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Antiviral activity: Maribavir selectively inhibited in vitro HCMV replication in yield reduction, DNA hybridization, and plaque reduction assays in human cell lines at noncytotoxic sub-micromolar concentrations. 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 mean EC50 values were 0.08 μM (n=10, range 0.03-0.13 μM) and 0.31 μM (n=10, range 0.12-0.56 μM) using DNA hybridization and plaque reduction assays, respectively Maribavir is highly selective for human CMV. There is no significant difference in baseline maribavir EC50 values across the four human CMV glycoprotein B genotypes.
Combination antiviral activity: When maribavir was tested in combination with other antiviral compounds, it showed additive interactions with letermovir, foscarnet, cidofovir, and GW275175X (a benzimidazole CMV terminase inhibitor) against wild type and mutant human CMV, strong antagonism with ganciclovir, and strong synergy with the mechanistic target of rapamycin (mTOR) inhibitor sirolimus.
Viral resistance: In cell culture: Maribavir does not affect the UL54-encoded 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, L397R, T409M, H411L/N/Y, and C480F. 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 301-311del) conferred only mild maribavir resistance (<5-fold increase in EC50).
In clinical studies: In Phase 2 Study 202 and Study 203 evaluating maribavir in 279 hematopoietic stem cell transplant (HSCT) or solid organ transplant (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. The pUL27 mutation G344D was not shown to confer maribavir resistance.
In Phase 3 Study 303, 60/234 patients (25.6%) were identified with treatment-emergent mutations in pUL97 that confer resistance to maribavir: C480F, F342Y, H411N, H411Y, T409M, F342Y+H411Y, F342Y+T409M+H411N, H411Y+C480F, T409M+C480F, T409M+H411Y, H411L+H411Y+C480F, H411N+C480F. Treatment-emergent mutations in pUL97 were identified in 43.2% of subjects (60/139) who had post-baseline genotyping performed after detection of a CMV DNA viral load above a pre-defined cut-off level of ≥500 copies/mL (455 IU/mL).
Cross resistance: There is clinical evidence of cross-resistance to maribavir and ganciclovir/valganciclovir at UL97: F342Y- 4.5-fold and 6.0-fold increase in EC50 to maribavir and ganciclovir, respectively; and C480F- 224-fold and 2.3-fold increase in EC50 to maribavir and ganciclovir, respectively. The prevalence of F342Y, the only cross-resistant mutation present in Study 303 subjects prior to maribavir treatment, was low (3/309 subjects with baseline UL97 genotyping).
Pharmacodynamic effects: Cardiac electrophysiology: The effect of maribavir at doses up to 1,200 mg on the QTc interval was evaluated in a randomised, single dose, placebo and active controlled (moxifloxacin 400 mg oral) 4 period crossover thorough QT trial in 52 healthy subjects. Maribavir does not prolong QTc to any clinically relevant extent following the 1,200 mg dose, with peak plasma concentrations approximately twice the steady-state peak concentration following 400 mg twice daily doses in transplant patients.
Clinical trials: LIVTENCITY was evaluated in a Phase 3, multicentre, randomised, open-label, active controlled superiority study (Study 303) to assess the efficacy and safety of LIVTENCITY treatment compared to IAT in 352 HSCT and SOT recipients with CMV infections that were refractory to treatment with ganciclovir, valganciclovir, foscarnet, or cidofovir, including CMV infections with or without confirmed resistance to 1 or more anti-CMV agents.
Patients were stratified by transplant type (HSCT or SOT) and screening viral load and then randomised in a 2:1 allocation ratio to receive LIVTENCITY 400 mg twice daily or IAT (ganciclovir, valganciclovir, foscarnet, or cidofovir) for an 8-week treatment period and a 12- week follow-up phase. (See Table 1.)
Click on icon to see table/diagram/imageThe primary efficacy endpoint was confirmed CMV viremia clearance (plasma CMV DNA concentration below the lower limit of quantification (<LLOQ; i.e., <137 IU/mL) as assessed by COBAS AmpliPrep/COBAS TaqMan CMV test) at Week 8. The key secondary endpoint was CMV viremia clearance and CMV infection symptom control at the end of Study Week 8 with maintenance of this treatment effect through Study Week 16.
For the primary endpoint, LIVTENCITY was superior to IAT (56% vs. 24%, respectively). For the key secondary endpoint, 19% vs 10% achieved both CMV viremia clearance and CMV infection symptom control in the LIVTENCITY and IAT group, respectively (see Table 2).
Click on icon to see table/diagram/imageThe reasons for failure to meet the primary endpoint are summarized in Table 3. (See Table 3.)
Click on icon to see table/diagram/imageThe treatment effect was consistent across key subgroups and supports the generalizability of the study outcomes (see Table 4).
Click on icon to see table/diagram/imageRecurrence: Recurrence requiring anti-CMV treatment after Week 8 was reported for 34/131 (26.0%) LIVTENCITY patients compared to 10/28 (35.7%) IAT patients. The median time to recurrence after CMV viremia clearance was 21 days (range 13, 80) in the LIVTENCITY group and 22 days (range 14, 36) in the IAT group.
Rescue arm: Twenty-two patients received LIVTENCITY as rescue therapy due to worsening of CMV viremia or new/persistent symptomatic CMV infections 7 (31.8%) or lack of improvement in CMV infection plus intolerance to IAT 15 (68.2%). Of the 22 patients, 11 (50.0%) patients achieved confirmed CMV viremia clearance at Week 8 of the LIVTENCITY rescue treatment phase and 11 (50.0%) patients were non-responders.
