Osaka, Japan & Cambridge, Mass., United States:
− LIVTENCITY Is the First and Only Treatment Approved for This Indication by the EC1
− CMV Is One of the Most Common and Serious Post-transplant Infections and Can Lead to Loss of Transplanted Organ and Failure of Graft 2,3
Takeda (TSE:4502/NYSE:TAK) immediately introduced that the European Commission (EC) has granted Marketing Authorization for LIVTENCITYTM (maribavir) for the remedy of cytomegalovirus (CMV) an infection and/or illness which might be refractory (with or with out resistance) to one or extra prior therapies, together with ganciclovir, valganciclovir, cidofovir or foscarnet, in grownup sufferers who’ve undergone a haematopoietic stem cell transplant (HSCT) or stable organ transplant (SOT).4 LIVTENCITY is the first and solely oral remedy that inhibits CMV-specific UL97 protein kinase and its pure substrates.1
CMV is one of the most typical infections skilled by transplant sufferers with a world estimated incidence charge of 16-56% in SOT and 30-80% in HSCT recipients.5,6 More than 34,000 SOTs,7 together with liver, kidney, and coronary heart transplant, and greater than 48,000 HSCTs8 have been carried out in Europe and neighboring nations in 2019. Although prevention and administration of CMV an infection in SOT and HSCT sufferers with accessible therapies might assist enhance outcomes,5 breakthrough infections can nonetheless happen with prophylaxis,9 and a few CMV infections might not reply to remedy.10
“The European Society for Organ Transplantation (ESOT) understands that the transplant patient journey extends well beyond the transplant itself. When not successfully treated, CMV poses a challenge to transplant recipients and their physicians and often leads to increased organ rejection, higher hospitalization rates, and greater burden on healthcare resources, contributing to inequities for patients across the system,” mentioned Dr. Luciano Potena, ESOT President. “The approval of LIVTENCITY by the EC recognizes the need for a new antiviral approach for managing CMV infection that is refractory (with or without resistance) to one or more prior CMV therapies.”
The centralized advertising authorization is legitimate in all EU member states in addition to in Iceland, Liechtenstein, Norway, and Northern Ireland, and was based mostly on the Phase 3 SOLSTICE trial, which evaluated the security and efficacy of LIVTENCITY versus standard antiviral therapies—ganciclovir, valganciclovir, cidofovir or foscarnet—for the remedy of grownup HSCT and SOT recipients with CMV an infection refractory (with or with out resistance) to prior therapies.
The EC approval marks the fourth approval of LIVTENCITY for post-transplant refractory (with or with out resistance) CMV an infection, following the U.S., Canada, and Australia.13-15
“Patients who receive a transplant can face a difficult journey on the road to recovery that involves medicines to suppress their immune system. The additional burden of a CMV infection that has become refractory to treatment, and which could threaten their transplant, poses a challenge to patients being offered a second chance at life,” mentioned Ramona Sequeira, President, Global Portfolio Division, Takeda. “With the EC approval of LIVTENCITY, we are privileged to offer healthcare providers in the EU and EEA* with an additional oral antiviral treatment for post-transplant refractory CMV.”
