order in the U.S. in early December.

This double-blind study randomized adult CMV-seropositive allogeneic hematopoietic-cell transplant recipients to receive PREVYMIS or placebo orally or intravenously through Week 14 post-transplant. PREVYMIS was dosed at 480 mg/day (or 240 mg/day when co-administered with cyclosporine). Patients who developed clinically-significant CMV infection, defined as CMV disease or CMV viremia requiring preemptive treatment, discontinued study drug and received anti-CMV treatment. All patients in the study were followed through Week 48 post-transplant.

Key prespecified secondary endpoints of the study were the proportion of patients with clinically-significant CMV infection through Week 14 and the time to clinically-significant CMV infection in the primary efficacy population. All treated patients were included in the safety analyses. Prespecified exploratory endpoints of the study included cumulative all-cause mortality, time to engraftment, and the incidence of graft-versus-host disease or non-CMV infections.

Additional Selected Safety Information about PREVYMIS (letermovir)

The concomitant use of PREVYMIS and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (PREVYMIS or concomitant drugs) or reduced therapeutic effect of PREVYMIS or the concomitant drug. Consider the potential for drug interactions prior to and during PREVYMIS therapy; review concomitant medications during PREVYMIS therapy; and monitor for adverse reactions associated with PREVYMIS and concomitant medications.

The cardiac adverse event rate (regardless of investigator-assessed causality) was higher in patients receiving PREVYMIS than placebo (13% vs. 6%). The most common cardiac adverse events were tachycardia (reported in 4% PREVYMIS patients and 2% placebo patients) and atrial fibrillation (reported in 3% PREVYMIS patients and 1% placebo patients). These adverse events were reported as mild or moderate in severity.

The rate of adverse events occurring in at least 10% of PREVYMIS-treated HSCT recipients and at a frequency at least 2% greater than placebo were nausea (27% vs. 23%), diarrhea (26% vs. 24%), vomiting (19% vs. 14%), peripheral edema (14% vs. 9%), cough (14% vs. 10%), headache (14% vs. 9%), fatigue (13% vs. 11%), and abdominal pain (12% vs. 9%).

The most frequently reported adverse event that led to study drug discontinuation was nausea (occurring in 2% of PREVYMIS patients and 1% of placebo patients). Hypersensitivity reaction, with associated moderate dyspnea, occurred in one patient following the first infusion of IV PREVYMIS after switching from oral PREVYMIS, leading to treatment discontinuation.

Co-administration of PREVYMIS (letermovir) with drugs that are inhibitors of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) transporters may result in increases in letermovir plasma concentrations.

Co-administration of PREVYMIS with midazolam results in increased midazolam plasma concentration. Co-administration of PREVYMIS with drugs that are CYP3A substrates may result in clinically relevant increases in the plasma concentrations of co-administered CYP3A substrates.

Co-administration of PREVYMIS with drugs that are substrates of OATP1B1/3 transporters may result in a clinically relevant increase in plasma concentrations of co-administered OATP1B1/3 substrates.

The magnitude of CYP3A- and OATP1B1/3-mediated drug interactions on co-administered drugs may be different when PREVYMIS is co-administered with cyclosporine. See the prescribing information for cyclosporine for information on drug interactions with cyclosporine.

If dose adjustments of concomitant medications are made due to treatment with PREVYMIS, doses should be readjusted after PREVYMIS treatment is completed.

Established or potentially clinically significant drug interactions may occur with co-administration of PREVYMIS and drug/drug classes, including, but not limited to, the following:

  • Antidiabetic agents
    • Glyburide: increases glyburide concentration
    • Repaglinide: increases repaglinide concentration
    • Rosiglitazone: increases rosiglitazone concentration
  • Antipsychotics
  • Ergot alkaloids
    • Ergotamine: increases ergotamine concentration; co-administration is contraindicated
    • Dihydroergotamine: increases dihydroergotamine concentration; co-administration is contraindicated
  • HMG-CoA reductase inhibitors
    • Pitavastatin, Simvastatin: increases HMG-CoA reductase inhibitors concentration; co-administration is contraindicated when PREVYMIS is co-administered with cyclosporine
    • Atorvastatin: increases atorvastatin concentration
    • Fluvastatin, Lovastatin, Pravastatin, Rosuvastatin: increases HMG-CoA reductase inhibitors concentration
  • Immunosuppressants
    • Cyclosporine: increases both cyclosporine and letermovir concentrations
    • Sirolimus: increases sirolimus concentration
    • Tacrolimus: increases tacrolimus concentration
  • Proton pump inhibitors
    • Omeprazole: decreases omeprazole concentration
    • Pantoprazole: decreases pantoprazole concentration
  • CYP3A substrate examples
    • Alfentanil, fentanyl, midazolam and quinidine: may increase CYP3A substrate concentration
    • Pimozide and ergot alkaloids are contraindicated

The safety and efficacy of PREVYMIS (letermovir) in patients below 18 years of age have not been established.

For patients with creatinine clearance (CLcr) greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment of PREVYMIS is required based on renal impairment. The safety of PREVYMIS in patients with end-stage renal disease (CLcr less than 10 mL/min), including patients on dialysis, is unknown.

No dosage adjustment of PREVYMIS is required based on mild (Child-Pugh Class A) to moderate (Child-Pugh Class B) hepatic impairment. PREVYMIS is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment.

About PREVYMIS (letermovir)

PREVYMIS is a member of a new class of non-nucleoside CMV inhibitors (3,4 dihydro-quinazolines) and inhibits viral replication by specifically targeting the viral terminase complex. Cross resistance is not likely with drugs outside of this class. PREVYMIS is fully active against viral populations with substitutions conferring resistance to CMV DNA polymerase inhibitors. These DNA polymerase inhibitors are fully active against viral populations with substitutions conferring resistance to PREVYMIS. PREVYMIS has no activity against other viruses. Letermovir has been granted orphan designation for the prevention of CMV disease in at-risk populations in the U.S., EU and Japan.

Under an agreement signed in 2012, Merck (through a subsidiary) purchased worldwide rights to develop and commercialize letermovir from AiCuris GmbH & Co KG (www.aicuris.com).

About Merck

For more than a century, Merck, a leading global biopharmaceutical company known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world’s most challenging diseases. 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. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world - including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease and infectious diseases including HIV and Ebola. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.

Forward-Looking Statement

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 2016 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 PREVYMIS (letermovir) at http://www.merck.com/product/usa/pi_circulars/p/prevymis/prevymis_pi.pdf and Patient Information for PREVYMIS at http://www.merck.com/product/usa/pi_circulars/p/prevymis/prevymis_ppi.pdf.

Source: www.mrknewsroom.com