Chemical formula: C₁₅H₁₉Cl₂N₃O₄ Molecular mass: 376.23 g/mol
Maribavir is a competitive inhibitor of the UL97 protein kinase. UL97 inhibition occurs at the viral DNA replication phase, inhibiting UL97 serine/threonine kinase by competitively inhibiting the binding of ATP to the kinase ATP-binding site, without affecting the concatemer maturation process, abolishing phosphotransferase inhibiting CMV DNA replication and maturation, CMV DNA encapsidation, and CMV DNA nuclear egress.
Maribavir inhibited human CMV replication in virus yield reduction, DNA hybridization, and plaque reduction assays in human lung fibroblast cell line (MRC-5), human embryonic kidney (HEK), and human foreskin fibroblast (MRHF) cells. The EC50 values ranged from 0.03 to 2.2 µM depending on the cell line and assay endpoint. The cell culture antiviral activity of maribavir has also been evaluated against CMV clinical isolates. The median EC50 values were 0.1 μM (n=10, range 0.03-0.13 μM) and 0.28 μM (n=10, range 0.12-0.56 μM) using DNA hybridization and plaque reduction assays, respectively. No significant difference in EC50 values across the four human CMV glycoprotein B genotypes (N = 2, 1, 4, and 1 for gB1, gB2, gB3, and gB4, respectively) was seen.
When maribavir was tested in in vitro combination with other antiviral compounds, strong antagonism was seen with ganciclovir.
No antagonism was seen in combination with cidofovir, foscarnet and letermovir.
Maribavir does not affect the UL54encoded DNA polymerase that, when presenting certain mutations, confers resistance to ganciclovir/valganciclovir, foscarnet and/or cidofovir. Mutations conferring resistance to maribavir have been identified on gene UL97: L337M, F342Y, V353A, V356G, L397R, T409M, H411L/N/Y, D456N, V466G C480F, P521L, and Y617del. These mutations confer resistance that ranges from 3.5-fold to > 200-fold increase in EC50 values. UL27 gene variants (R233S, W362R, W153R, L193F, A269T, V353E, L426F, E22stop, W362stop, 218delC, and 301311del) conferred only mild maribavir resistance (<5-fold increase in EC50), while L335P conferred high maribavir resistance.
In Phase 2 Study 202 and Study 203 evaluating maribavir in 279 HSCT or SOT recipients, post-treatment pUL97 genotyping data from 23 of 29 patients who initially achieved viremia clearance and later experienced recurrent CMV infection while on maribavir showed 17 patients with mutations T409M or H411Y and 6 patients with mutation C480F. Among 25 patients who did not respond to >14 days of maribavir therapy, 9 had mutations T409M or H411Y, and 5 patients had mutation C480F. Additional pUL27 genotyping was performed on 39 patients in Study 202 and 43 patients in Study 203. The only resistance-associated amino acid substitution in pUL27 that was not detected at baseline was G344D. Phenotypic analysis of pUL27 and pUL97 recombinants showed that pUL97 mutations T409M, H411Y, and C480F conferred 78-fold, 15-fold, and 224-fold increases, respectively, in maribavir EC50 compared with the wild-type strain, whereas the pUL27 mutation G344D showed no difference in maribavir EC50 as compared to the wild-type strain.
In Phase 3 Study 303 evaluating maribavir in patients with phenotypic resistance to valganciclovir/ganciclovir, DNA sequence analysis of the entire coding regions of pUL97 and pUL27 was performed on 134 paired sequences from maribavir-treated patients. The treatment-emergent pUL97 substitutions F342Y (4.5-fold), T409M (78-fold), H411L/N/Y (69-, 9-, and 12-fold, respectively), and/or C480F (224-fold) were detected in 60 subjects and were associated with nonresponse (47 subjects were on-treatment failures and 13 subjects were relapsers). One subject with the pUL27 L193F substitution (2.6-fold reduced susceptibility to maribavir) at baseline did not meet the primary endpoint. In addition, the following multiple mutations were associated with non-response; F342Y+T409M+H411N (78-fold), C480F+H411L+H411Y (224-fold), F342Y+H411Y (56-fold), T409M+C480F (224-fold) and H411Y+C480F (224-fold).
Cross-resistance has been observed between maribavir and ganciclovir/valganciclovir (vGCV/GCV) in cell culture and in clinical studies. In the phase 3 Study 303, a total of 44 patients in the maribavir arm had a treatment emergent resistance associated substitutions (RAS) to Investigator assigned treatment (IAT). Of these 24 had treatment-emergent C480F or the F342Y RAS, both are crossresistant to both ganciclovir/valganciclovir and maribavir. Of these 24 patients, 1 (0.04%) achieved the primary endpoint. Overall, only eight of these 44 patients achieved the primary endpoint. pUL97 vGCV/GCV resistance-associated substitutions F342S/Y, K355del, V356G, D456N, V466G, C480R, P521L, and Y617del reduce susceptibility to maribavir >4.5-fold. Other vGCV/GCV resistance pathways have not been evaluated for cross-resistance to maribavir. pUL54 DNA polymerase substitutions conferring resistance to vGCV/GCV, cidofovir, or foscarnet remained susceptible to maribavir.
