Practice guidelines
Cytomegalovirus Infection In Solid Organ Transplant Recipients
Cytomegalovirus (CMV) infection can occur either from a primary infection or the reactivation of an endogenous infection. It is one of the most common complications affecting solid organ transplant recipients.
Donor and recipient CMV serostatus is the highest risk factor. Incidence is highest among CMV-seronegative patients receiving an organ from a CMV-seropositive donor. Transplantation of an organ or blood from a donor may lead to the development of CMV in the recipient, who is then unable to mount an effective immune response to control primary infection with posttransplant drug-induced immunosuppression.
Other risk factors include:
CMV-related diseases significantly contribute to the morbidity and mortality of solid organ transplant recipients.
Clinical PresentationThe clinical presentation varies as CMV may attack any organ. Since this is the case, the patient may present with symptoms such as viral syndrome with fever and general malaise, or tissue invasive disease manifesting as:
DiagnosisClinicians should suspect CMV-related disease in solid organ transplant recipients who present with:
The diagnosis of CMV disease requires certain clinical signs and symptoms in addition to evidence of CMV in clinical specimens. Clinicians can perform a blood test to detect CMV by polymerase chain reaction (PCR) in patients suspected of CMV disease. CMV antigenemia may be used if PCR testing is not available.
In patients with presumed CMV syndrome, in addition to testing for CMV in the blood, diagnosis includes ≥2 of the following:
In patients with suspected tissue-invasive disease, obtain a biopsy from the site of concern and perform histology and immunohistochemistry for identification of CMV cytopathic or viral changes. Evaluation of tissue-invasive disease may also include upper or lower endoscopy or imaging studies. Additionally, other blood tests to consider include complete blood count with differential, as well as renal and hepatic function tests.
ManagementTreatment consists of antiviral therapy and adjustments to immunosuppressive therapy.
Antiviral TherapyGive patients with mild to moderate disease who can tolerate and adhere to oral therapy, valganciclovir 900 mg orally every 12 hours (adjusted for renal impairment).Treat patients with severe or life-threatening disease with ganciclovir 5 mg/kg IV every 12 hours (adjusted for renal impairment). In patients intolerant to valganciclovir or ganciclovir, use foscarnet.
Suspect antiviral resistance in patients with prior cumulative exposure to valganciclovir or ganciclovir > 6 weeks and clinical treatment failure despite ≥ 2 weeks of antiviral treatment.
Maribavir is FDA approved for treatment of post-transplant CMV infection in patients ≥ 12 years old and weighing ≥ 35 kg, which is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir, or foscarnet.
Confirm resistance using genotypic assays to identify viral mutations. Treat patients with proven or suspect antiviral resistance with increased dose of ganciclovir, foscarnet, combination therapy, or alternative medications.
Reduction of Immunosuppressive TherapyConsider reduction of immunosuppressive therapy when patients have severe CMV disease, inadequate clinical response to therapy, high CMV viral load, or cytopenias
Reduction of immunosuppression is not appropriate in patients with concomitant graft rejection. It's important to monitor patients weekly with PCR assay or antigenemia assay, if PCR unavailable.
Administer antiviral therapy for ≥ 2 weeks until disease resolves clinically and viral eradication is achieved, proven with negative DNA testing on 1 or 2 consecutive weekly samples. Consider secondary prophylaxis to prevent recurrent CMV infection after resolution of CMV infection and/or disease, especially in high-risk patients.
Prevention of CMV DiseaseIdentifying high-risk patients by type of transplant and screening donors and recipients for CMV antibody can aid in prevention of the disease. Moreover, consider administering antiviral prophylaxis using universal prophylaxis or preemptive screening and treatment.
ComplicationsCMV disease is associated with complications such as acute and chronic allograft injury, acute graft rejection, lymphoproliferative disorders, and opportunistic infections. These infections include bacterial, fungal, and viral. CMV disease may also increase mortality in patients receiving kidney, heart, and lung transplantations.
