FDA Approves LIVTENCITY (Maribavir) for the Treatment of Adults and Pediatric Patients with Post-Transplant CMV Infection/Disease That Is Refractory to Treatment with Ganciclovir, Valganciclovir, Cidofovir or Foscarnet

On November 23, 2021, the U.S. Food and Drug Administration (FDA) approved LIVTENCITY (maribavir)  for the treatment of adults and pediatric patients (12 years of age and older and weighing at least 35 kg) with post-transplant cytomegalovirus (CMV) infection/disease that is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir or foscarnet.

The approved recommended dosage of LIVTENCITY in adult and pediatric patients (12 years of age and older and weighing at least 35 kg) is 400 mg (two 200 mg tablets) orally twice daily with or without food.

Additional information regarding dosage and administration as well as warnings and precautions about risk of reduced antiviral activity when co-administered with ganciclovir and valganciclovir, virologic failure during treatment and relapse post-treatment, risk of adverse reactions or loss of virologic response due to drug interactions can be found in the full prescribing information linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK)

MOA: Maribavir competitively inhibits the protein kinase activity of human CMV enzyme pUL97 which results in inhibition of the phosphorylation of proteins.

General PK: Following oral administration, plasma maribavir exposure (C_max and AUC) increased approximately dose-proportionally following a single dose of 50 to 1600 mg (0.125 to four times the recommended dose) and multiple doses up to 2400 mg per day (three times the recommended daily dose). With twice-daily dosing, steady state is reached within 2 days, with mean accumulation ratios of C_max and AUC ranging from 1.37 to 1.47. The PK parameters of maribavir are displayed below.

Table 1: PK Properties of Maribavir

^a When taken orally with a moderate fat meal versus fasted, the AUC0‑∞ and C_max geometric mean ratios [90% CI] of maribavir are 0.864 [0.804, 0.929] and 0.722 [0.656, 0.793], respectively.

^b In vitro studies have shown that maribavir is biotransformed into a major circulating inactive metabolite: VP 44469 (N-dealkylated metabolite), with a metabolic ratio of 0.15 - 0.20

^c Dosing in mass balance study: single-dose administration of [¹⁴C] maribavir oral solution 400 mg containing 200 nCi of total radioactivity.

Table 2. Multiple-Dose PK Parameters of Maribavir

^a PK parameter values based on post-hoc estimates from maribavir population PK model in transplant patients with CMV receiving 400 mg of maribavir twice daily with or without food.

^b tau is maribavir dosing interval: 12 hours

Drug Interactions

Ganciclovir or Valganciclovir: co-administration with LIVTENCITY is not recommended. LIVTENCITY may antagonize the antiviral activity of ganciclovir and valganciclovir by inhibiting human CMV pUL97 kinase, which is required for activation/phosphorylation of ganciclovir and valganciclovir.

Strong CYP3A4 inducers: co-administration with LIVTENCITY is not recommended except the following anticonvulsants.

• Carbamazepine: adjust LIVTENCITY dose to 800 mg twice daily
• Phenobarbital and phenytoin: adjust LIVTENCITY dose to 1200 mg twice daily

Antimycobacterials and herbal products: co-administration of LIVTENCITY and rifabutin, rifampin, and St. John’s wort is not recommended due to potential for a decrease in efficacy of LIVTENCITY.

Sensitive CYP3A4, P-gp, or breast cancer resistance protein (BCRP) substrates: Use caution and frequently monitor levels of the following drugs when co-administered with  LIVTENCITY: with digoxin, cyclosporine, everolimus, sirolimus, and tacrolimus.  When co-administered with rosuvastatin, the patient should be closely monitored for rosuvastatin-related events, especially the occurrence of myopathy and rhabdomyolysis.

LIVTENCITY is a weak CYP3A4 inhibitor, and a P-gp and BCRP inhibitor. Co-administration of LIVTENCITY with drugs that are sensitive substrates of CYP3A, P-gp or BCRP may result in a clinically relevant increase in plasma concentrations of these substrates.

Use in Specific Populations

There were no clinically significant differences in the PK of maribavir based on age (18-79 years), gender, race (Caucasian, Black, Asian, or others), ethnicity (Hispanic/Latino or non-Hispanic/Latino), body weight (36-141 kg), mild to severe renal impairment (measured CrCL 12-70 mL/min), or mild to moderate hepatic impairment (Child-Pugh Class A or B).

Pediatric patients: The PK of maribavir in patients less than 18 years of age have not been evaluated. Using modeling and simulation, the recommended dosing regimen is expected to result in comparable steady-state plasma exposures of maribavir in patients 12 years of age and older and weighing at least 35 kg as observed in adults.

Efficacy and Safety

Efficacy of LIVTENCITY was demonstrated in a Phase 3, multicenter, randomized, open-label, active-controlled superiority trial of hematopoietic stem cell transplant or solid organ transplant recipients with CMV infections that were refractory to treatment with ganciclovir, valganciclovir, foscarnet, or cidofovir, including CMV infections with or without confirmed resistance to one or more of the Investigator-Assigned Treatments. The primary efficacy endpoint was confirmed CMV DNA level < LLOQ (i.e., <137 IU/mL) as assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test) at the end of Week 8. The response rate was 56% in the maribavir group and 24% in the active control group (adjusted p-value: <0.001). Additional information regarding efficacy trial(s) can be found in the full prescribing information linked below.

The most common adverse events (all grades, > 10%) in subjects treated with LIVTENCITY were taste disturbance, nausea, diarrhea, vomiting, and fatigue.

Full prescribing information is available at https://go.usa.gov/xemc9.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at  https://www.fda.gov/safety/medwatch/default.htm, by faxing (1-800-FDA-0178), or by mailing the postage- paid address form provided online, or by telephone (1-800-FDA-1088).

The Office of Clinical Pharmacology (OCP) is pleased to offer the e-mail subscription service Clinical Pharmacology Corner. This is a free service from FDA to provide occasional updates from OCP regarding newly approved therapies, new regulatory and scholarly publications, upcoming events and other items of interest. Subscribe today at https://updates.fda.gov/subscriptionmanagement (note: this link does not work with Internet Explorer) and select Clinical Pharmacology Corner under Drugs.

We always welcome your thoughts regarding the format, content, and utility of this communication. Comments may be sent via email to [email protected].

This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.