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 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.
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version on businesswire.com: http://www.businesswire.com/news/home/20171206005351/en/
Merck & Co., Inc.Media:Pam Eisele, 267-305-3558Robert
Consalvo, 908-740-6518orInvestors:Teri Loxam, 908-740-1986Amy Klug,
908-740-1898
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