- LIVTENCITY Is the First and Only Inhibitor of CMV-specific
UL97 Protein Kinase Approved in China for the Treatment of Adults
With Post-transplant CMV Infection/Disease Refractory* to
Conventional Anti-CMV Treatment - Approval Based on Phase 3
TAK-620-303 SOLSTICE Study Demonstrating Maribavir Was Superior to
Conventional Therapies at Week 8, for Primary Endpoint1 - CMV Is
One of the Most Common and Serious Post-transplant Infections and
Can Lead to Other Serious Infections, Loss of Transplanted Organ
and Failure of Graft2,3
Takeda (TSE:4502/NYSE:TAK) today announced that LIVTENCITY®
(maribavir) has been approved by the National Medical Products
Administration (NMPA) of China for the treatment of adult patients
with post-hematopoietic stem cell transplant (HSCT) or solid organ
transplant (SOT) cytomegalovirus (CMV) infection/disease that is
refractory to treatment (with or without genotypic resistance) with
ganciclovir, valganciclovir, cidofovir or foscarnet. LIVTENCITY is
the first and only inhibitor of CMV-specific UL97 protein kinase in
China for this indication. LIVTENCITY was granted Breakthrough
Therapy Designation by China Center for Drug Evaluation (CDE) in
2021.
“The approval of LIVTENCITY by the NMPA of China recognizes the
critical need for post-transplant care and that CMV infection, when
not successfully treated, can pose serious challenges to transplant
recipients that can lead to complications such as increased organ
rejection and hospitalization rates,” said Ramona Sequeira,
president, Global Portfolio Division, Takeda. “This approval will
help redefine the CMV treatment landscape for transplant patients
in China and is a positive step forward toward addressing an unmet
need for this community.”
The NMPA approval is based on the results of the Phase 3
SOLSTICE trial, which evaluated the safety and efficacy of
maribavir versus conventional antiviral therapies – ganciclovir,
valganciclovir, cidofovir or foscarnet – for the treatment of
patients with CMV infection/disease refractory* to prior therapies.
In the SOLSTICE trial, LIVTENCITY was superior to conventional
therapies at Week 8 for the primary endpoint of confirmed CMV
viremia clearancea in post-transplant adults with refractory* CMV
infection.1
The NMPA approval marks the 12th approval of LIVTENCITY around
the world for post-transplant CMV refractory* to prior therapies,
including four other major markets beyond China: the United States,
Canada, Australia and the European Union.4-7
Out of the estimated 200,000 adult transplants per year
globally, CMV is one of the most common infections experienced by
transplant patients with an estimated incidence rate of 16%-56% in
SOT and 30%-80% in HSCT recipients.8,9
About LIVTENCITY
LIVTENCITY (maribavir), an orally bioavailable anti-CMV
compound, is the first and only antiviral agent that targets and
inhibits the UL97 protein kinase and thus its natural substrates.1
It is approved by the National Medical Products Administration
(NMPA) of China for the treatment of adults with post-HSCT or SOT
cytomegalovirus (CMV) infection/disease that is refractory to
treatment (with or without genotypic resistance) with ganciclovir,
valganciclovir, cidofovir or foscarnet.
Product Name
LIVTENCITY 200 mg film coated tablets.
Generic Name
Maribavir
Posology and Administration
LIVTENCITY should be initiated by a
physician experienced in the management of patients who have
undergone solid organ transplant or hematopoietic stem cell
transplant. Posology: The recommended dose of LIVTENCITY is 400 mg
(two 200 mg tablets) twice daily resulting in a daily dose of 800
mg for 8 weeks. Treatment duration may need to be individualized
based on the clinical characteristics of each patient. Pediatric
population: The safety and efficacy of LIVTENCITY in patients below
18 years of age have not been established. No data are available.
Method of administration: Oral use. LIVTENCITY is intended for oral
use only and can be taken with or without food. The film coated
tablet can be taken as a whole tablet, a crushed tablet, or a
crushed tablet through a nasogastric or orogastric tube.
