Letermovir Prophylaxis Associated with Lower
All-Cause Mortality Through Week 24 Post-Transplant
Company Plans to Submit New Drug
Applications for Letermovir in U.S. and EU in 2017
Merck & Co., Inc. (NYSE:MRK), known as MSD outside the
United States and Canada, today announced results of the pivotal
Phase 3 clinical study of letermovir, an investigational antiviral
medicine for the prevention of clinically-significant
cytomegalovirus (CMV) infection in adult (18 years and older)
CMV-seropositive recipients of an allogeneic hematopoietic stem
cell transplant (HSCT), also known as bone marrow transplant (BMT).
The study met its primary efficacy endpoint, showing that
significantly fewer patients with undetectable CMV DNA at the start
of study treatment developed clinically significant CMV infection
through Week 24 post-HSCT (using a non-complete equals failure
approach, in which patients who discontinued from the study prior
to Week 24 post-transplant or had a missing outcome at Week 24
post-transplant were counted as failures). In the study, letermovir
prophylaxis was associated with lower all-cause mortality through
Week 24 post-HSCT. Based on these results, Merck plans to submit
regulatory applications for the approval of letermovir in the
United States and European Union (EU) in 2017.
Results from the study were presented for the first time at the
BMT Tandem Meetings, the combined annual meetings of the Center for
International Blood & Marrow Transplant Research (CIBMTR) and
the American Society for Blood and Marrow Transplantation (ASBMT),
in Orlando, Fla., Feb. 22-26.
“These results showed that letermovir prophylaxis beginning
after HSCT and continuing through Day 100 post-transplant
significantly reduced CMV infection requiring preemptive antiviral
therapy through Week 24 post-transplant,” 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, who presented the data. “In this study, letermovir was
associated with lower all-cause mortality. Based on these findings,
letermovir as primary prophylaxis of CMV infection represents a
potential new strategy for the prevention of CMV in this high-risk
patient population.”
CMV is the most common clinically significant viral infection in
allogeneic HSCT recipients. HSCT is a medical procedure in the
field of hematologic oncology, most often performed for the
treatment of patients with certain cancers of the blood or bone
marrow, such as leukemia and lymphoma. While preemptive therapy
(treatment when CMV DNA is detected in the blood) with antiviral
medicines can reduce the incidence of CMV disease, CMV reactivation
post-HSCT is associated with higher mortality despite the use of
preemptive therapy.
“There is an unmet need for therapeutic options in the
prevention of CMV infection in hematopoietic stem cell transplant
recipients,” said Dr. Nicholas Kartsonis, vice president,
infectious disease clinical research, Merck Research Laboratories.
“As part of Merck’s long-standing commitment to developing
innovative approaches in the fight against infectious diseases, we
look forward to submitting regulatory applications for letermovir
this year.”
About the pivotal Phase 3 study
CMV seropositive HSCT recipients 18 years or older who had
undetectable plasma CMV DNA within 5 days of randomization were
eligible for the study. Patients were randomized in a 2:1 ratio to
receive either letermovir or placebo administered once daily,
either in oral tablet or intravenous formulation, through Week 14
(Day 100) post-HSCT. Letermovir was dosed at 480 mg/day (or 240
mg/day if the patient was on the immunosuppressant medication
cyclosporine). Letermovir was started after HSCT; as early as on
the day of transplant and no later than 28 days post-transplant.
Patients were assessed weekly through Week 14 and biweekly through
Week 24 for the primary efficacy endpoint of clinical significant
CMV infection. Patients who developed clinically significant CMV
infection, defined as the onset of CMV disease or initiation of
anti-CMV preemptive therapy based on documented viremia (as
measured by the central laboratory) and the clinical condition of
the patient, discontinued study drug and received anti-CMV
preemptive therapy. Patients continued to be followed for safety
every other month through Week 48 post-HSCT.
The primary endpoint of the study was the proportion of patients
with clinically significant CMV infection through Week 24 post-HSCT
among patients with undetectable CMV DNA at the start of study
treatment. Patients who discontinued the study early for any reason
or who had missing data at Week 24 post-HSCT were considered study
failures. All adverse events were analyzed through 14 days after
the last dose of study drug.
The study met its primary efficacy endpoint, showing that of 495
treated patients who had undetectable CMV DNA at the start of study
treatment, significantly fewer patients developed clinically
significant CMV infection in the letermovir arm (37.5%, n=122/325)
compared to the placebo arm (60.6%, n=103/170) through Week 24
post-HSCT [treatment difference: -23.5 (95% confidence interval
-32.5 to -14.6), one-sided p<0.0001].
Efficacy was consistently demonstrated across patient subgroups.
Letermovir demonstrated significant benefit compared to placebo in
time to clinically significant CMV infection through Week 24
post-HSCT in both patients at higher risk and lower risk for CMV
disease at baseline (log-rank two-sided p<0.0001 for both
groups).
In addition, a secondary endpoint evaluating the
end-of-treatment period (at Week 14 post-HSCT) showed that
significantly fewer patients developed clinically significant CMV
infection in the letermovir arm (19.1%, n=62/325) compared to the
placebo arm (50.0%, n=85/170) through Week 14 (Day 100) post-HSCT
[treatment difference: -31.3 (95% confidence interval -39.9 to
-22.6), one-sided p<0.0001].
In this study, letermovir was associated with lower all-cause
mortality through Week 24 post-HSCT (9.8%, n=32/325) compared to
placebo (15.9%, n=27/170), log-rank two-sided p=0.0317.
The most common adverse events of any severity reported for the
letermovir and placebo arms, respectively, were: graft-versus-host
disease (GVHD) (39.1%, 38.5%), diarrhea (26.0%, 24.5%) and nausea
(26.5%, 23.4%). Common adverse events that were reported more
frequently in the letermovir arm than the placebo arm included:
vomiting (18.5%, 13.5%), cough (14.2%, 10.4%) and peripheral edema
(14.5%, 9.4%). The most common serious adverse events reported for
the letermovir and placebo arms, respectively, were: infection
(20.6%, 18.8%), GVHD (9.9%, 10.4%) and acute kidney injury (1.3%,
4.7%). Letermovir was not associated with myelotoxicity or
nephrotoxicity.
About letermovir
Letermovir is an investigational once-daily antiviral medicine
under development for the prevention of CMV infection and disease.
It 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. Letermovir has
no activity against other viruses. Letermovir has been granted
orphan designation by the European Medicines Agency, the U.S. Food
and Drug Administration (FDA) and the Japanese Ministry of Health,
Labour and Welfare for the prevention of CMV infection and disease
in at-risk populations. Letermovir also has been granted Fast Track
designation by the FDA.
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 infection
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 or
primary infection to 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 injury to a transplanted organ. In severely
immunocompromised patients, CMV infection can be
life-threatening.
About Merck
For over a century, Merck has been a global health care leader
working to help the world be well. Merck is known as MSD outside
the United States and Canada. 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. For more information, visit
www.merck.com and connect with us on Twitter, Facebook, YouTube and
LinkedIn.
Forward-Looking Statement
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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
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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
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actual results may differ materially from those set forth in the
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MerckMedia:Pam Eisele, 267-305-3558Robert Consalvo,
908-236-1127orInvestors:Teri Loxam, 908-740-1986Amy Klug,
908-740-1898
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