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


November 13, 2017 8:00 am ET

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

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

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

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
  • 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
    • 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

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 (

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,
and connect with us on Twitter,
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 (

# # #

Please see Prescribing Information for PREVYMIS (letermovir) at
and Patient Information for PREVYMIS at

Pamela Eisele, 267-305-3558
Robert Consalvo, 908-740-6518
Teri Loxam, 908-740-1986
Amy Klug, 908-740-1898

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