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

Rhea-AI Summary

Takeda (TSE:4502/NYSE:TAK) 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. LIVTENCITY is the first and only inhibitor of CMV-specific UL97 protein kinase in China for this indication. The approval is based on the Phase 3 SOLSTICE trial, where LIVTENCITY was superior to conventional therapies at Week 8 for the primary endpoint of confirmed CMV viremia clearance in post-transplant adults with refractory CMV infection. This approval marks the 12th approval of LIVTENCITY around the world for post-transplant CMV refractory to prior therapies, including major markets like the United States, Canada, Australia, and the European Union.

Insights

Medical Research Analyst

The recent approval of LIVTENCITY® in China represents a significant milestone in the treatment of post-transplant cytomegalovirus (CMV) infections, a common complication affecting a sizeable proportion of transplant recipients. The drug's efficacy, demonstrated in the Phase 3 SOLSTICE trial, shows a clear advantage over conventional therapies, which may lead to an increase in demand and could have positive financial implications for Takeda.

The pharmaceutical industry often sees stock volatility around drug approval announcements, especially for treatments that address unmet medical needs. LIVTENCITY®, as a first-in-class CMV-specific UL97 protein kinase inhibitor, could potentially capture a significant market share in China, given the high incidence of CMV infections post-transplant. This could result in increased revenue for Takeda in the mid to long term, assuming successful market penetration and adoption by healthcare providers.

Healthcare Industry Analyst

From an industry perspective, the approval of LIVTENCITY® by the NMPA is a noteworthy event, as it not only adds a new drug to Takeda's portfolio but also alters the competitive landscape for CMV treatment in China. The introduction of a novel mechanism of action could prompt a shift in treatment protocols and establish a new standard of care. This, in turn, could influence the strategies of other pharmaceutical companies in the antiviral space.

Additionally, the Breakthrough Therapy Designation previously granted to LIVTENCITY® underscores the drug's potential to address a significant health issue. Such designations can expedite the development and review process, leading to faster market entry, which is particularly valuable in a market as large as China. This early mover advantage is crucial and could result in a durable competitive edge.

Financial Analyst

Investors should consider the broader financial implications of LIVTENCITY®'s approval. Takeda's expansion into the Chinese market with a novel therapy could positively impact its stock performance, particularly if sales projections are met or exceeded. The drug's approval across multiple major markets suggests confidence in its global commercial viability.

However, investors should also be mindful of potential risks, such as market acceptance, pricing and reimbursement challenges and competition from existing and future treatments. The performance of LIVTENCITY® should be monitored in the context of Takeda's overall portfolio and the company's ability to leverage this approval to strengthen its position in the antiviral drug market.

- 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 Graft^2,3

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 clearance^a in post-transplant adults with refractory^* CMV infection.¹

The NMPA approval marks the 12^th 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

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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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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International Media

JC Molina

jc.molina@takeda.com

China Media

Shirley Zhu

Shirley.zhu@takeda.com

Source: Takeda Pharmaceutical Company Limited

FAQ

What is the significance of LIVTENCITY's approval by the NMPA of China?

LIVTENCITY (maribavir) has been approved by the NMPA of China for the treatment of adult patients with post-transplant CMV infection/disease that is refractory to treatment, marking a significant milestone in addressing the unmet need for this community.

What is the primary endpoint of the Phase 3 SOLSTICE trial?

The primary endpoint of the SOLSTICE trial was confirmed CMV viremia clearance at Week 8 for post-transplant adults with refractory CMV infection.

How common is CMV infection in transplant patients 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.

How many approvals has LIVTENCITY received worldwide?

LIVTENCITY has received 12 approvals worldwide for post-transplant CMV refractory to prior therapies, including major markets like the United States, Canada, Australia, and the European Union.