Effect on mortality: In pivotal study 303, the number of deaths reported was 14/235 (6.0%) in maribavir group compared with 5/116 (4.3%) within 8 weeks of observation. The number of reported deaths within 20 weeks of observation was 25/235 (10.7%) in maribavir group and 11/116 (9.5%) in IAT group.
Phase 2 studies: Study 202 was a Phase 2, randomised study to assess the safety and anti-CMV activity of 400 mg, 800 mg, and 1,200 mg twice daily of LIVTENCITY for the treatment of 120 transplant recipients with CMV infections that are resistant or refractory to treatment with ganciclovir/valganciclovir or foscarnet. By Week 6, 28/40 (70%) patients receiving 400 mg twice daily had achieved confirmed undetectable plasma CMV DNA. The mean (SD) exposure to patients receiving 400 mg LIVTENCITY-treated patients was 85 (55) days with a maximum of 177 days. The virologic response of doses of 400 mg, 800 mg, or 1,200 mg twice daily of LIVTENCITY were comparable within 6 weeks.
Study 203 was a Phase 2, randomised, dose-ranging study to assess the safety and anti-CMV activity of 400 mg, 800 mg, and 1,200 mg twice daily LIVTENCITY versus valganciclovir for the pre-emptive treatment of 159 SOT or HSCT recipients with CMV infection without CMV organ disease or resistant/refractory CMV infection.
By Weeks 3 and 6, 26/40 (65%) and 31/40 (78%) patients receiving 400 mg twice daily had achieved confirmed undetectable plasma CMV DNA compared to 22/40 (55%) and 26/40 (65%) patients receiving valganciclovir, respectively. The mean (SD) exposure to patients receiving 400 mg of LIVTENCITY was 50 (29) days with a maximum of 92 days. The virologic response of doses up to 1,200 mg twice daily and durations of up to 12 weeks of LIVTENCITY were comparable.
Overall, the favourable results observed in Study 303 were consistent with the results from the Phase 2 studies; thus, these earlier studies provide further support for the use of LIVTENCITY in the treatment of post-transplant CMV infection and disease in adults.
Pharmacokinetics: Maribavir pharmacological activity is due to the parent drug. The pharmacokinetics of maribavir have been characterised following oral administration in healthy subjects and transplant patients. Maribavir exposure increased in approximately dose proportionally. In healthy subjects, the geometric mean steady state AUC0-τ, 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 as follows, 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 pharmacokinetic properties of maribavir following administration of LIVTENCITY are displayed in Table 5. The multiple-dose pharmacokinetic parameters are provided in Table 6. (See Table 5 and Table 6.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageAbsorption: 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.
The intrasubject variability (<22%) and inter-subject variability (<37%) in maribavir PK parameters are low to moderate.
Effect of food: In healthy subjects, oral administration of a single 400 mg dose of maribavir with a high fat, high caloric meal did not have any statistically significant effect on the overall exposure (AUC) and resulted in 28% decrease in Cmax of maribavir. Maribavir can be administered orally with or without food as has been done in the clinical studies.
Distribution: 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 can penetrate the blood-retinal barrier and may cross the blood-brain barrier, but CNS penetration is expected to be low compared to plasma levels (see Precautions).
Metabolism: 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 UGT1A1/1A3/2B7 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.
In in vitro studies, metabolism of maribavir is not mediated by CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A5, UGT1A4, UGT1A6, UGT1A10, or UGT2B15.
Special Populations: Impaired renal function: No clinically significant effect of mild/moderate (CLcr, between 30 and 80 mL/min) or severe (CLcr less than 30 mL/min) renal impairment 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 less than 9%.
Impaired hepatic function: 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.
Age, gender, race, ethnicity, weight, and transplant type: Age (12-79 years), gender, race (Caucasian, Black, Asian, or others), ethnicity (Hispanic/Latino or non-Hispanic/Latino) and body weight (36 to 141 kg) and transplant type did not have clinically significant effect on the pharmacokinetics of maribavir based on population PK analysis.
Transplant types: 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.
Pediatric patients: The pharmacokinetics 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.
Toxicology: Preclinical safety data: Carcinogenicity: Two-year carcinogenic studies were conducted in both mice and rats at doses up to 150 and 100 mg/kg/day, respectively. 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 there was an equivocal elevation in the incidence of hemangioma, hemangiosarcoma, and combined hemangioma/hemangiosarcoma. The incidence in the treatment arm (12.9%) only marginally exceeded the reported historical control values of 12% at Charles Rivers laboratories and up to 8.3% at Covance laboratories (now LabCorp) in mice of similar strain. In female mice there was also an equivocal increase in the incidence of adenocarcinoma and combined adenoma/adenocarcinoma of the uterus in the 150 mg/kg/day group but is unlikely to be test article related as the incidence (4% increase for adenomas) was within historical control values (4.29%) observed in the laboratory. The incidence of both tumours showed borderline significant trends.
Genotoxicity: Maribavir was not mutagenic in a bacterial mutation assay. In the mouse lymphoma assay, maribavir demonstrated mutagenic potential in the absence of metabolic activation and the results were equivocal in the presence of metabolic activation (not concentration-dependent and not reproduced in the repeat assay). Maribavir was not clastogenic in the in vivo rat bone marrow micronucleus assay up to very high dose of 1,200 mg/kg that was toxic and close to producing lethality. Given the negative results of the in vivo rat micronucleus assay the weight of evidence indicates that maribavir does not exhibit genotoxic potential.
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