PREVYMIS now approved for CMV prophylaxis
after kidney transplant in Donor CMV-seropositive/Recipient
CMV-seronegative patients
Merck (NYSE: MRK), known as MSD outside of the United States and
Canada, today announced the U.S. Food and Drug Administration (FDA)
has approved a new indication for PREVYMIS® (letermovir) for
prophylaxis of cytomegalovirus (CMV) disease in adult kidney
transplant recipients at high risk (Donor
CMV-seropositive/Recipient CMV-seronegative [D+/R-]) following a
priority review.
PREVYMIS is an antiviral agent that was initially approved by
the FDA in 2017 for prophylaxis of CMV infection and disease in
adult CMV-seropositive recipients [R+] of an allogeneic
hematopoietic stem cell transplant (HSCT). PREVYMIS is administered
once-daily as an oral tablet or as an injection for intravenous
infusion.
PREVYMIS is contraindicated in patients receiving pimozide or
ergot alkaloids. Increased pimozide concentrations due to
concomitant administration of PREVYMIS may lead to QT prolongation
and torsades de pointes. Increased ergot alkaloids concentrations
due to concomitant administration of PREVYMIS 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. 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. See additional Selected Safety Information
below.
“PREVYMIS has been an important addition to the care of
high-risk adult CMV-seropositive patients who have received
allogeneic stem cell transplants to help prevent CMV infection and
disease. We are delighted that PREVYMIS is now approved to help
prevent CMV disease in adult kidney transplant patients at high
risk,” said Dr. Elizabeth Rhee, vice president, global clinical
development, Merck Research Laboratories. “At Merck, we are proud
to continue to bring innovative medicines to people to address
serious infectious diseases.”
Phase 3 study for PREVYMIS in high-risk adult kidney
transplant recipients [CMV D+/R-]
The FDA approval of PREVYMIS for CMV disease prophylaxis in
adult kidney transplant recipients was supported by a Phase 3,
randomized, multicenter, double-blind, active comparator-controlled
non-inferiority trial (P002, NCT03443869) in 589 adult kidney
transplant recipients at high risk (CMV D+/R-). Participants were
randomized (1:1) to receive either PREVYMIS concomitantly with
acyclovir (n=292), or valganciclovir concomitantly with a placebo
to acyclovir (n=297). Study drug was initiated between Day 0 and
Day 7 post-kidney transplant and continued through Week 28 (~200
days) post-transplant. Study drug was administered either orally or
IV; the dose of PREVYMIS was the same regardless of the route of
administration. Three participants received IV PREVYMIS for a mean
duration of 1.7 days. Participants were monitored through Week 52
post-transplant. The median age was 51 years (range: 18 to 82
years); 72% were male; 84% were White; 9% were Black; 3% were
multiple; 2% were Asian; 1% Alaskan native or American Indian; 17%
were Hispanic or Latino; and 60% received a kidney from a deceased
donor. The most common primary reasons for transplant were
congenital cystic kidney disease (17%), hypertension (16%), and
diabetes/diabetic nephropathy (14%).
The study demonstrated that PREVYMIS was non-inferior to
valganciclovir, the current standard of care, for the primary
endpoint of incidence of CMV disease (CMV end-organ disease or CMV
syndrome, confirmed by an independent adjudication committee)
through Week 52 post-kidney transplant. The proportion of study
participants with CMV disease through Week 52 post-kidney
transplant was 10% with PREVYMIS and 12% with valganciclovir
(stratum-adjusted treatment difference = -1.4, [95% confidence
interval, -6.5, 3.8], meeting the pre-specified non-inferiority
margin of 10%). The incidence of CMV syndrome (defined as evidence
of CMV in blood by viral isolation, rapid culture, antigenemia, or
nucleic acid testing, and two or more of the following: 1) fever
≥38°C for at least 2 days, 2) new or increased malaise/fatigue, 3)
leukopenia or neutropenia on two separate measurements at least 24
hours apart, 4) ≥5% atypical lymphocytes, 5) thrombocytopenia, 6)
elevation of ALT or AST to 2x the upper limit of normal) was 8% vs
11%, respectively. The incidence of CMV end organ disease was 2% vs
less than 1%, respectively. For purposes of these analyses,
participants who discontinued prematurely from the study for any
reason or were missing data at the timepoint were not counted as
failures. The number of participants who discontinued from the
study before Week 52 was 32 (11%) in the PREVYMIS arm and 28 (9%)
in the valganciclovir arm. The number of participants with a
missing outcome in the Week 52 visit window was 24 (8%) in the
PREVYMIS arm and 25 (8%) in the valganciclovir arm.
Efficacy was comparable across all subgroups. This included the
subgroups that used or did not use highly cytolytic,
anti-lymphocyte immunotherapy during induction, which was a
stratification factor at randomization.
In an exploratory analysis of the incidence of CMV disease
through Week 28 post-transplant, the difference (PREVYMIS –
valganciclovir) was -1.7% with a 95% CI of (-3.4, 0.1). No subjects
in the PREVYMIS group experienced CMV disease through Week 28
post-transplant (end of treatment period) compared with five
subjects in the valganciclovir group.
The safety of PREVYMIS was also evaluated in the Phase 3 (P002)
study. Adverse events (AEs) were those reported while participants
were on study medication or within two weeks of study medication
completion/discontinuation. Diarrhea was reported in at least 10%
of participants in the PREVYMIS group and at a frequency greater
than valganciclovir (PREVYMIS, 32%; valganciclovir, 29%). Study
drug was discontinued due to an AE in 4% of PREVYMIS participants
and 14% of valganciclovir participants. The most frequently
reported AEs that led to study drug discontinuation were
neutropenia (PREVYMIS, 1%; valganciclovir, 2%) and leukopenia
(PREVYMIS, 1%; valganciclovir, 5%).