About Takeda’s SOLSTICE Trial
The TAK-620-303 (SOLSTICE) trial (NCT02931539, EudraCT
2015-004725-13) was a global, multicenter, randomized, open-label,
active-controlled superiority trial to assess the efficacy and
safety of treatment with either maribavir or conventional antiviral
therapy in 352 hematopoietic stem cell transplant and solid organ
transplant recipients with CMV infection refractory* to one or a
combination of the conventional antiviral therapies: ganciclovir,
valganciclovir, foscarnet, or cidofovir. Adult patients underwent a
2-week screening period, followed by randomization 2:1 to maribavir
(n=235) (400 mg, twice daily) or conventional antiviral therapies
(n=117) (as dosed by the investigator) for up to 8 weeks. After
completion of the treatment period, subjects entered a 12-week
follow-up phase.1
The trial’s primary efficacy endpoint was confirmed CMV viremia
clearance a at the end of Week 8. The key secondary endpoint was
confirmed CMV viremia clearance and CMV infection symptom control†
at the end of Study Week 8 with maintenance of this treatment
effect through Study Week 16.1
About CMV
CMV is a beta herpesvirus that commonly infects humans;
serologic evidence of prior infection can be found in 40-100% of
various adult populations.10 CMV typically resides latent and
asymptomatic in the body but may reactivate during periods of
immunosuppression. Serious disease may occur in individuals with
compromised immune systems, which includes patients who receive
immunosuppressants associated with various types of transplants
including HSCT or SOT.8 Out of the estimated 200,000 adult
transplants per year globally, CMV is one of the most common viral
infections experienced by transplant recipients, with an estimated
incidence rate between 16-56% in SOT recipients and 30-80% in HSCT
recipients.8,9
In transplant recipients, reactivation of CMV can lead to
serious consequences including graft loss and, in extreme cases,
can be fatal.1,2 Existing therapies to treat post-transplant CMV
infections may demonstrate serious side effects that require dose
adjustments or may fail to adequately suppress viral replication.11
Additionally, existing therapies may require or prolong
hospitalization due to administration.11,12
About Takeda
Takeda is focused on creating better health for people and a
brighter future for the world. We aim to discover and deliver
life-transforming treatments in our core therapeutic and business
areas, including gastrointestinal and inflammation, rare diseases,
plasma-derived therapies, oncology, neuroscience and vaccines.
Together with our partners, we aim to improve the patient
experience and advance a new frontier of treatment options through
our dynamic and diverse pipeline. As a leading values-based,
R&D-driven biopharmaceutical company headquartered in Japan, we
are guided by our commitment to patients, our people and the
planet. Our employees in approximately 80 countries and regions are
driven by our purpose and are grounded in the values that have
defined us for more than two centuries. For more information, visit
www.takeda.com.
LIVTENCITY Safety Information
Contraindications
Hypersensitivity to the active substance or to any of the
excipients and co-administration with ganciclovir or
valganciclovir.
Special warnings and precautions for use
Virologic failure can occur during and after treatment with
LIVTENCITY. Some maribavir pUL97 resistance-associated
substitutions confer cross-resistance to ganciclovir and
valganciclovir. CMV DNA levels should be monitored, and resistance
mutations should be investigated in patients who do not respond to
treatment. Treatment should be discontinued if maribavir resistance
mutations are detected.
LIVTENCITY is not expected to be effective in treating CMV CNS
infections (e.g. meningo encephalitis).
LIVTENCITY has the potential to increase the concentrations of
immunosuppressants that are cytochrome P450 (CYP)3A/P-gp substrates
with narrow therapeutic margins (including tacrolimus,
cyclosporine, sirolimus and everolimus). The plasma levels of these
immunosuppressants must be frequently monitored throughout
treatment with LIVTENCITY, especially following initiation and
after discontinuation of LIVTENCITY, and doses should be adjusted,
as needed.
