European Commission (EC) Approves LIVTENCITYTM▼ (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

Takeda (TSE:4502/NYSE:TAK) today announced that the European Commission (EC) has granted Marketing Authorization for LIVTENCITY^TM (maribavir) for the treatment of cytomegalovirus (CMV) infection and/or disease that are refractory (with or without resistance) to one or more prior therapies, including ganciclovir, valganciclovir, cidofovir or foscarnet, in adult patients who have undergone a haematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT).⁴ LIVTENCITY is the first and only oral treatment that inhibits CMV-specific UL97 protein kinase and its natural substrates.¹

CMV is one of the most common infections experienced by transplant patients with a global estimated incidence rate of 16-56% in SOT and 30-80% in HSCT recipients.^5,6 More than 34,000 SOTs,⁷ including liver, kidney, and heart transplant, and more than 48,000 HSCTs⁸ were performed in Europe and neighboring countries in 2019. Although prevention and management of CMV infection in SOT and HSCT patients with available therapies may help improve outcomes,⁵ breakthrough infections can still occur with prophylaxis,⁹ and some CMV infections may not respond to treatment.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,” said 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 marketing authorization is valid in all EU member states as well as in Iceland, Liechtenstein, Norway, and Northern Ireland, and was based on the Phase 3 SOLSTICE trial, which evaluated the safety and efficacy of LIVTENCITY versus conventional antiviral therapies—ganciclovir, valganciclovir, cidofovir or foscarnet—for the treatment of adult HSCT and SOT recipients with CMV infection refractory (with or without resistance) to prior therapies.

The EC approval marks the fourth approval of LIVTENCITY for post-transplant refractory (with or without resistance) CMV 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,” said 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 commonly infects humans; serologic evidence of prior infection can be found in 40-100% of various adult populations.¹⁴ 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.⁵ 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.^5,6

In transplant recipients, reactivation of CMV can lead to serious consequences including loss of the transplanted organ and, in extreme cases, can be fatal.^2,3 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.¹⁰ Additionally, existing therapies may require or prolong hospitalization due to administration.^10,15

About LIVTENCITY

LIVTENCITY^TM (maribavir), an orally bioavailable anti-CMV compound, is the first and only antiviral agent that targets and inhibits the UL97 protein kinase and its natural substrates.¹⁶ It is approved by the U.S. Food and Drug Administration for the treatment of adults and pediatric patients (12 years of age or older and weighing at least 35 kg) with post-transplant CMV infection/disease that is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir, or foscarnet.¹² It is approved by the EC for the treatment of CMV infection and/or disease that are refractory (with or without resistance) to one or more prior therapies, including ganciclovir, valganciclovir, cidofovir or foscarnet in adult patients who have undergone a HSCT or SOT.⁴ It is also approved by Health Canada for the treatment of adults with post-transplant cytomegalovirus (CMV) infection/disease who are refractory (with or without genotypic resistance) to one or more prior antiviral therapies.¹¹ LIVTENCITY is also approved in Australia for the treatment of adults with post-transplant CMV infection and disease resistant, refractory, or intolerant to one or more prior therapies.¹³

Product name		LIVTENCITY 200 mg film coated tablets.
Generic name		Maribavir
Indications and effects		LIVTENCITY is indicated for the treatment of cytomegalovirus (CMV) infection and/or disease that are refractory (with or without resistance) to one or more prior therapies, including ganciclovir, valganciclovir, cidofovir or foscarnet in adult patients who have undergone a haematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT).   Consideration should be given to official guidance on the appropriate use of antiviral agents.
Posology and Administration		LIVTENCITY should be initiated by a physician experienced in the management of patients who have undergone solid organ transplant or haematopoietic 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 individualised based on the clinical characteristics of each patient. Paediatric 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 haematopoietic stem cell transplant and solid organ transplant recipients with CMV infection refractory, with or without resistance, 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.¹⁶

The trial’s primary efficacy endpoint was confirmed CMV DNA level <LLOQ (lower limit of quantification, [i.e., <137 IU/mL] in 2 consecutive samples separated by at least 5 days as assessed by COBAS^® AmpliPrep/COBAS^® TaqMan^® CMV test) at the end of Week 8. The key secondary endpoint was CMV DNA level <LLOQ and CMV infection symptom control^† at the end of Study Week 8 with maintenance of this treatment effect through Study Week 16.¹⁶

About Takeda

Takeda is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to discover and deliver life-transforming treatments, guided by our commitment to patients, our people and the planet. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Rare Genetics and Hematology, Neuroscience, and Gastroenterology (GI). We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people’s lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries and regions. For more information, visit https://www.takeda.com.

LIVTENCITY Safety Information for Europe

Please consult the LIVTENCITY ^▼ Summary of Product Characteristics (SmPC) before prescribing, particularly in relation to dosing and treatment monitoring.

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 administered 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 (see Table 1).
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, Diarrhoea, 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 diarrhoea (2%) and nausea, weight decreased, fatigue, immunosuppressant drug concentration level increased, and vomiting (all occurring at > 1%).

For Europe, please consult the LIVTENCITY Summary Product Characteristics before prescribing

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

Please consult with your local regulatory agency for approved labeling in your country.

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.

^*European Economic Area (EEA) countries include Iceland, Liechtenstein and Norway.

^†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

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 solid organ transplantation: a review. Infect Chemother. 2013;45(3):260.

3. Camargo JF, et al. Emerging concepts in cytomegalovirus infection following hematopoietic stem cell transplantation. Hematol Oncol Stem Cell Ther. 2017;10(4):233-238.

4. LIVTENCITY^TM (maribavir) European Summary of Product Characteristics.

5. Azevedo L, et al. Cytomegalovirus infection in transplant recipients. Clinics (Sao Paolo). 2015;70(7):515-523.

6. 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.

7. Vanholder R, et al. Organ donation and transplantation: a multi-stakeholder call to action. Nat Rev Nephrol. 2021;17:554-568.

8. Passweg JR, et al; European Society for Blood and Marrow Transplantation Hematopoietic cell transplantation and cellular therapy survey of the EBMT: monitoring of activities and trends 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 infection and disease in transplant recipients for use in clinical trials. Clin Infect Dis. 2019;68(8):1420-1426. doi:10.1093/cid/ciy696

11. Takeda. Health Canada approves Takeda’s LIVTENCITY^TM (maribavir) the first and only treatment for adults with post-transplant cytomegalovirus (CMV) 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) 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. https://www.takeda.com/newsroom/newsreleases/2021/takeda-livtencity-maribavir-approved-by-us-fda/.

13. 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

14. de la Hoz R. Diagnosis and treatment approaches to CMV infections in adult patients. J Clin Virol. 2002;25(Suppl 1):S1-S12.

15. Martín-Gandul C, et al. Clinical impact of neutropenia related with the preemptive therapy of CMV infection in solid organ transplant recipients. J Infect. 2014;69(5):500-506.

16. Avery RK, et al. 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

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