Maribavir Demonstrates Positive Safety Results Compared to Investigator-Assigned Therapy in Transplant Recipients

Few hematopoietic cell transplant (HCT) recipients treated with either maribavir (Livtencity) or investigator-assigned therapy (IAT) for refractory cytomegalovirus (CMV) infection with or without resistance experienced adverse graft outcomes, according to results from a safety analysis of the phase 3 SOLSTICE study (NCT02931539), according to a presentation at the EBMT 48th Annual Meeting.¹

“Lower rates of neutropenia and hypokalemia were also observed with maribavir than valganciclovir [Valcyte], ganciclovir [Zirgan], and foscarnet [Foscavir], respectively, and a lower proportion of HCT recipients discontinued treatment with maribavir than IAT,” said Catherine Cordonnier, MD, professor emeritus of hematology, University Paris-Est-Creteil during an EBMT presentation of the data.

Due to limited uses of conventional anti-CMV therapies as a result of safety issues, the SOLSTICE study examines maribavir, a potent and oral antiviral with multimodal anti-CMV activity, compared to IAT within a subgroup of patients with HCT. Findings from the SOLSTICE study show maribavir to be superior to IAT including valganciclovir,ganciclovir, foscarnet, or cidofovir (Vistide).²

Results show that more than twice as many transplant recipients with relapsed/refractory CMV infection or disease who received maribavir (n = 131/235) achieved CMV viremia clearance at study week 8 compared to those on conventional antiviral therapies (n = 28/117), at 55.7% and 23.9%, respectively (95% CI, 32.8%; 22.8%-42.7%; P < .001). Additionally, there is a reported benefit of maribavir over conventional antivirals which was found to be maintained through week 16 of the study.

In November 2021, the FDA approved maribavir for the treatment of adult and pediatric patients aged 12 years and older weighing at least 35 kg who have post-transplant CMV infection that does not respond to available antiviral treatment based on data from the SOLSTICE trial.³

The multicenter, open-label, active-controlled, phase 3 trial enrolled transplant recipients with CMV infection who were refractory with or without resistance to 1 or a combination of conventional treatment approaches.

Patients underwent a 2-week screening period at the start of the study prior to being randomized 2:1 to receive either maribavir at a dose of 400 mg or investigator-assigned treatment (IAT) for 8 weeks. A total of 352 patients were randomized including 141 (40.1%) HCT recipients (93 maribavir, 48 IAT [20 valganciclovir/ganciclovir, 18 foscarnet, 5 cidofovir, 4 >1 IAT, 1 not treated]). Once the treatment period was completed, patients had 12 weeks of follow-up.

For inclusion in the trial, participants were required to be a recipient of hematopoietic stem cell or solid organ transplant, have documented resistance mutations, have a current CMV infection that is refractory to the most recently administered of the four anti-CMV treatment agents, and have a documented CMV infection in whole blood or plasma.

The primary end point of the trial was proportion of patients who achieved confirmed CMV viremia clearance at the end of week 8. This was defined as plasma CMV DNA of less than 137 IU/mL in 2 consecutive tests at least 5 days apart at a central laboratory, versus IAT at the end of study week 8. One key secondary end point included demonstrating improvement with maribavir over conventional therapies in clearance of CMV viremia and associated symptom control maintained through study week 16.

Based on data from the subgroup analysis of the trial, maribavir led more than triple the amount of transplant recipients with confirmed genotypic-resistant CMV infection at baseline experiencing CMV viremia clearance at study week 8 compared with those who received conventional approaches, at 62.8% (n = 76/121) versus 20.3% (n = 14/69), respectively (95% CI, 44.1%; 31.3%-56.9%).

A total of 55.6% of solid organ transplant recipients with relapsed/refractory CMV who received maribavir reported having a confirmed CMV viremia clearance compared to 26.1% of those given conventional approaches. In HCT recipients with relapsed/refractory CMV infection, a consistent benefit of maribavir versus IAT for the primary end point was seen at 55.9% compared to 20.8% of patients.

During the overall study period and before rescue of alternative anti-CMV therapy, 25 (26.9%) patients treated with maribavir and 10 (20.8%) patients treated with IAT experienced new GvHD. Median time from HCT to antiviral treatment start date was 71.5 days (21, 2091) for the patients who were treated with maribavir, and 81 days (20, 512) for patients treated with IAT.

The median time to new GvHD after the first dose of study-assigned treatment was 33.0 (4–98) days for maribavir and 47.0 (2–123) days for IAT. Only 1 HCT recipient treated with maribavir experienced graft loss which occurred after 124 days on the study.

Rates of overall treatment-emergent adverse events (TEAEs) reported by more than 10% of the HCT patients in either the maribavir or IAT arm were 98.9% compared to 95.7%. Some of the most common TEAEs include nausea (28.3% vs 31.9%), dysgeusia (27.2% vs 6.4%), diarrhea (22.8% vs 21.3%), vomiting (21.7% vs 29.8%), pyrexia (19.6% vs 19.1%), and neutropenia (17.4% vs 27.7%).

Additionally, the frequency of hypokalemia was lower in the maribavir group than foscarnet (6 [6.5%]) vs 6 [33.3%]) and a lower proportion of patients with maribavir experienced neutropenia than with valganciclovir/ganciclovir (16 [17.4%] vs 9 [45.0%]). More patients experienced dysgeusia with maribavir than IAT (25 [27.2%] vs 3 [6.4%]).

Treatment-related TEAEs were observed in 46 (50.0%) patients treated with maribavir and 25 (53.2%) patients treated with IAT. Treatment-related dysgeusia occurred more frequently with maribavir (23 [25.0%]) than IAT (1 [2.1%]) and there were fewer reported treatment-related neutropenia cases with maribavir (4 [4.3%]) than valganciclovir/ganciclovir (6 [30.0%]).

A total of 21.7% of patients who received maribavir reported TEAEs which led to treatment discontinuation compared to 42.6% of those treated with IAT. TEAEs which led to death occurred in 10.9% of patients receiving maribavir and 10.6% for those receiving IAT.

“These data allow us to consider that maribavir is a promising treatment for refractory and resistant CMV infection when compared to conventional antivirals,” said Cordonnier.

References:

Maribavir versus investigator-assigned therapy for refractory CMV infection (with/without resistance) in hematopoietic cell transplant recipients: subgroup safety analysis of a phase 3 study. Presented at: 48th EBMT Annual Meeting; March 19-23, 2022. Abstract OS04-03. Virtual.

Efficacy and Safety Study of Maribavir Treatment Compared to Investigator-assigned Treatment in Transplant Recipients With Cytomegalovirus (CMV) Infections That Are Refractory or Resistant to Treatment With Ganciclovir, Valganciclovir, Foscarnet, or Cidofovir. Clinicaltrials.gov. Accessed March 22, 2022. https://clinicaltrials.gov/ct2/show/NCT02931539

FDA approves first treatment for common type of post-transplant infection that is resistant to other drugs. News release. FDA; November 23, 2021. Accessed November 24, 2021. https://bit.ly/3FMaI5q