The concomitant use of LIVTENCITY and certain medicinal products
may result in known or potentially significant medicinal product
interactions, some of which may lead to:
- possible clinically significant adverse reactions from greater
exposure of concomitant medicinal products.
- reduced therapeutic effect of LIVTENCITY.
Sodium content: This medicinal product contains less than 1 mmol
sodium (23 mg) per tablet, that is to say essentially ‘sodium
free’.
Pregnancy & Breast-feeding: LIVTENCITY is not recommended
during pregnancy and in women of childbearing potential not using
contraception. Breast feeding should be discontinued during
treatment with LIVTENCITY.
Interactions
If dose adjustments of concomitant medicinal products are made
due to treatment with maribavir, doses should be readjusted after
treatment with maribavir is completed.
Effect of other medicinal products on maribavir:
Co-administration of maribavir with strong cytochrome P450 3A
(CYP3A) inducers rifampicin, rifabutin or St. John’s wort is not
recommended. If co-administration of maribavir with other strong or
moderate CYP3A inducers (e.g., carbamazepine, efavirenz,
phenobarbital and phenytoin) cannot be avoided, the maribavir dose
should be increased to 1 200 mg twice daily. No dose adjustment is
needed when maribavir is co-administrated with CYP3A
inhibitors.
Effect of maribavir on other medicinal products:
Co-administration of maribavir with valganciclovir and ganciclovir
is contraindicated. Concomitant administration of maribavir and
medicinal products that are sensitive substrates of CYP1A2 with a
narrow therapeutic window (e.g., tizanidine and theophylline)
should be avoided due to the risk for lack of efficacy of CYP1A2
substrates.
When the immunosuppressants tacrolimus, cyclosporine, everolimus
or sirolimus are co-administered with maribavir, immunosuppressant
levels should be frequently monitored throughout treatment with
maribavir, especially following initiation and after
discontinuation of maribavir and dose adjusted, when needed.
Caution should be exercised when maribavir and sensitive P-gp
substrates (e.g., digoxin, dabigatran) are co administered. Serum
digoxin concentrations should be monitored, and dose of digoxin may
need to be reduced, as needed.
Co-administration of maribavir with sensitive BCRP substrates
such as rosuvastatin, is expected to increase their exposure and
lead to undesirable effects.
Adverse Reactions
Very common
(≥1/10)
Taste disturbance, Diarrhea, Nausea,
Vomiting, Fatigue
Common
(≥1/100 to <1/10)
Headache, Abdominal pain upper, Decreased
appetite, Immunosuppressant drug level increased, Weight
decreased
The most commonly reported serious adverse reactions were
diarrhea (2%) and nausea, weight decreased, fatigue,
immunosuppressant drug concentration level increased, and vomiting
(all occurring at >1%).
Please consult the LIVTENCITY (maribavir) approved label
before prescribing, particularly in relation to dosing and
treatment monitoring.
For the European Union, please consult the Summary of
Products Characteristics (SmPC).
For China, please consult the LIVTENCITY China Package
Leaflet.
For full U.S. Prescribing Information, including the approved
indication and important safety information, please visit:
https://content.takeda.com/?contenttype=pi&product=liv&language=eng&country=usa&documentnumber=1
Important Notice
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Takeda’s other reports filed with the U.S. Securities and Exchange
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Takeda does not undertake to update any of the forward-looking
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Medical information
This press release contains information about products that may
not be available in all countries, or may be available under
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dosages, or in different strengths. Nothing contained herein should
be considered a solicitation, promotion or advertisement for any
prescription drugs including the ones under development.
* Including a subgroup with genotypic resistance to conventional
therapies. a Defined as confirmed CMV DNA concentration below the
lower limit of quantification (<LLOQ; i.e., <137 IU/mL) in
two consecutive samples separated by at least five days. † CMV
infection symptom control was defined as resolution or improvement
of tissue-invasive disease or CMV syndrome for symptomatic patients
at baseline, or no new symptoms for patients who were asymptomatic
at baseline.