About CMV
CMV is a beta herpesvirus that generally infects people; serologic proof of prior an infection could be present in 40-100% of numerous grownup populations.14 CMV sometimes resides latent and asymptomatic in the physique however might reactivate during times of immunosuppression. Serious illness might happen in people with compromised immune methods, which incorporates sufferers who obtain immunosuppressants related to numerous sorts of transplants together with HSCT or SOT.5 Out of the estimated 200,000 grownup transplants per yr globally, CMV is one of the most typical viral infections skilled by transplant recipients, with an estimated incidence charge between 16-56% in SOT recipients and 30-80% in HSCT recipients.5,6
In transplant recipients, reactivation of CMV can lead to critical penalties together with loss of the transplanted organ and, in excessive circumstances, could be deadly.2,3 Existing therapies to deal with post-transplant CMV infections might show critical unwanted side effects that require dose changes or might fail to adequately suppress viral replication.10 Additionally, present therapies might require or lengthen hospitalization due to administration.10,15
About LIVTENCITY
LIVTENCITYTM (maribavir), an orally bioavailable anti-CMV compound, is the first and solely antiviral agent that targets and inhibits the UL97 protein kinase and its pure substrates.16 It is authorised by the U.S. Food and Drug Administration for the remedy of adults and pediatric sufferers (12 years of age or older and weighing not less than 35 kg) with post-transplant CMV an infection/illness that’s refractory to remedy (with or with out genotypic resistance) with ganciclovir, valganciclovir, cidofovir, or foscarnet.12 It is authorised by the EC for the remedy of CMV an infection and/or illness which might be refractory (with or with out resistance) to one or extra prior therapies, together with ganciclovir, valganciclovir, cidofovir or foscarnet in grownup sufferers who’ve undergone a HSCT or SOT.4 It can be authorised by Health Canada for the remedy of adults with post-transplant cytomegalovirus (CMV) an infection/illness who’re refractory (with or with out genotypic resistance) to one or extra prior antiviral therapies.11 LIVTENCITY can be authorised in Australia for the remedy of adults with post-transplant CMV an infection and illness resistant, refractory, or illiberal to one or extra prior therapies.13
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Product identify
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LIVTENCITY 200 mg movie coated tablets.
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Generic identify
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Maribavir
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Indications and results
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LIVTENCITY is indicated for the remedy of cytomegalovirus (CMV) an infection and/or illness which might be refractory (with or with out resistance) to one or extra prior therapies, together with ganciclovir, valganciclovir, cidofovir or foscarnet in grownup sufferers who’ve undergone a haematopoietic stem cell transplant (HSCT) or stable organ transplant (SOT).
Consideration must be given to official steering on the acceptable use of antiviral brokers.
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Posology and Administration
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LIVTENCITY must be initiated by a doctor skilled in the administration of sufferers who’ve undergone stable organ transplant or haematopoietic stem cell transplant.
Posology: The advisable dose of LIVTENCITY is 400 mg (two 200 mg tablets) twice every day leading to a every day dose of 800 mg for 8 weeks. Treatment length may have to be individualised based mostly on the scientific traits of every affected person.
Paediatric inhabitants: The security and efficacy of LIVTENCITY in sufferers under 18 years of age haven’t been established. No information can be found.
Method of administration: Oral use.
LIVTENCITY is meant for oral use solely and could be taken with or with out meals. The movie coated pill could be taken as an entire pill, a crushed pill, or a crushed pill by way of a nasogastric or orogastric tube.
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About Takeda’s SOLSTICE Trial
The TAK-620-303 (SOLSTICE) trial (NCT02931539, EudraCT 2015-004725-13) was a world, multicenter, randomized, open-label, active-controlled superiority trial to assess the efficacy and security of remedy with both maribavir or standard antiviral remedy in 352 haematopoietic stem cell transplant and stable organ transplant recipients with CMV an infection refractory, with or with out resistance, to one or a mixture of the standard antiviral therapies: ganciclovir, valganciclovir, foscarnet, or cidofovir. Adult sufferers underwent a 2-week screening interval, adopted by randomization 2:1 to maribavir (n=235) (400 mg, twice every day) or standard antiviral therapies (n=117) (as dosed by the investigator) for up to 8 weeks. After completion of the remedy interval, topics entered a 12-week follow-up section.16
The trial’s major efficacy endpoint was confirmed CMV DNA stage <LLOQ (decrease restrict of quantification, [i.e., <137 IU/mL] in 2 consecutive samples separated by not less than 5 days as assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV take a look at) at the finish of Week 8. The key secondary endpoint was CMV DNA stage <LLOQ and CMV an infection symptom management† at the finish of Study Week 8 with upkeep of this remedy impact by way of Study Week 16.16
About Takeda
Takeda is a world, values-based, R&D-driven biopharmaceutical chief headquartered in Japan, dedicated to uncover and ship life-transforming therapies, guided by our dedication to sufferers, our individuals and the planet. Takeda focuses its R&D efforts on 4 therapeutic areas: Oncology, Rare Genetics and Hematology, Neuroscience, and Gastroenterology (GI). We additionally make focused R&D investments in Plasma-Derived Therapies and Vaccines. We are specializing in creating extremely progressive medicines that contribute to making a distinction in individuals’s lives by advancing the frontier of new remedy choices and leveraging our enhanced collaborative R&D engine and capabilities to create a strong, modality-diverse pipeline. Our staff are dedicated to bettering high quality of life for sufferers and to working with our companions in well being care in roughly 80 nations and areas. For extra data, go to https://www.takeda.com.