Substitutions pUL97 F342Y and C480F are maribavir treatment-emergent resistance-associated substitutions that confer >1.5-fold reduced susceptibility to vGCV/GCV, a fold reduction that is associated with phenotypic resistance to vGCV/GCV. The clinical significance of this cross-resistance to vGCV/GCV for these substitutions has not been determined. Maribavir resistant virus remained susceptible to cidofovir and foscarnet. Additionally, there are no reports of any pUL27 maribavir resistance-associated substitutions being evaluated for vGCV/GCV, cidofovir, or foscarnet crossresistance. Given the lack of resistance-associated substitutions for these drugs mapping to pUL27, cross-resistance is not expected for pUL27 maribavir substitutions.
Maribavir pharmacological activity is due to the parent medicinal product. The pharmacokinetics of maribavir have been characterised following oral administration in healthy subjects and transplant patients. Maribavir exposure increased in an approximately dose proportionally manner. In healthy subjects, the geometric mean steady-state AUC0-t, Cmax and Ctrough values were 101 µg*h/mL, 16.4 µg/mL and 2.89 µg/mL, respectively, following 400 mg twice daily oral maribavir doses.
In transplant recipients, maribavir steady state exposure following oral administration of 400 mg twice daily doses are provided below, based on a population pharmacokinetics analysis. Steady-state was reached in 2 days, with an accumulation ratio of 1.47 for AUC and 1.37 for Cmax. The intrasubject variability (<22%) and intersubject variability (<37%) in maribavir PK parameters are low to moderate.
Maribavir pharmacokinetic properties in transplant recipients based on a population pharmacokinetics analysis:
| Parameter GM (% CV) | AUC0-tau µg*h/mL | Cmax µg/mL | Ctrough µg/mL |
|---|---|---|---|
| Maribavir 400 mg twice daily | 128 (50.7%) | 17.2 (39.3%) | 4.90 (89.7%) |
GM: Geometric mean, % CV: Geometric coefficient of variation
Maribavir was rapidly absorbed with peak plasma concentrations occurring 1.0 to 3.0 hours post dose. Exposure to maribavir is unaffected by crushing the tablet, administration of crushed tablet through nasogastric (NG)/orogastric tubes or co-administration with proton pump inhibitors (PPIs), histamine H2 receptor antagonists (H2 blockers) or antacids.
In healthy subjects, oral administration of a single 400 mg dose of maribavir with a high fat meal resulted in no change in the overall exposure (AUC) and a 28% decrease in Cmax of maribavir, which was not considered clinically relevant.
Based on population pharmacokinetic analyses, the apparent steady-state volume of distribution is estimated to be 27.3 L.
In vitro binding of maribavir to human plasma proteins was 98.0% over the concentration range of 0.05-200 μg/mL. Ex vivo protein binding of maribavir (98.5%-99.0%) was consistent with in vitro data, with no apparent difference observed among healthy subjects, subjects with hepatic (moderate) or renal (mild, moderate or severe) impairment, human immunodeficiency virus (HIV) patients, or transplant patients.
Maribavir may cross the blood-brain barrier in humans but CNS penetration is expected to be low compared to plasma levels.
In vitro data indicate that maribavir is a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and organic cation transporter 1 (OCT1) transporters. Changes in maribavir plasma concentrations due to inhibition of P-gp/BCRP/OCT1 were not clinically relevant.
Maribavir is primarily eliminated by hepatic metabolism via CYP3A4 (primary metabolic pathway fraction metabolised estimated to be at least 35%), with secondary contribution from CYP1A2 (fraction metabolised estimated at no more than 25%). The major metabolite of maribavir is formed by N-dealkylation of the isopropyl moiety and is considered pharmacologically inactive. The metabolic ratio for this major metabolite in plasma was 0.15-0.20. Multiple UGT enzymes, namely UGT1A1, UGT1A3, UGT2B7, and possibly UGT1A9, are involved in the glucuronidation of maribavir in humans, however, the contribution of glucuronidation to the overall clearance of maribavir is low based on in vitro data.
Based on in vitro studies, metabolism of maribavir is not mediated by CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A5, 1A4, UGT1A6, UGT1A10, or UGT2B15.