References
- Avery R, Alain S, Alexander BD, et al. SOLSTICE Trial
Investigators. Maribavir for refractory cytomegalovirus infections
with or without resistance post-transplant: results from a phase 3
randomized clinical trial. Clin Infect Dis. 2022;75(4):690–701.
doi:10.1093/cid/ciab988
- Ramanan P, Razonable RR. Cytomegalovirus infections in solid
organ transplantation: a review. Infection & Chemotherapy.
2013;45(3):260
- Camargo JF, Komanduri KV. Emerging concepts in cytomegalovirus
infection following hematopoietic stem cell transplantation.
Hematol Oncol Stem Cell Ther. 2017;10(4):233-238.
doi:10.1016/j.hemonc.2017.05.001
- Takeda. Health Canada approves Takeda’s LIVTENCITYTM
(maribavir) the first and only treatment for adults with
post-transplant cytomegalovirus (CMV) infection. Published
September 20, 2022. Accessed December 12, 2023.
https://www.takeda.com/en-ca/newsroom/news-releases/2022/health-canada-approves-takedas-livtencity-maribavir-the-first-and-only-treatment-for-adults-with-post-transplant-cytomegalovirus-cmv-infection/
- Takeda. Takeda’s LIVTENCITY (maribavir) approved by U.S. FDA as
the first and only treatment for people ages 12 and older with
post-transplant cytomegalovirus (CMV), refractory (with or without
genotypic resistance) to conventional antiviral therapies.
Published November 23, 2021. Accessed December 12, 2023.
https://www.businesswire.com/news/home/20211123006185/en/Takeda%E2%80%99s-LIVTENCITYTM-maribavir-Approved-by-U.S.-FDA-as-the-First-and-Only-Treatment-for-People-Ages-12-and-Older-with-Post-Transplant-Cytomegalovirus-CMV-Refractory-With-or-Without-Genotypic-Resistance-to-Conventional-Antiviral-Therapies
- Therapeutic Goods Administration (TGA). LIVTENCITY maribavir
200 mg film coated tablet bottle (380132) [Australian product
information]. Therapeutic Goods Administration (TGA). Published
October 8, 2022. https://www.tga.gov.au/resources/artg/380132
- Takeda. European Commission (EC) approves LIVTENCITY
(maribavir) for the treatment of adults with post-transplant
cytomegalovirus (CMV) infection and/or disease that are refractory
(with or without resistance) to one or more prior therapies.
Published November 11, 2022. Accessed December 12, 2023.
https://www.takeda.com/newsroom/newsreleases/2022/european-commission-ec-approves-livtencitytm-maribavir/
- Azevedo LS, Pierrotti LC, Abdala E, et al. Cytomegalovirus
infection in transplant recipients. Clinics (Sao Paolo).
2015;70(7):515-523. doi:10.6061/clinics/2015(07)09
- Styczynski J. Who is the patient at risk of CMV recurrence: a
review of the current scientific evidence with a focus on
hematopoietic cell transplantation. Infect Dis Ther. 2018;(7):1-16.
doi:10.1007/s40121-017-0180-z
- de la Hoz RE, Stephanie G, Sherlock C. Diagnosis and treatment
approaches to CMV infections in adult patients. J Clin Virol.
2002;25(Suppl 1):S1-S12. doi:10.1016/s1386-6532(02)00091-4
- Chemaly RF, Chou S, Einsele H, et al. Definitions of resistant
and refractory cytomegalovirus infection and disease in transplant
recipients for use in clinical trials. Clin Infect Dis.
2019;68(8):1420-1426. doi:10.1093/cid/ciy696
- Martín-Gandul C, Pérez-Romero P, González-Roncero FM, et al.
Clinical impact of neutropenia related with the preemptive therapy
of CMV infection in solid organ transplant recipients. J Infect.
2014;69(5):500-6. doi:10.1016/j.jinf.2014.07.001
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version on businesswire.com: https://www.businesswire.com/news/home/20231221976317/en/
International Media JC Molina jc.molina@takeda.com
China Media Shirley Zhu Shirley.zhu@takeda.com
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