Merck Receives Positive CHMP Opinion for PREVYMIS (letermovir) in the European Union

KENILWORTH, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of PREVYMIS™ (letermovir) for prophylaxis of cytomegalovirus (CMV) reactivation and disease in adult CMV-seropositive recipients [R+] of an allogeneic haematopoietic stem cell transplant (HSCT).

The CHMP positive opinion will be considered by the European Commission. If the CHMP opinion is affirmed, the European Commission will grant a centralized marketing authorization with unified labeling that is valid in the 28 countries of the European Union (EU), as well as European Economic Area members, Iceland, Liechtenstein and Norway. Merck anticipates that the European Commission decision will be adopted within approximately two months.

In the pivotal Phase 3 clinical trial evaluating letermovir, significantly fewer patients in the PREVYMIS arm (38%, n=122/325) compared to the placebo arm (61%, n=103/170) developed clinically significant CMV infection, discontinued treatment or had missing data through Week 24 post-HSCT [treatment difference: -23.5 (95% confidence interval -32.5 to -14.6), (p<0.0001)], the primary efficacy endpoint.

PREVYMIS was approved by the U.S. Food and Drug Administration (FDA) on Nov. 8. In the U.S., PREVYMIS is indicated for prophylaxis of cytomegalovirus infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant. Merck also has filed letermovir for regulatory approval in other markets including Japan, where it is currently under review.

Selected Safety Information about PREVYMIS (letermovir) in the U.S.

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.

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. Healthcare professionals should 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 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 (letermovir) 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:

• Anti-arrhythmic agents
  • Amiodarone: increases amiodarone concentration
• Anticoagulants
  • Warfarin: decreases warfarin concentration
• Anticonvulsants
  • Phenytoin: decreases phenytoin concentration
• Antidiabetic agents
  • Glyburide: increases glyburide concentration
  • Repaglinide: increases repaglinide concentration
  • Rosiglitazone: increases rosiglitazone concentration
• Antifungals
  • Voriconazole: decreases voriconazole concentration

• Antimycobacterial
  • Rifampin: decreases letermovir concentration
• Antipsychotics
  • Pimozide: increases pimozide concentration; co-administration is contraindicated
• 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 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 (letermovir). 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, and is under accelerated review in 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 CMV and Treatment

CMV is a common virus that infects people of all ages. Many adults in the United States are CMV seropositive, meaning they have CMV antibodies in their blood, indicating a previous exposure to or primary infection with CMV. People with normal immune systems rarely develop CMV symptoms after initial infection, with the virus typically remaining inactive or latent in the body for life. A weakened immune system may give the virus a chance to reactivate, potentially leading to symptomatic disease or a secondary infection due to other pathogens. CMV disease can lead to end-organ damage, including gastrointestinal tract disease, pneumonia or retinitis. Transplant recipients who develop CMV infection post-transplant are at increased risk for transplant failure and death. CMV prophylaxis with certain existing antivirals has been associated with drug-specific effects, including myelosuppression and renal toxicity, in HSCT recipients.

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).

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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.

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