Takeda Announces Approval of LIVTENCITY® (maribavir) in Japan for Post-Transplant Cytomegalovirus (CMV) Infection/Disease That Is Refractory to Existing Anti-CMV Therapies
Takeda announced the Japanese Ministry of Health, Labour and Welfare's approval of LIVTENCITY® (maribavir) for post-transplant cytomegalovirus (CMV) infection/disease resistant to existing anti-CMV therapies. LIVTENCITY is the first and only post-transplant treatment in Japan that targets pUL97 kinase. The approval is based on Phase 3 SOLSTICE trial results, which demonstrated significant improvement with maribavir over alternative treatments in clearing CMV viremia by Week 8. The trial included 235 maribavir patients and 117 on alternative treatments, with adverse reactions in 60.3% of maribavir patients. An additional Japanese Phase 3 study showed 33.3% efficacy at clearing CMV viremia by Week 8, with adverse reactions in 36.6% of patients.
- Approval of LIVTENCITY in Japan for post-transplant CMV infection/disease.
- First and only post-transplant treatment in Japan targeting pUL97 kinase.
- Phase 3 SOLSTICE trial showed significant improvement in clearing CMV viremia by Week 8.
- 33.3% efficacy in Japanese Phase 3 study in clearing CMV viremia by Week 8.
- 60.3% of maribavir patients in the SOLSTICE trial experienced adverse reactions.
- 36.6% of patients had adverse reactions in the Japanese Phase 3 study.
LIVTENCITY approval in Japan represents a significant development in post-transplant care. The drug specifically targets the pUL97 kinase, a unique approach not seen in current anti-CMV treatments. This unique mechanism sets LIVTENCITY apart, offering hope to patients who are refractory to existing therapies.
From a clinical perspective, the Phase 3 SOLSTICE trial showed statistically significant improvement in CMV viremia clearance in patients using maribavir compared to alternative treatments. 60.3% of patients did experience adverse reactions, which is considerable but not unusual for post-transplant treatments.
This drug could potentially reduce organ rejection rates and subsequent hospitalizations, addressing a critical need in the transplant community. However, the efficacy rate in the Japanese open-label study was 33.3% for refractory cases, suggesting that while effective, it may not work for all patients. This data should be tempered with the understanding that post-transplant patients are a complex and high-risk group.
The approval of LIVTENCITY in Japan could have a positive financial impact on Takeda. Japan's pharmaceutical market is substantial and being the first to offer a unique post-transplant anti-CMV treatment positions Takeda advantageously. The targeted market includes patients refractory to other treatments, representing a niche but high-need segment.
The Phase 3 trial results and subsequent approval indicate robust R&D capabilities, which could enhance investor confidence. However, the high rate of adverse reactions (up to 60.3%) might pose a risk that could affect market penetration and adoption rates.
Long-term, continued post-marketing surveillance and further studies could either bolster the drug's profile or reveal additional challenges. Investors should keep an eye on subsequent revenue reports and adoption rates in Japan.
For retail investors, understanding the landscape of post-transplant infections is key. Cytomegalovirus (CMV) is a common and severe risk for transplant patients. The introduction of LIVTENCITY addresses an unmet medical need, which could significantly affect patient outcomes and the overall post-transplant therapeutic market.
Investor interest might rise as Takeda positions itself as a leader in this niche market. Given the competition and existing treatments not targeting pUL97 kinase, LIVTENCITY’s unique mechanism offers a competitive edge.
However, the rate of adverse reactions and the moderate efficacy in the Japanese study underscore the need for cautious optimism. Adoption by the healthcare community will hinge not only on efficacy but also on safety profiles and comparative outcomes.
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LIVTENCITY Is the First and Only Post-Transplant Anti-CMV Treatment Approved in
Japan That Targets/Inhibits UL97 Protein Kinase1 - CMV Is One of the Most Common and Serious Post-transplant Infections and Can Lead to Secondary Infections and Serious Consequences, Including Loss of Transplanted Organ and Failure of Graft2,3
“We are pleased by the approval of LIVTENCITY in
The approval is primarily based on the results of the Phase 3 SOLSTICE trial (NCT02931539), which evaluated the safety and efficacy of LIVTENCITY versus alternative antiviral treatments for patients with CMV infection/disease refractory* to prior therapies who underwent hematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT), and the Japanese Phase 3 open-label study in patients with CMV infection, including those with refractory* CMV infection who underwent HSCT or SOT (NCT05137717).
