Merck Receives FDA Approval of PREVYMIS™ (letermovir) for Prevention of Cytomegalovirus (CMV) Infection and Disease in Adult Allogeneic Stem Cell Transplant Patients


November 9, 2017 6:45 am ET

CMV Prophylaxis with PREVYMIS Associated with Lower All-Cause Mortality Through Week 24 and Week 48 Post-Transplant

Merck & Co., Inc. (NYSE: MRK), known as MSD outside the United States
and Canada, today announced that the U.S. Food and Drug Administration
(FDA) has approved PREVYMIS™ (letermovir) once-daily tablets for oral
use and injection for intravenous infusion. PREVYMIS is indicated for
prophylaxis (prevention) of cytomegalovirus (CMV) infection and disease
in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic
stem cell transplant (HSCT).

CMV is a common and potentially serious viral infection in allogeneic
HSCT recipients. CMV-seropositive patients who undergo an HSCT are at
high risk for CMV reactivation. Any level of CMV infection is associated
with increased mortality in HSCT patients.

In the pivotal Phase 3 clinical trial supporting approval, significantly
fewer patients in the PREVYMIS group (38%, n=122/325) compared to the
placebo group (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. All-cause mortality
in patients receiving PREVYMIS was lower compared to placebo, 12% vs.
17%, respectively, at week 24 post-transplant. In this study, the
incidence of bone marrow suppression in the PREVYMIS group was
comparable to the placebo group. The median time to engraftment was 19
days in the PREVYMIS group and 18 days in the placebo group.

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 (letermovir) 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.

“Our findings demonstrate that letermovir is a significant and welcomed
advance in the prevention of clinically significant CMV infection and
lowers mortality in this highly vulnerable patient population,” 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 Boston.

The recommended dosage of PREVYMIS is 480 mg administered once daily,
initiated as early as Day 0 and up to Day 28 post-transplantation
(before or after engraftment), and continued through Day 100
post-transplantation. If PREVYMIS is co-administered with cyclosporine,
the dosage of oral or intravenous PREVYMIS should be decreased to 240 mg
once daily. PREVYMIS is available as 240 mg and 480 mg tablets, which
may be administered with or without food. PREVYMIS is also available as
240 mg and 480 mg injection for intravenous infusion via a peripheral
catheter or central venous line at a constant rate over one hour.

“PREVYMIS is the first new medicine for CMV infection approved in the
U.S. in 15 years,” said Dr. Roy Baynes, senior vice president, head of
clinical development, and chief medical officer, Merck Research
Laboratories. “PREVYMIS continues Merck’s longstanding tradition of
bringing forward important new therapies to address serious infectious
diseases. We are proud to add this breakthrough medicine to our existing
offerings for physicians and patients.”

PREVYMIS is expected to be available in December. The list price
(wholesaler acquisition cost) per day for PREVYMIS tablets is $195.00
and for PREVYMIS injection is $270.00. Wholesaler acquisition costs do
not include discounts that may be paid on the product.

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.

Clinical data supporting PREVYMIS (letermovir)

To evaluate prophylaxis with PREVYMIS as a preventive strategy for CMV
infection or disease in transplant recipients at high risk for CMV
reactivation, the efficacy of PREVYMIS was assessed in a multicenter,
double-blind, placebo-controlled Phase 3 trial in adult CMV-positive
recipients [R+] of an allogeneic HSCT. Patients were randomized (2:1) to
receive either PREVYMIS at a dose of 480 mg once daily adjusted to 240
mg when co-administered with cyclosporine, or placebo. Study drug was
initiated after HSCT (at any time from Day 0-28 post-transplant) and
continued through Week 14 post-transplant. Patients were monitored
through Week 24 post-transplant for the primary efficacy endpoint, with
continued follow-up through Week 48 post-transplant. The primary
efficacy endpoint was the incidence of clinically significant CMV
infection through Week 24 post-transplant, defined as the occurrence of
either CMV end-organ disease, or initiation of anti-CMV pre-emptive
therapy based on documented CMV viremia and the clinical condition of
the patient. The Non-Completer equals Failure approach was used, where
patients who discontinued from the trial prior to Week 24
post-transplant or had a missing outcome at Week 24 post-transplant were
counted as failures.

Among the 565 treated patients, 34% were engrafted at baseline and 30%
had one or more factors associated with additional risk for CMV
reactivation. The most common primary reasons for transplant were acute
myeloid leukemia (38%), myelodysplastic syndrome (16%), and lymphoma

Fewer patients in the PREVYMIS group had clinically significant CMV
infection by Week 24 post-HSCT compared to the placebo group, 18% vs.
42%, respectively. Through the Week 14 post-HSCT treatment period, 8% of
patients in the PREVYMIS group and 39% of patients in the placebo group
experienced clinically significant CMV infection. Clinically significant
CMV infection was defined as CMV end-organ disease or initiation of
pre-emptive therapy based on documented CMV viremia and the clinical
condition of the patient.

Efficacy results were consistent across high- and low-risk strata for
CMV reactivation.

PREVYMIS demonstrated significant benefit compared to placebo in time to
clinically significant CMV infection through Week 24 post-HSCT (18.9%
vs. 44.3% cumulative rate; stratified log-rank test, two-sided p-value
<0.0001). Post-hoc analysis demonstrated that among PREVYMIS-treated
patients, inclusion in the high-risk stratum for CMV reactivation at
baseline, occurrence of graft-versus-host disease (GVHD), and steroid
use at any time after randomization may be associated with the
development of clinically significant CMV infection between Week 14 and
Week 24 post-transplant.

The Kaplan-Meier event rate for all-cause mortality in the PREVYMIS vs.
placebo groups was 12% vs. 17% at Week 24 post-transplant, and 24% vs.
28% at Week 48 post-transplant.

Additional Selected Safety Information about PREVYMIS (letermovir)

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 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

Established or potentially clinically significant drug interactions may
occur with co-administration of PREVYMIS and drug/drug classes (without
cyclosporine, unless otherwise indicated), 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;
      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 (letermovir) in patients below 18
years of age have not been established.

For patients with 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

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. 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 the 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 (

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
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respect to pipeline products that the products will receive the
necessary regulatory approvals or that they will prove to be
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risks or uncertainties materialize, actual results may differ materially
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Risks and uncertainties include but are not limited to, general industry
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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


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

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