LIVTENCITY Safety Information for Europe
Please seek the advice of the LIVTENCITY▼Summary of Product Characteristics (SmPC) earlier than prescribing, notably in relation to dosing and remedy monitoring.
Contraindications
Hypersensitivity to the lively substance or to any of the excipients and co administration with ganciclovir or valganciclovir.
Special warnings and precautions for use
Virologic failure can happen throughout and after remedy with LIVTENCITY. Some maribavir pUL97 resistance-associated substitutions confer cross-resistance to ganciclovir and valganciclovir. CMV DNA ranges must be monitored and resistance mutations must be investigated in sufferers who don’t reply to remedy. Treatment must be discontinued if maribavir resistance mutations are detected.
LIVTENCITY shouldn’t be anticipated to be efficient in treating CMV CNS infections (e.g. meningo encephalitis).
LIVTENCITY has the potential to enhance the concentrations of immunosuppressants which might be cytochrome P450 (CYP)3A/P-gp substrates with slender therapeutic margins (together with tacrolimus, cyclosporine, sirolimus and everolimus). The plasma ranges of these immunosuppressants have to be regularly monitored all through remedy with LIVTENCITY, particularly following initiation and after discontinuation of LIVTENCITY, and doses must be adjusted, as wanted.
The concomitant use of LIVTENCITY and sure medicinal merchandise might end in identified or doubtlessly vital medicinal product interactions, some of which can lead to:
- potential clinically vital hostile reactions from larger publicity of concomitant medicinal merchandise.
- lowered therapeutic impact of LIVTENCITY.
Sodium content material: This medicinal product accommodates lower than 1 mmol sodium (23 mg) per pill, that’s to say basically ‘sodium free’.
Pregnancy & Breast-feeding: LIVTENCITY shouldn’t be advisable throughout being pregnant and in girls of childbearing potential not utilizing contraception. Breast feeding must be discontinued throughout remedy with LIVTENCITY.
Interactions
If dose changes of concomitant medicinal merchandise are made due to remedy with maribavir, doses must be readjusted after remedy with maribavir is accomplished.
Effect of different medicinal merchandise on maribavir: Co-administration of maribavir with sturdy cytochrome P450 3A (CYP3A) inducers rifampicin, rifabutin or St. John’s wort shouldn’t be advisable. If co-administration of maribavir with different sturdy or reasonable CYP3A inducers (e.g., carbamazepine, efavirenz, phenobarbital and phenytoin) can’t be prevented, the maribavir dose must be elevated to 1 200 mg twice every day. No dose adjustment is required when maribavir is co administered with CYP3A inhibitors.
Effect of maribavir on different medicinal merchandise: Co-administration of maribavir with valganciclovir and ganciclovir is contraindicated.
Concomitant administration of maribavir and medicinal merchandise which might be delicate substrates of CYP1A2 with a slender therapeutic window (e.g., tizanidine and theophylline) must be prevented due to the danger for lack of efficacy of CYP1A2 substrates.
When the immunosuppressants tacrolimus, cyclosporine, everolimus or sirolimus are co-administered with maribavir, immunosuppressant ranges must be regularly monitored all through remedy with maribavir, particularly following initiation and after discontinuation of maribavir and dose adjusted, when wanted.
Caution must be exercised when maribavir and delicate P-gp substrates (e.g., digoxin, dabigatran) are co administered. Serum digoxin concentrations must be monitored, and dose of digoxin may have to be lowered, as wanted (see Table 1).
Co-administration of maribavir with delicate BCRP substrates resembling rosuvastatin, is anticipated to enhance their publicity and lead to undesirable results.
