Takeda's Antiviral Maribavir Succeeds in Phase 3 Trial, Poised to Redefine Treatment of Cytomegalovirus Infection in Transplant Recipients

February 16, 2021 /BioValleyBIOON/ -- Takeda Pharmaceutical Company Limited (Takeda) recently at the 2021 Transplantation and Cell Therapy (TCT)MeetingAnnounced the latest Phase 3 data from the TAK-620-303 (SOLSTICE, NCT02931539) trial. This study was conducted in transplant recipients with refractory/resistant (R/R) cytomegalovirus (CMV) infection/disease, comparing the investigational antiviral drug TAK-620 (maribavir) with conventional antiviral therapy (investigator-assigned treatment [IAT], consisting of one or a combination of the following: ganciclovir, valganciclovir, foscarnet, cidofovir). The primary endpoint was confirmed CMV viremia clearance at Week 8 (end of the treatment period), and the key secondary endpoints were sustained CMV clearance and symptom control through Week 16.

The results showed that,Maribavir demonstrates superior efficacy compared to conventional antiviral therapy (IAT),The primary endpoint and key secondary endpoints of the study were met. Furthermore, maribavir, compared with conventional antiviral therapy,Lower treatment-related toxicity.

Cytomegalovirus (CMV) is a DNA virus belonging to the Betaherpesvirinae subfamily, characterized by high species specificity; humans are the sole host for human cytomegalovirus (HCMV). CMV is a common virus that can infect individuals of all age groups. By the age of 40, more than half of adults have been infected with CMV, most of whom remain asymptomatic and show no clinical signs. However, in immunocompromised individuals (including organ orStem CellsIn transplant recipients, CMV infection is a serious clinical complication that can lead to invasive tissue disease and ultimately prove fatal. Existing antiviral therapies are available for the treatment of CMV; however, their use may be limited by side effects and/or drug resistance.

Maribavir is an orally bioavailable anti-cytomegalovirus (CMV) compound and is currently the only one in Phase 3 clinical development for solidOrgan Transplantation(SOT) or hematopoietic cell transplantation (HCT) for the treatment of CMV infection/disease in post-transplant patients. In China, maribavir was approved in April 2020Clinical TrialsImplied indication: for the treatment of cytomegalovirus (CMV) infection or disease.

Obi Umeh, M.D., Vice President of Takeda and Global Program Lead for maribavir, stated: “We are excited about the results of the SOLSTICE trial. The detailed findings shared at the 2021 TCT meeting represent a significant advancement for transplant patients at increased risk of CMV, where uncontrolled CMV infection/disease can pose serious challenges. If approved, maribavir has the potential to redefine the treatment landscape for refractory post-transplant CMV, regardless of resistance status.”

Regarding the primary endpoint: At Week 8 of the study, the proportion of transplant recipients with refractory/resistant (R/R) CMV disease/infection who achieved confirmed clearance of CMV viremia was more than twofold higher in the maribavir group (55.7%, n=131/235) than in the conventional therapy group (23.9%, n=28/117) (95% CI for the difference: 32.8%, 22.8–42.7; p<0.001). Subgroup analysis of the primary endpoint (randomized set) showed: (1) solid organOrgan Transplantation(1) Among solid organ transplant (SOT) recipients, 55.6% of patients in the maribavir group achieved confirmed clearance of CMV viremia, compared with 26.1% in the conventional therapy group; (2) among hematopoietic cell transplant (HCT) recipients receiving antiviral treatment for refractory/resistant (R/R) CMV infection/disease, 55.9% of patients in the maribavir group achieved confirmed clearance of CMV viremia, compared with 20.8% in the conventional therapy group; (3) regardless of baseline viral load category (low [<9,100 IU/mL] or medium/high [≥9,100 IU/mL]), a higher proportion of transplant recipients with R/R CMV infection/disease treated with maribavir achieved confirmed clearance of CMV viremia by Week 8 compared with those receiving conventional therapy (low viral load: 62.1% vs. 24.7%; medium/high viral load: 43.9% vs. 21.9%).

Regarding key secondary endpoints: Data demonstrated that maribavir was superior to conventional antiviral regimens in clearing CMV viremia and maintaining control of related symptoms through Week 16. Analysis of key secondary endpoints (randomized set) showed that 18.7% (44/235) of transplant recipients treated with maribavir maintained clearance of CMV viremia and symptom control at Week 16 of the study, compared with 10.3% (12/117) of those receiving conventional therapy (p=0.013).

In this study, transplant recipients treated with maribavir exhibited lower treatment-related toxicities, which are common with conventional antiviral therapies. Specifically, the incidence of treatment-related neutropenia was lower in transplant recipients treated with maribavir than in those treated with valganciclovir/ganciclovir (1.7% [4/234] vs. 25% [14/56]), and the incidence of treatment-related acute kidney injury was lower in those treated with maribavir than in 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 therapy group. TEAEs leading to discontinuation occurred in 13.2% (31/234) of patients in the maribavir group and 31.9% (37/116) of patients in the conventional therapy group. Two deaths occurred due to treatment-related serious TEAEs (one in each treatment group).

Francisco M. Marty, Associate Professor of Medicine at Harvard Medical School and Associate Physician at Brigham and Women’s Hospital, stated: “We are pleased that the SOLSTICE trial met its primary endpoint, which compared maribavir with available antiviral regimens in transplant recipients with recurrent/refractory CMV infection. More than half of the patients treated with maribavir achieved successful treatment of CMV infection within 8 weeks, and they experienced less neutropenia and acute kidney injury compared with currently available antiviral regimens (valganciclovir/ganciclovir and foscarnet, respectively). These new findings represent a significant advance in the search for new therapies for cytomegalovirus in transplant recipients.”

CMV (Image source: std-gov.org)

Cytomegalovirus (CMV) is a betaherpesvirus that commonly infects humans; serological evidence of prior infection is present in 40%–100% of the adult population. However, individuals with compromised immune systems may develop severe disease, including patients receiving immunosuppressive therapy associated with various types of transplantation, such as hematopoietic cell transplantation (HCT) or solid organ transplantation (SOT). CMV typically remains latent and asymptomatic within the body but can reactivate during periods of immunosuppression. Among an estimated 200,000 adult transplantations performed annually, CMV is one of the most common viral infections in transplant recipients, with an estimated incidence of 16%–56% in SOT recipients and 30%–70% in HCT recipients. Reactivation of CMV can lead to serious consequences, including loss of the transplanted organ and, in extreme cases, death. Current therapies for treating post-transplant CMV infection may exhibit toxicity, require dose adjustments, necessitate hospitalization, or fail to adequately suppress viral replication.

Maribavir belongs to a class of drugs known as benzimidazole nucleosides, which target and inhibit the CMV UL97 protein kinase, thereby potentially affecting several key processes in CMV replication, including viral DNA replication, viral gene expression, capsid assembly, and the egress of mature capsids from the nucleus of infected cells.

Maribavir is an orally bioavailable antiviral therapy currently in Phase III clinical development, evaluating its efficacy in hematopoietic stem cell transplant recipients with cytomegalovirus (CMV) infection who are resistant or refractory to current standard CMV therapies.Stem CellsTransplantation (HSCT) or solid organOrgan Transplantation(SOT) Therapeutic potential in recipients. Currently, maribavir has not been approved in any country. In both 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 in transplant recipients. (Bioon.com)

Original Source: Takeda’s Maribavir Phase 3 Trial Met Primary Endpoint of Superiority to Conventional Antiviral Therapy for Cytomegalovirus