By Thomas Leung, PharmD
Antimicrobial Stewardship Program, Standford Health Care
Background
Maribavir is a novel benzimidazole riboside cytomegalovirus (CMV) pUL97 protein kinase inhibitor.1 Through competitive inhibition, it attaches to the pUL97 encoded serine/threonine kinase at the adenosine triphosphate (ATP) binding site, preventing phosphotransferase activity required for viral deoxyribonucleic acid (DNA) replication, encapsidation, and nuclear egress.1-3
On Nov. 23, 2021, the Food and Drug Administration (FDA) approved maribavir as the first drug to treat adult and pediatric patients with post-transplant CMV infections that do not respond to currently available antiviral treatment.3-4 Maribavir originally was developed by GlaxoSmithKline for use in human immunodeficiency virus (HIV) patients with CMV retinitis.3,5 However, drug development was discontinued because of the reduction of disease resulting from advances in HIV therapy. Subsequently, in August 2003, maribavir was licensed to ViroPharma to develop the drug as a preventive option for CMV infections in transplant patients.5 However, in a Phase III clinical trial, maribavir failed to demonstrate efficacy for the prevention of CMV infection in transplant recipients. Patients in this clinical trial received maribavir 100 mg twice daily, which raised concerns about the medication being underdosed.3,6 In June 2011, maribavir was granted Orphan Drug Designation by the FDA for the treatment of clinically significant CMV viremia and disease in at-risk patients.3 On Dec. 15, 2017, the FDA granted Breakthrough Therapy Designation for maribavir for the treatment of CMV infection in transplant patients resistant or refractory to prior therapy.3
Maribavir’s unique mechanism of action allows it to retain activity against CMV that is resistant to valganciclovir, cidofovir, and foscarnet.1-3 Additionally, maribavir has a favorable side effect profile when compared to traditional CMV therapies, with dysgeusia as the most common adverse effect. These factors were primary drivers to investigate the use of maribavir in patients with resistant or refractory CMV.1,3,7-9
Microbiology
In addition to antiviral activity against CMV, maribavir has in vitro activity against Epstein-Barr virus (EBV). However, clinical studies have not evaluated the use of maribavir for EBV.2-3,10 Maribavir has no antiviral activity against herpes simplex virus (HSV) 1 and 2, varicella zoster (VZV), human herpesvirus 6, human herpes virus 8, and various animal CMV.2-3,10 For patients who require HSV or VZV coverage, an additional antiviral, such as acyclovir, may be indicated.
Pharmacokinetics/Pharmacodynamics (PK/PD)
Following oral administration, plasma maribavir exposure (Cmax and area under the curve [AUC]) increases proportionally to the dose following a single dose of 50 mg to 1,600 mg and multiple doses up to 2,400 mg per day.3 Maribavir PK is time-independent. With twice-daily dosing, steady state is reached within two days. The mean accumulation ratios of Cmax and AUC range from 1.37 µg/mL to 1.47 µg/mL.3 Maribavir is primarily metabolized by the liver via CYP3A4 into the inactive metabolite N-dealkylayted maribavir.1-3
No clinically significant differences in maribavir were noted based on age (18-79 years), gender, race (Caucasian, Black, Asian, and others), ethnicity (Hispanic/Latino or non-Hispanic/Latino), body weight (36 kg to 141 kg), mild to severe renal impairment (measured creatinine clearance ranging from 12 mL/min to 70 mL/min), or mild to moderate hepatic impairment (Child-Pugh Class A or B).1,3
Although maribavir was approved by the FDA for use in patients 12 years of age and older, its PK has not been evaluated formally in patients younger than 18 years old. However, based on modeling and simulation, the recommended dosing regimen for adults is expected to result in comparable steady state plasma exposures of maribavir in patients 12 years of age or older weighing at least 35 kg.1,3
Similar antiviral effects were associated with doses of 400 mg, 800 mg, and 1,200 mg taken twice daily, based on exposure response analyses from two Phase II dose-ranging studies for CMV treatment.1,3,8-9 The proportions of patients with confirmed undetectable plasma CMV DNA within six weeks of treatment were found to be 70%, 63%, and 68% in the first Phase II trial and 79%, 83%, and 79% in the second Phase II trial for maribavir at 400 mg, 800 mg, and 1,200 mg taken twice daily.8-9 Adverse drug effects were similar across the three dosing regimens, but the 1,200 mg twice daily group had the highest incidence of dysgeusia.8-9
Clinical Data