Adverse Reactions
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Very widespread
(≥1/10)
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Taste disturbance, Diarrhoea, Nausea, Vomiting, Fatigue
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Common
(≥1/100 to <1/10)
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Headache, Abdominal ache higher, Decreased urge for food, Immunosuppressant drug stage elevated*, Weight decreased
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The mostly reported critical hostile reactions have been diarrhoea (2%) and nausea, weight decreased, fatigue, immunosuppressant drug focus stage elevated, and vomiting (all occurring at > 1%).
For Europe, please seek the advice of the LIVTENCITY Summary Product Characteristics earlier than prescribing
For full U.S. Prescribing Information, together with the authorised indication and essential security data, please go to: https://content.takeda.com/?contenttype=pi&product=liv&language=eng&country=usa&documentnumber=1
Please seek the advice of along with your native regulatory company for authorised labeling in your nation.
Important Notice
For the functions of this discover, “press release” means this doc, any oral presentation, any query and reply session and any written or oral materials mentioned or distributed by Takeda Pharmaceutical Company Limited (“Takeda”) relating to this launch. This press launch (together with any oral briefing and any question-and-answer in reference to it) shouldn’t be supposed to, and doesn’t represent, characterize or kind half of any supply, invitation or solicitation of any supply to buy, in any other case purchase, subscribe for, trade, promote or in any other case dispose of, any securities or the solicitation of any vote or approval in any jurisdiction. No shares or different securities are being provided to the public by means of this press launch. No providing of securities shall be made in the United States besides pursuant to registration beneath the U.S. Securities Act of 1933, as amended, or an exemption therefrom. This press launch is being given (along with any additional data which can be supplied to the recipient) on the situation that it’s for use by the recipient for data functions solely (and never for the analysis of any funding, acquisition, disposal or every other transaction). Any failure to adjust to these restrictions might represent a violation of relevant securities legal guidelines.
The firms through which Takeda instantly and not directly owns investments are separate entities. In this press launch, “Takeda” is usually used for comfort the place references are made to Takeda and its subsidiaries usually. Likewise, the phrases “we”, “us” and “our” are additionally used to refer to subsidiaries usually or to those that work for them. These expressions are additionally used the place no helpful function is served by figuring out the explicit firm or firms.
Forward-Looking Statements
This press launch and any supplies distributed in reference to this press launch might include forward-looking statements, beliefs or opinions relating to Takeda’s future business, future place and outcomes of operations, together with estimates, forecasts, targets and plans for Takeda. Without limitation, forward-looking statements usually embody phrases resembling “targets”, “plans”, “believes”, “hopes”, “continues”, “expects”, “aims”, “intends”, “ensures”, “will”, “may”, “should”, “would”, “could” “anticipates”, “estimates”, “projects” or related expressions or the destructive thereof. These forward-looking statements are based mostly on assumptions about many essential elements, together with the following, which may trigger precise outcomes to differ materially from these expressed or implied by the forward-looking statements: the financial circumstances surrounding Takeda’s international business, together with common financial circumstances in Japan and the United States; aggressive pressures and developments; modifications to relevant legal guidelines and laws, together with international well being care reforms; challenges inherent in new product growth, together with uncertainty of scientific success and choices of regulatory authorities and the timing thereof; uncertainty of industrial success for new and present merchandise; manufacturing difficulties or delays; fluctuations in curiosity and foreign money trade charges; claims or considerations relating to the security or efficacy of marketed merchandise or product candidates; the affect of well being crises, like the novel coronavirus pandemic, on Takeda and its prospects and suppliers, together with international governments in nations through which Takeda operates, or on different aspects of its business; the timing and affect of post-merger integration efforts with acquired firms; the potential to divest belongings that aren’t core to Takeda’s operations and the timing of any such divestment(s); and different elements recognized in Takeda’s most up-to-date Annual Report on Form 20-F and Takeda’s different studies filed with the U.S. Securities and Exchange Commission, accessible on Takeda’s web site at: https://www.takeda.com/investors/sec-filings/ or at www.sec.gov. Takeda doesn’t undertake to replace any of the forward-looking statements contained on this press launch or every other forward-looking statements it could make, besides as required by regulation or inventory trade rule. Past efficiency shouldn’t be an indicator of future outcomes and the outcomes or statements of Takeda on this press launch might not be indicative of, and should not an estimate, forecast, assure or projection of Takeda’s future outcomes.
