Takeda’s LIVTENCITY (maribavir) Approved by U.S. FDA as the First and Only Treatment for Post-Transplant Refractory Cytomegalovirus Infection
Takeda
Biopharmaceutical Manufacturer
FDA
U.S. Food and Drug Administration
Takeda Pharmaceutical Company Limited (Takeda) recently announced that the U.S. Food and Drug Administration (FDA) has been approvedAntiviral Drug Livtencity (maribavir, TAK-620), used for treating post-transplant cytomegalovirus (CMV) infection that is refractory to conventional antiviral therapy (with or without genotypic resistance) in transplant recipients. Livtencity is specifically applicable to: recipients of solid organOrgan Transplantation(SOT) or hematopoieticStem CellsFor adult and pediatric patients (aged ≥12 years, weight ≥35 kg) undergoing transplantation (HSCT), treating post-transplant CMV infections that are refractory to (with or without genotypic resistance) ganciclovir, valganciclovir, foscarnet, and cidofovir.Livtencity blocks viral replication by inhibiting the activity of CMV protein kinase pUL97.
It is worth mentioning that,Livtencity is the first and only drug approved by the U.S. FDA for the treatment of post-transplant CMV infection that is refractory to conventional antiviral therapy (with or without genotypic resistance).Livtencity was approved through the priority review process and has been previouslyFDAGranted Orphan Drug Designation (ODD) and Breakthrough Therapy Designation (BTD). Currently, Livtencity is also in Phase 3.Clinical TrialIn China, as the first-line treatment drug for CMV infection in HSCT recipients. CMV is a DNA virus of the β-herpesvirus subfamily, with high species specificity, and humans are the only host of human cytomegalovirus (HCMV). CMV is a common virus that can infect people of all ages. By the age of 40, more than half of adults have been infected with CMV, and most do not exhibit related symptoms or signs. However, in individuals with weakened immune systems (including organ or...Stem CellsIn the population of transplant recipients, CMV infection is a serious clinical complication.
CMV is one of the most common and serious infections after transplantation, in solidOrgan TransplantationThe incidence rate in recipients is approximately 16-56%, in hematopoiesisStem CellsThe incidence among transplant recipients is approximately 30%-70%.CMV can be acquired or reactivated after transplantation, which has a significant negative impact on transplant recipients and can lead to serious consequences, including graft loss and transplant failure. Transplant recipients facing CMV infection are at much higher risk of complications and death. Existing antiviral therapies are available for treating CMV, but their use may be limited due to side effects and/or drug resistance. CMV infections that are drug-resistant or unresponsive to existing treatments are particularly concerning. This approval will provide a treatment option for this patient population, helping to address a significant unmet medical need in this field.
The active pharmaceutical ingredient of Livtencity is maribavir, an orally bioavailable anti-cytomegalovirus (CMV) compound. It is the only CMV antiviral drug that specifically targets and inhibits the pUL97 protein kinase and its natural substrates. Current CMV management involves challenging trade-offs, including the management of toxicity and clearance of viremia. Livtencity has the potential to redefine the treatment approach for refractory CMV post-transplant, with or without resistance.
This approval is based on the pivotal Phase 3 TAK-620-303 (SOLSTICE, NCT02931539) trial, the primary results of which were presented in February this year at the 2021 Transplantation & Cellular Therapy (TCT) Meetings.ConferenceAs announced, the subgroup analysis results were published in March this year at the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) in 2021. The main results showed,Maribavir Demonstrates Superior Efficacy Compared to Conventional Antiviral Therapy (IAT), Meeting the Primary and Key Secondary Endpoints of the Study. Additionally, maribavir shows lower treatment-related toxicity compared to conventional antiviral therapy. Subgroup analysis supports the efficacy outcomes observed in the overall randomized population.
Ramona Sequeira, President of Takeda’s U.S. Business Unit and Global Portfolio Commercialization, said: “Today’s approval will redefine the management of CMV after transplantation. Livtencity is the first and only drug for treating post-transplant CMV infection with or without resistance in transplant recipients. Transplant recipients face a long and complex medical journey; with this approval, we are honored to offer these patients a new oral antiviral treatment to combat CMV infection and disease. We thank those who participated in ourClinical Trial"Patients and clinicians, as well as our scientists and researchers, have contributed to this."