Maribavir received FDA approval based on the findings from the SOLSTICE trial, a Phase III randomized, open-label, multicenter, controlled trial of hemopoietic stem cell transplant or solid organ transplant patients with refractory CMV with or without genotypic resistance.2,4,7 Patients were randomized in a 2:1 ratio to receive either oral maribavir 400 mg by mouth twice daily or investigator assigned therapy (IAT), which included monotherapy or combination therapy of oral valganciclovir, intravenous (IV) ganciclovir, IV foscarnet, or IV cidofovir for eight weeks.7 The study protocol allowed patients assigned IAT to receive maribavir rescue after three weeks of treatment. For the primary endpoint, maribavir demonstrated superiority to IAT with respect to confirmed CMV viremia clearance at the end of week 8 (55.7% vs. 23.9%; P < 0.001).7 Maribavir also demonstrated an improved safety profile compared to IAT, with higher rates of dysgeusia, but lower rates of leukopenia, neutropenia, hypokalemia, and acute kidney injury.7
In the SOLSTICE trial follow-up period, CMV viremia clearance and symptom control at week 8 through week 16 also favored maribavir over IAT; however, the absolute difference was less pronounced (18.7% vs. 10.3%; P = 0.013).1,3,7 The SOLSTICE trial also evaluated the incidence of treatment emergent maribavir resistance in 214 patients. Treatment emergent maribavir resistance was found in 58 patients (27.1%) associated with substitutions in pUL97 F342Y, T409M, H411L/N/Y, and/or C480F. These substitutions reduced susceptibility ranging from 4.5- to 224-fold. One patient had a pUL27 L193F substitution mutation conferring 2.6-fold reduced susceptibility to maribavir. Of these 58 patients, 47 (81%) failed to achieve CMV viremia clearance at the end of eight weeks.1,3,7 Although maribavir has been shown to be superior to standard of care therapy for patients with refractory CMV disease and offers a favorable side effect profile, patients treated with maribavir should be monitored closely after completion of therapy to assess for relapse and emergence of resistance. Currently, Takeda is conducting a Phase III clinical trial to assess the role of maribavir as primary treatment of CMV infection in hematopoietic stem cell transplant patients (NCT02927067).
Conclusion
Maribavir is a novel CMV protein kinase inhibitor with a unique mechanism of action that retains activity against drug-resistant CMV and is the only FDA-approved drug to treat patients with refractory or resistant CMV disease. Additionally, maribavir offers a favorable side effect profile, with the most common adverse drug reaction being dysgeusia. When compared to valganciclovir, cidofovir, and foscarnet, maribavir has lower rates of neutropenia and renal injury. While maribavir was found to be superior to standard of care therapy in patients with resistant and refractory disease, its use outside of this patient population should be carefully considered, given concerns of relapse disease and emergence of resistance. Access to maribavir may of concern as well, since the distribution is limited to select specialty pharmacies and the cost of therapy is $683 per day, and the average wholesale price $1,067 per day of therapy — although significantly lower costs generally are negotiated.
REFERENCES
- Livtencity. Package insert. Takeda Pharmaceuticals America, Inc; 2021.
- Grayson ML. Kucers’ The Use of Antibiotics: A Clinical Review of Antibacterial, Antifungal, Antiparasitic and Antiviral Drugs. 6th ed. Hodder Arnold; 2010.
- U.S. Food and Drug Administration. Maribavir Sponsor Briefing Document. Updated Nov. 22, 2021. https://www.fda.gov/media/152715/download
- U.S. Food and Drug Administration. FDA approves first treatment for common type of post-transplant infection that is resistant to other drugs. Nov. 23, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-common-type-post-transplant-infection-resistant-other-drugs
- Trofe J, Pote L, Wade E, et al. Maribavir: A novel antiviral agent with activity against cytomegalovirus. Ann Pharmacother 2008;42:1447-1457.
- Marty FM, Ljungman P, Papanicolaou GA, et al. Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: A phase 3, double-blind, placebo-controlled, randomised trial [published correction appears in Lancet Infect Dis 2011;11:343]. Lancet Infect Dis 2011;11:284-292.
- Avery RK, Alain S, Alexander BD, et al. Maribavir for refractory cytomegalovirus infections with or without resistance post-transplant: Results from a Phase 3 randomized clinical trial. Clin Infect Dis 2021;ciab988. doi:10.1093/cid/ciab988. [Online ahead of print].
- Papanicolaou GA, Silveira FP, Langston AA, et al. Maribavir for refractory or resistant cytomegalovirus infections in hematopoietic-cell or solid-organ transplant recipients: A randomized, dose-ranging, double-blind, Phase 2 study. Clin Infect Dis 2019;68:1255-1264.
- Maertens J, Cordonnier C, Jaksch P, et al. Maribavir for preemptive treatment of cytomegalovirus reactivation. N Engl J Med 2019;381:1136-1147.
- Williams SL, Hartline CB, Kushner NL, et al. In vitro activities of benzimidazole D- and L-ribonucleosides against herpesviruses. Antimicrob Agents Chemother 2003;47:2186-2192.
The FDA approved maribavir as the first drug to treat adult and pediatric patients with post-transplant cytomegalovirus infections that do not respond to currently available antiviral treatment.
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