This article originally appeared on Clinical Advisor
Takeda Announces China NMPA Approval Of LIVTENCITY® (maribavir) For The Treatment Of Adults With Post-transplant Cytomegalovirus (CMV) Refractory To Prior Therapies
- 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
OSAKA, Japan & CAMBRIDGE, Massachusetts--(BUSINESS WIRE)-- 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:
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
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Very common
(≥1/10)
Taste disturbance, Diarrhea, Nausea, Vomiting, Fatigue
Common
(≥1/100 to 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
For the purposes of this notice, "press release" means this document, any oral presentation, any question and answer session and any written or oral material discussed or distributed by Takeda Pharmaceutical Company Limited ("Takeda") regarding this release. This press release (including any oral briefing and any question-and-answer in connection with it) is not intended to, and does not constitute, represent or form part of any offer, invitation or solicitation of any offer to purchase, otherwise acquire, subscribe for, exchange, sell or otherwise dispose of, any securities or the solicitation of any vote or approval in any jurisdiction. No shares or other securities are being offered to the public by means of this press release. No offering of securities shall be made in the United States except pursuant to registration under the U.S. Securities Act of 1933, as amended, or an exemption therefrom. This press release is being given (together with any further information which may be provided to the recipient) on the condition that it is for use by the recipient for information purposes only (and not for the evaluation of any investment, acquisition, disposal or any other transaction). Any failure to comply with these restrictions may constitute a violation of applicable securities laws.
The companies in which Takeda directly and indirectly owns investments are separate entities. In this press release, "Takeda" is sometimes used for convenience where references are made to Takeda and its subsidiaries in general. Likewise, the words "we", "us" and "our" are also used to refer to subsidiaries in general or to those who work for them. These expressions are also used where no useful purpose is served by identifying the particular company or companies.
Forward-Looking Statements
This press release and any materials distributed in connection with this press release may contain forward-looking statements, beliefs or opinions regarding Takeda's future business, future position and results of operations, including estimates, forecasts, targets and plans for Takeda. Without limitation, forward-looking statements often include words such as "targets", "plans", "believes", "hopes", "continues", "expects", "aims", "intends", "ensures", "will", "may", "should", "would", "could" "anticipates", "estimates", "projects" or similar expressions or the negative thereof. These forward-looking statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those expressed or implied by the forward-looking statements: the economic circumstances surrounding Takeda's global business, including general economic conditions in Japan and the United States; competitive pressures and developments; changes to applicable laws and regulations, including global health care reforms; challenges inherent in new product development, including uncertainty of clinical success and decisions of regulatory authorities and the timing thereof; uncertainty of commercial success for new and existing products; manufacturing difficulties or delays; fluctuations in interest and currency exchange rates; claims or concerns regarding the safety or efficacy of marketed products or product candidates; the impact of health crises, like the novel coronavirus pandemic, on Takeda and its customers and suppliers, including foreign governments in countries in which Takeda operates, or on other facets of its business; the timing and impact of post-merger integration efforts with acquired companies; the ability to divest assets that are not core to Takeda's operations and the timing of any such divestment(s); and other factors identified in Takeda's most recent Annual Report on Form 20-F and Takeda's other reports filed with the U.S. Securities and Exchange Commission, available on Takeda's website at: https://www.Takeda.Com/investors/sec-filings/ or at www.Sec.Gov. Takeda does not undertake to update any of the forward-looking statements contained in this press release or any other forward-looking statements it may make, except as required by law or stock exchange rule. Past performance is not an indicator of future results and the results or statements of Takeda in this press release may not be indicative of, and are not an estimate, forecast, guarantee or projection of Takeda's future results.
Medical information
This press release contains information about products that may not be available in all countries, or may be available under different trademarks, for different indications, in different 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 (
The views and opinions expressed herein are the views and opinions of the author and do not necessarily reflect those of Nasdaq, Inc.
China Approves Takeda's Post-transplant Cytomegalovirus Treatment
(RTTNews) - Takeda (TAK) said that Livtencity (maribavir) has been approved by the National Medical Products Administration or NMPA of China for the treatment of adult patients with post-hematopoietic stem cell transplant or solid organ transplant cytomegalovirus or 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.
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.
For More Such Health News, visit rttnews.Com.
The views and opinions expressed herein are the views and opinions of the author and do not necessarily reflect those of Nasdaq, Inc.
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