Takeda Announces China NMPA Approval of LIVTENCITY® (maribavir) for the Treatment of Adults With Post-transplant Cytomegalovirus (CMV) Refractory to Prior Therapies

OSAKA, Japan & CAMBRIDGE, Massachusetts -- Businesswire -- Takeda (TSE:4502/NYSE:TAK (https://cts.businesswire.com/ct/CT?id=smartlink&url=https%3A%2F%2Fwww.takeda.com%2Finvestors%2Foverview%2F&esheet=53874021&newsitemid=20231221976317&lan=en-US&anchor=TSE%3A4502%2FNYSE%3ATAK&index=1&md5=1a3d0985a9865ad699dce8b95d092f9c)) 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 clearance[a] 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.

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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

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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). (https://cts.businesswire.com/ct/CT?id=smartlink&url=https%3A%2F%2Fwww.ema.europa.eu%2Fen%2Fdocuments%2Fproduct-information%2Flivtencity-epar-product-information_en.pdf&esheet=53874021&newsitemid=20231221976317&lan=en-US&anchor=Summary+of+Products+Characteristics+%28SmPC%29&index=3&md5=378b8124007126a8e21f41ea92936af0)

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.

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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 (<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

[1] 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 [2] Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infection & Chemotherapy. 2013;45(3):260 [3] 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 [4] 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/ [5] 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 [6] 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 [7] 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/ [8] 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 [9] 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 [10] 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 [11] 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 [12] 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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