Maribavir Molecular Structure
The TAK-620-303 study was conducted in transplant recipients with refractory, with or without resistance (R/R), cytomegalovirus (CMV) infection/disease. It compared the investigational antiviral drug TAK-620 (maribavir) with conventional antiviral drugs (investigator-assigned treatment [IAT], a combination of one or more of the following drugs: ganciclovir, valganciclovir, foscarnet, cidofovir). The primary endpoint of the study was the confirmed CMV viremia clearance rate at Week 8 of treatment (end of the treatment period), and the key secondary endpoint was the maintenance of CMV clearance and symptom control until Week 16.
Results from the entire study population indicate:Maribavir Showed Superiority in CMV Viremia Clearance Rate Compared to Conventional Antiviral Therapy at Week 8 of the Study.Specifically: At Week 8 of the study, the proportion of transplant recipients with confirmed CMV viremia clearance who were receiving antiviral therapy, with or without resistance (R/R), and had CMV disease/infection was more than double in the maribavir treatment group (55.7%, n=131/235) compared to the conventional treatment group (23.9%, n=28/117) (adjusted difference [95% CI]: 32.8% [22.8-42.7]; p<0.001).
Subgroup analysis showed that: Among transplant recipients confirmed to have genotypic resistant CMV infection at baseline, the proportion of patients achieving confirmed CMV viremia clearance at Week 8 of the study (end of the treatment period) was more than three times higher in the maribavir treatment group (62.8%, 76/121) compared to the IAT treatment group (20.3%, 14/69) (adjusted difference [95% CI]: 44.1% [31.3, 56.9]).
In the study, transplant recipients treated with maribavir demonstrated a lower incidence of treatment-related toxicities, which are commonly observed in conventional antiviral therapies. Specifically, transplant recipients treated with maribavir had a lower incidence of treatment-related neutropenia compared to those treated with valganciclovir/ganciclovir (1.7% [4/234] vs 25% [14/56]) and a lower incidence of treatment-related acute kidney injury compared to those treated with foscarnet (1.7% [4/234] vs 19.1% [9/47]). The incidence of treatment-emergent adverse events (TEAEs) of any grade was 97.4% (228/234) in the maribavir group and 91.4% (106/116) in the conventional treatment group. The most common TEAEs in the maribavir group were dysgeusia (35.9%, 84/234), nausea (8.5%, 20/234), and vomiting (7.7%). The incidence of TEAEs leading to discontinuation of the study drug was 13.2% (31/234) in the maribavir group and 31.9% (37/116) in the conventional treatment group. There were two deaths due to serious treatment-related TEAEs, one in each treatment group.
CMV Infection (Image Source: virtual.tts.org)
Cytomegalovirus (CMV) is a β-herpesvirus that commonly infects humans; there is serological evidence of prior infection in 40%-100% of the adult population. CMV typically remains latent and asymptomatic within the body but can reactivate during periods of immunosuppression. Severe disease may occur in individuals with compromised immune systems, including those who have undergone hematopoietic cell transplantation (HCT) or solid organ transplantation.Organ Transplantation(SOT) and other transplant-related immunosuppressant patients. Among the estimated 200,000 adult transplant cases each year, CMV is one of the most common viral infections in transplant recipients, with an estimated incidence rate of 16-56% in SOT recipients and 30-70% in HCT recipients. In transplant recipients, reactivation of CMV can lead to serious consequences, including loss of the transplanted organ, and in extreme cases, it may be fatal. Existing therapies for treating post-transplant CMV infection may exhibit severe side effects, require dose adjustments, or fail to adequately suppress viral replication. Additionally, existing treatments may necessitate or prolong hospitalization due to the administration of the therapy.
Maribavir belongs to a class of drugs called benzimidazole nucleosides, which can specifically inhibit the pUL97 protein kinase of CMV, potentially affecting several key processes of CMV replication, including viral DNA replication, viral gene expression, capsid formation, and the escape of mature capsids from the nucleus of infected cells.
Maribavir is an orally bioavailable antiviral therapy being developed for hematopoietic patients with CMV infection who are resistant or refractory to current standard CMV treatments.Stem CellsTransplantation (HSCT) or solidOrgan Transplantation(SOT) recipients. In the United States and the European Union, maribavir has been granted Orphan Drug Designation (ODD) for the treatment of clinically significant CMV viremia in high-risk patient populations and for the treatment of CMV disease in immunocompromised patients. In the United States, maribavir has also been granted Breakthrough Therapy Designation (BTD) for the treatment of CMV infection that is resistant or refractory to prior therapies in transplant recipients.In China, maribavir was approved in April 2020Clinical TrialImplied License, Development Indication: For the treatment of CMV infection or disease。