The elimination half-life and oral clearance of maribavir are estimated at 4.3 hours and 2.9 L/h, respectively, in transplant patients. After single dose oral administration of [14C]-maribavir, approximately 61% and 14% of the radioactivity were recovered in urine and faeces, respectively, primarily as the major and inactive metabolite. Urinary excretion of unchanged maribavir is minimal.
No clinically significant effect of mild, moderate or severe renal impairment (measured creatinine clearance ranging from 12 to 70 mL/min) was observed on maribavir total PK parameters following a single dose of 400 mg maribavir. The difference in maribavir PK parameters between subjects with mild/moderate or severe renal impairment and subjects with normal renal function was <9%. As maribavir is highly bound to plasma proteins, it is unlikely that maribavir will be significantly removed by haemodialysis or peritoneal dialysis.
No clinically significant effect of moderate hepatic impairment (Child-Pugh Class B, score of 7-9) was observed on total or unbound maribavir PK parameters following a single dose of 200 mg of maribavir. Compared to the healthy control subjects, AUC and Cmax were 26% and 35% higher, respectively, in subjects with moderate hepatic impairment. It is not known whether the exposure to maribavir will increase in patients with severe hepatic impairment.
Age (18-79 years), gender, race (Caucasian, Black, Asian, or others), ethnicity (Hispanic/Latino or non-Hispanic/Latino) and body weight (36 to 141 kg) did not have clinically significant effect on the pharmacokinetics of maribavir based on population PK analysis.
Transplant types (HSCT vs. SOT) or between SOT types (liver, lung, kidney, or heart) or presence of gastrointestinal (GI) graft-versus host disease (GvHD) do not have a clinically significant impact on PK of maribavir.
Regenerative anaemia and mucosal cell hyperplasia in the intestinal tract, observed with dehydration was noted in rats and monkeys, together with clinical observations of soft to liquid stool, and electrolyte changes (in monkeys only). A no observed adverse effect level (NOAEL) was not established in monkeys and was <100 mg/kg/day, which is approximately 0.25 the human exposure at the recommended human dose (RHD). In rats the NOAEL was 25 mg/kg/day, at which exposures were 0.05 and 0.1 times the human exposure at the RHD in males and females, respectively.
Maribavir did not demonstrate phototoxicity in vitro, therefore, the potential for phototoxicity in humans is considered unlikely.
Maribavir was detected at low levels in the choroid plexus of rats and the brain and CSF of the monkey.
No carcinogenic potential was identified in rats up to 100 mg/kg/day at which exposures in males and females were 0.2 and 0.36 times, respectively the human exposure at the RHD. In male mice, an equivocal elevation in the incidence of haemangioma, haemangiosarcoma, and combined haemangioma/hemangiosarcoma across multiple tissues at 150 mg/kg/day is of uncertain relevance in terms of its translation to human risk given the lack of an effect in female mice or in rats after 104 weeks of administration, lack of neoplastic proliferative effects in male and female mice after 13 weeks administration, the negative genotoxicity package and the difference in duration of administration in humans. There were no carcinogenic findings at the next lower dose of 75 mg/kg/day, which is approximately 0.35 and 0.25 in males and females, respectively, the human exposure at the RHD.
Maribavir was not mutagenic in a bacterial mutation assay, nor clastogenic in the bone marrow micronucleus assay. In mouse lymphoma assays, maribavir demonstrated mutagenic potential in the absence of metabolic activation and the results were equivocal in the presence of metabolic activation. Overall, the weight of evidence indicates that maribavir does not exhibit genotoxic potential.
In the combined fertility and embryofoetal development study in rats, there were no effects of maribavir on fertility. However, in male rats decreases in sperm straight line velocity, were observed at doses ≥100 mg/kg/day (which is estimated to be less than the human exposure at the RHD), but without any impact on male fertility.
In a combined fertility and embryofoetal development study in rats, maribavir was not teratogenic and had no effect on embryofoetal growth or development at doses up to 400 mg/kg/day. A decrease in the number of viable foetuses due to increase in early resorptions and post-implantation losses was observed in females at all tested maribavir doses which were also maternally toxic. The lowest dose corresponded to approximately half the human exposure at the RHD. In the pre and postnatal developmental toxicity study conducted in rats, decreased pup survival due to poor maternal care and reduced body weight gain associated with a delay in developmental milestones (pinna detachment, eye opening and preputial separation) were observed at maribavir doses ≥150 mg/kg/day. Postnatal development was not affected at 50 mg/kg/day. Fertility and mating performance of the F1 generation, and their ability to maintain pregnancy and to deliver live offspring, was unaffected up to 400 mg/kg/day.
In rabbits, maribavir was not teratogenic at doses up to 100 mg/kg/day (approximately 0.45 times the human exposure at the RHD).
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