Medical data
This press launch accommodates details about merchandise that might not be accessible in all nations, or could also be accessible beneath completely different emblems, for completely different indications, in numerous dosages, or in numerous strengths. Nothing contained herein must be thought-about a solicitation, promotion or commercial for any prescribed drugs together with the ones beneath growth.
*European Economic Area (EEA) nations embody Iceland, Liechtenstein and Norway.
†CMV an infection symptom management was outlined as decision or enchancment of tissue-invasive illness or CMV syndrome for symptomatic sufferers at baseline, or no new signs for sufferers who have been asymptomatic at baseline.
References
1. Avram S, et al. Novel drug targets in 2021. Nat Rev Discov. 2022;21(5):328-328.
2. Ramanan P, et al. Cytomegalovirus infections in stable organ transplantation: a overview. Infect Chemother. 2013;45(3):260.
3. Camargo JF, et al. Emerging ideas in cytomegalovirus an infection following hematopoietic stem cell transplantation. Hematol Oncol Stem Cell Ther. 2017;10(4):233-238.
4. LIVTENCITYTM (maribavir) European Summary of Product Characteristics.
5. Azevedo L, et al. Cytomegalovirus an infection in transplant recipients. Clinics (Sao Paolo). 2015;70(7):515-523.
6. Styczynski J. Who is the affected person in danger of CMV recurrence: a overview of the present scientific proof with a concentrate on hematopoietic cell transplantation. Infect Dis Ther. 2018;7:1-16.
7. Vanholder R, et al. Organ donation and transplantation: a multi-stakeholder name to motion. Nat Rev Nephrol. 2021;17:554-568.
8. Passweg JR, et al; European Society for Blood and Marrow Transplantation Hematopoietic cell transplantation and mobile remedy survey of the EBMT: monitoring of actions and developments over 30 years. Bone Marrow Transplant. 2021;56(7):1651-1664. doi:10.1038/s41409-021-01227-8
9. Marty FM, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med. 2017;377(25):2433-2444. doi:10.1056/NEJMoa1706640
10. Chemaly RF, et al. Definitions of resistant and refractory cytomegalovirus an infection and illness in transplant recipients for use in scientific trials. Clin Infect Dis. 2019;68(8):1420-1426. doi:10.1093/cid/ciy696
11. Takeda. Health Canada approves Takeda’s LIVTENCITYTM (maribavir) the first and solely remedy for adults with post-transplant cytomegalovirus (CMV) an infection. Published September 20, 2022. 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/.
12. Takeda. Takeda’s LIVTENCITY (maribavir) authorised by U.S. FDA as the first and solely remedy for individuals ages 12 and older with post-transplant cytomegalovirus (CMV), refractory (with or with out genotypic resistance) to standard antiviral therapies. Published November 23, 2021. https://www.takeda.com/newsroom/newsreleases/2021/takeda-livtencity-maribavir-approved-by-us-fda/.
13. Therapeutic Goods Administration (TGA). LIVTENCITY maribavir 200 mg movie coated pill bottle (380132) [Australian product information]. Therapeutic Goods Administration (TGA). Published October 8, 2022. https://www.tga.gov.au/resources/artg/380132
14. de la Hoz R. Diagnosis and remedy approaches to CMV infections in grownup sufferers. J Clin Virol. 2002;25(Suppl 1):S1-S12.
15. Martín-Gandul C, et al. Clinical affect of neutropenia associated with the preemptive remedy of CMV an infection in stable organ transplant recipients. J Infect. 2014;69(5):500-506.
16. Avery RK, et al. Maribavir for refractory cytomegalovirus infections with or with out resistance post-transplant: outcomes from a section 3 randomized scientific trial. Clin Infect Dis. 2022;75(4):690-701. doi:10.1093/cid/ciab988
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