The FDA has accepted a new drug application for maribavir for the treatment of post-transplant recipients with cytomegalovirus infection who are refractory and/or resistant to previous anti-CMV treatment.
The FDA has accepted a new drug application (NDA) for maribavir (TAK-620) for the treatment of post-transplant recipients with cytomegalovirus (CMV) infection who are refractory and/or resistant to previous anti-CMV treatment, according to an announcement from Takeda Pharmaceutical Company Limited.1
The application is based on data from the pivotal phase 3 TAK-620-303 (SOLSTICE) trial (NCT02931539), which showed that the agent was superior to conventional antiviral therapies such as ganciclovir (Zirgan), valganciclovir (Valcyte), foscarnet (Foscavir), or cidofovir (Vistide) alone or in combination in this population.2
Specifically, more than double transplant recipients with relapsed/refractory CMV who received maribavir experienced confirmed CMV viremia clearance at the end of the treatment phase (study week 8) vs conventional approaches, at 55.7% (n = 131/235) and 23.9% (n = 28/117), respectively (95% CI, 32.8%; 22.8-42.7; P <.001). These findings were noted to meet the primary end point of the study. The agent was also found to induce an improvement over conventional therapies in terms of clearance of CMV viremia and associated symptom control maintained through week 16, meeting a key secondary end point of the study.
The NDA also includes findings from a subgroup analysis of the study presented during the Virtual 47th Annual Meeting of the EBMT, which indicated that maribavir resulted in more than triple the amount of transplant recipients with confirmed genotypic resistant CMV infection at baseline achieving CMV viremia clearance at study week 8 vs those who were given conventional approaches, at 62.8% (n = 76/121) vs 20.3% (n = 14/69), respectively (95% CI, 44.1%; 31.3-56.9).3
“CMV infection puts transplant recipients at an increased risk of disease, such as pneumonia or gastrointestinal disease. It can also increase the risk of graft rejection, opportunistic co-infections, and in some cases, even death,” Michael Boeckh, MD, PhD, head of the Infectious Disease Sciences Program at the Vaccine and Infectious Disease Division of Fred Hutch, stated in a press release. “The results of the SOLSTICE trial are promising and show that maribavir may help with post-transplant CMV viremia, including cases of drug resistance for which there is an unmet need.”
The orally bioavailable anti-CMV compound is currently only antiviral agent that is in phase 3 development for the treatment of patients with CMV following solid organ transplant (SOT) or hematopoietic cell transplant.
In the multicenter, open-label, active-controlled phase 3 SOLSTICE trial, investigators set out to evaluate maribavir vs investigator-assigned treatment of conventional antiviral therapy in transplant recipients with CMV infection who are refractory with or without resistance to 1 or a combination of the conventional approaches.
Study participants first underwent a screening period of 2 weeks; then, they underwent a 2:1 randomization to either maribavir at 400 mg (n = 235) or investigator-assigned treatment (n = 177) for 8 weeks. Once treatment was completed, patients had 12 weeks of follow-up.
The primary end point of the trial was the proportion of patients who achieved confirmed CMV viremia clearance, defined as plasma CMV DNA of less than 137 IU/mL in 2 consecutive tests at least 5 days apart at a central laboratory, vs IAT at the end of study week 8. An important secondary end point was the achievement of CMV viremia clearance and symptom control at end of study week 8 but maintained through week 16.
Additional data from the subgroup analyses of the primary end point in the overall randomized population showed 55.6% of SOT recipients with relapsed/refractory CMV infection who received maribavir experienced confirmed CMV viremia clearance vs 26.1% of those who were given conventional approaches. In HCT recipients with relapsed/refractory CMV infection, 55.9% vs 20.8% of those who received maribavir and conventional therapies, respectively, achieved confirmed CMV viremia clearance.
Moreover, more transplant recipients with relapsed/refractory CMV infection who received the investigational treatment had CMV clearance at week 8, irrespective of baseline viral load category vs those given standard approaches. Among those with low viral load category at baseline (less than 9100 IU/mL), these rates were 62.1% and 24.7% for those in the investigative and control arms, respectively; in those with intermediate/high baseline viral load category (9100 IU/mL or more), these rates were 43.9% and 21.9%, respectively.
Regarding safety, maribavir was associated with lower incidence of treatment-related adverse effects that are often experienced with conventional approaches. Specifically, those who received maribavir experienced less treatment-related neutropenia compared with valganciclovir/ganciclovir, at 1.7% and 25%, respectively; those in the investigative arm also experienced less treatment-related acute kidney injury vs those given foscarnet, at 1.7% and 19.1%, respectively.
Rates of treatment-emergent toxicities were 97.4% and 91.4% with maribavir and conventional approaches, respectively. The most frequently experienced treatment-emergent adverse effects (TEAEs) included dysgeusia (35.9%), nausea (8.5%), and vomiting (7.7%). Moreover, 13.2% and 31.9% of patients in the investigative and control arms, respectively, experienced TEAEs that resulted in discontinuation. Two serious AEs determined to be associated with treatment resulted in death (1 in each arm).