The Phase 3 study also collected information on laboratory
abnormalities reported through week 28 post-transplant. Selected
laboratory abnormalities were as follows:
PREVYMIS N=292
Valganciclovir
N=297
Absolute neutrophil count (cells/μL)
< 500
2%
7%
500 – < 750
1%
4%
750 – < 1000
1%
8%
Total < 1000
5%
18%
Hemoglobin (g/dL)
< 6.5
2%
0%
6.5 – < 8.0
4%
5%
8.0 – < 9.5
29%
32%
Total < 9.5
34%
37%
Platelets (cells/μL)
< 50000
0%
0%
50000 – < 100000
1%
3%
Total < 100000
1%
3%
Leukocytes (cells/μL)
< 1000
1%
2%
1000 – < 2000
5%
19%
2000 – < 2500
4%
14%
Total < 2500
10%
35%
Serum creatinine (mg/dL)
> 2.5
24%
22%
> 1.5 – 2.5
49%
52%
Total > 1.5
73%
73%
Dosing of PREVYMIS in high-risk adult kidney transplant
recipients
The recommended dosage of PREVYMIS is 480 mg administered once
daily orally or as an intravenous infusion, initiated as early as
Day 0 and up to Day 7 post-kidney transplant and continued through
Day 200 post-transplant. If PREVYMIS is co-administered with
cyclosporine, the dosage of oral or intravenous PREVYMIS should be
decreased to 240 mg once daily. PREVYMIS 240 mg and 480 mg tablets
may be administered with or without food. Following the completion
of PREVYMIS prophylaxis, monitoring for CMV reactivation is
recommended.
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. In patients
with CLcr less than 50 mL/min receiving PREVYMIS injection,
accumulation of the intravenous vehicle, hydroxypropyl betadex,
could occur. Serum creatinine levels should be closely monitored in
these patients.
PREVYMIS injection, which contains hydroxypropyl betadex, should
be used only in patients unable to take oral therapy. Patients
should be switched to oral PREVYMIS as soon as they are able to
take oral medications. PREVYMIS tablet and injection may be used
interchangeably at the discretion of the physician, and no dosage
adjustment is necessary when switching formulations.
No dosage adjustment of PREVYMIS is required for patients with
mild (Child-Pugh Class A) or 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 inhibits viral replication by targeting the CMV DNA
terminase complex. PREVYMIS is now approved for prophylaxis of CMV
disease in adult kidney transplant recipients at high risk (Donor
CMV-seropositive/Recipient CMV-seronegative [D+/R-]). Since 2017,
PREVYMIS has been the only drug approved in the United States for
prophylaxis of CMV infection and disease in adults who are
CMV-seropositive [R+] and have received an allogeneic HSCT, and has
also been approved for this indication in more than 60 countries
including EU member states, Canada, Japan and China. 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).
Selected Safety Information about PREVYMIS
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.
The rates of adverse events in the first 100 days following HSCT
occurring in at least 10% of transplant recipients treated with
PREVYMIS 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%).
Hypersensitivity reaction, with associated moderate dyspnea,
occurred in one HSCT subject following the first infusion of IV
PREVYMIS after switching from oral PREVYMIS, leading to treatment
discontinuation.
The most common adverse event occurring in at least 10% of
kidney transplant recipients treated with PREVYMIS and at a
frequency greater than valganciclovir was diarrhea (32% vs
29%).
If PREVYMIS is co-administered with cyclosporine, the dosage of
PREVYMIS should be decreased to 240 mg once daily.
Co-administration of PREVYMIS may alter the plasma
concentrations of other drugs and other drugs may alter the plasma
concentrations of PREVYMIS. Consult the full Prescribing
Information prior to and during treatment for potential drug
interactions.
Closely monitor serum creatinine levels in patients with CLcr
less than 50 mL/min using PREVYMIS injection.
PREVYMIS is not recommended for patients with severe (Child-Pugh
Class C) hepatic impairment.
The safety and efficacy of PREVYMIS 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.
About CMV
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 healthy
immune systems rarely develop CMV symptoms after initial infection,
with the virus typically remaining inactive or latent in the body
for life. CMV‐seronegative recipients who receive an organ from a
CMV‐seropositive donor [D+/R-] are at high risk of CMV disease
after transplantation.
About Merck
At Merck, known as MSD outside of the United States and Canada,
we are unified around our purpose: We use the power of leading-edge
science to save and improve lives around the world. For more than
130 years, we have brought hope to humanity through the development
of important medicines and vaccines. We aspire to be the premier
research-intensive biopharmaceutical company in the world – and
today, we are at the forefront of research to deliver innovative
health solutions that advance the prevention and treatment of
diseases in people and animals. We foster a diverse and inclusive
global workforce and operate responsibly every day to enable a
safe, sustainable and healthy future for all people and
communities. For more information, visit www.merck.com and connect
with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
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N.J., USA
This news release of Merck & Co., Inc., Rahway, 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
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There can be no guarantees with respect to pipeline candidates that
the candidates 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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the impact of the global outbreak of novel coronavirus disease
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The company undertakes no obligation to publicly update any
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(SEC) available at the SEC’s Internet site (www.sec.gov).
Please see Prescribing Information for PREVYMIS at
https://www.merck.com/product/usa/pi_circulars/p/prevymis/prevymis_pi.pdf
and Patient Information/Medication Guide for PREVYMIS at
https://www.merck.com/product/usa/pi_circulars/p/prevymis/prevymis_ppi.pdf.
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