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

KENILWORTH, N.J.–(BUSINESS WIRE)–$MRK #MRK–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:

  • 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 (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
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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.

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