In the SOLSTICE trial (maribavir n=235, alternative treatments n=117), maribavir showed statistically significant improvement when compared to alternative antiviral treatments at the end of Week 8 for the primary endpoint of confirmed CMV viremia clearancea in post-transplant (HSCT or SOT) adults with refractory* CMV infection.5 Of the 234 patients included in the safety evaluation, adverse reactions (related cases) were observed in 141 patients (
An open-label, multicenter, single-arm study was conducted to evaluate the efficacy and safety in Japanese patients in post-transplant (HSCT or SOT) adultsc (41 randomized, including 3 subjects with CMV infection refractory* to the most recently administered anti-CMV agent). The primary endpoint of CMV viremia clearanceb at the end of Study Week 8 was achieved in
About LIVTENCITY
LIVTENCITY (maribavir), an orally administered (tablet) anti-CMV compound, is the first and only antiviral agent that targets and inhibits the CMV-specific UL97 protein kinase and thus its natural substrates.1 As of June 2024, LIVTENCITY is approved in more than 30 countries for post-transplant CMV refractory* to prior therapies, including such major markets as
LIVTENCITY Product Overview in
Product Name |
LIVTENCITY 200 mg tablets. |
Generic Name |
Maribavir |
Indications |
The post-transplant cytomegalovirus (CMV) infection/disease that is refractory to existing anti-CMV therapies. |
Precautions concerning indications |
|
Dosage and Administration |
Usually, the recommended dosage for adultsc is 400 mg of maribavir to be administered orally twice daily. |
About Takeda’s SOLSTICE Trial
The TAK-620-303 (SOLSTICE) trial (NCT02931539, EudraCT 2015-004725-13) was a Phase 3 global, multicenter, randomized, open-label, active-controlled trial to assess the efficacy and safety of maribavir treatment compared to investigator-assigned treatment (alternative antiviral therapies) in 352 HSCT and SOT recipients with CMV infections that were refractory* or resistant to one or a combination of the alternative 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 alternative antiviral treatments (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.5 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 16.5
About Cytomegalovirus (CMV)
CMV is a beta herpesvirus that commonly infects humans; serologic evidence of prior infection can be found in 40
In transplant recipients, reactivation of CMV infection can lead to secondary infections and serious consequences, including graft loss and, in extreme cases, can be fatal.2,3,5
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
LIVTENCITY Safety Information
Contraindications
Contraindications include Hypersensitivity to the active substance or to any of the excipients and co‑administration with ganciclovir or valganciclovir.
Special warnings and precautions for use
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
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: If dose adjustments of concomitant medicinal products are made due to treatment with maribavir, doses should be readjusted after treatment with maribavir is completed.
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 (
Please consult the LIVTENCITY (maribavir) approved label before prescribing, particularly in relation to dosing and treatment monitoring.
For
For the European Union, please consult the Summary of Products Characteristics (SmPC).
For
For full
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* Including a subgroup with genotypic resistance to alternative antiviral treatments.
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.
b Defined as confirmed CMV DNA concentration below the lower limit of quantification (<LLOQ; i.e., <34.5 IU/mL) in two consecutive samples separated by at least five days.
c Defined as > 15 years old
† 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
- Avram S, et al. Novel drug targets in 2021. Nature Reviews Drug Discovery. 2022;21(5):328-328.
- Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infection & Chemotherapy. 2013;45(3):260
- 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
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LIVTENCITY Package Insert in
Japan . - 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
- 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
- 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
- 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
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International Media
Rand Walton
rand.walton@takeda.com
Japan Media
Shigeyuki Matsui
shigeyuki.matsui@takeda.com
Source: Takeda Pharmaceutical Company Limited
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