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).
# # #
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/20171113005143/en/
MerckMedia:Pamela Eisele, 267-305-3558orRobert Consalvo,
908-740-6518orInvestor:Teri Loxam, 908-740-1986orAmy Klug,
908-740-1898
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