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 (12%).
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 completed.
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 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 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,
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 (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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MerckMedia:Pam Eisele, 267-305-3558Robert Consalvo,
908-740-6518orInvestors:Teri Loxam, 908-740-1986Amy Klug,
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