Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Takeda Pharmaceuticals International AG Ireland Branch, Block 3 Miesian Plaza, 50-58 Baggot Street Lower, Dublin 2, D02 Y754, Ireland E-mail: medinfoEMEA@takeda.com
Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals
ATC code: J05AX10
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.
A Phase 3, multi-centre, randomised, open-label, active-controlled superiority study (Study SHP620-303) assessed the efficacy and safety of LIVTENCITY treatment compared to Investigator assigned treatment (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. Refractory CMV infection was defined as documented failure to achieve >1 log10 decrease in CMV DNA level in whole blood or plasma after a 14-day or longer treatment period with intravenous ganciclovir/oral valganciclovir, intravenous foscarnet, or intravenous cidofovir. This definition was applied to the current CMV infection and the most recently administered anti-CMV agent.
Patients were stratified by transplant type (HSCT or SOT) and screening CMV DNA levels and then randomised in a 2:1 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.
The mean age of trial subjects was 53 years and most subjects were male (61%), white (76%) and not Hispanic or Latino (83%), with similar distributions across the two treatment arms. Baseline disease characteristics are summarised in Table 3 below.
Table 3. Summary of the baseline disease characteristics of the study population in Study 303:
| Characteristica | IAT | LIVTENCITY 400 mg Twice Daily | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| (N=117) | (N=235) | |||||||||||||||||||||||||||||||
| IAT treatment prior to randomization, n (%)c | ||||||||||||||||||||||||||||||||
| Ganciclovir/Valganciclovir | 98 (84) | 204 (87) | ||||||||||||||||||||||||||||||
| Foscarnet | 18 (15) | 27 (12) | ||||||||||||||||||||||||||||||
| Cidofovir | 1 (1) | 4 (2) | ||||||||||||||||||||||||||||||
| IAT treatment after randomization, n (%) | ||||||||||||||||||||||||||||||||
| Foscarnet | 47 (41) | n/a | ||||||||||||||||||||||||||||||
| Ganciclovir/Valganciclovir | 56 (48) | n/a | ||||||||||||||||||||||||||||||
| Cidofovir | 6 (5) | n/a | ||||||||||||||||||||||||||||||
| Foscarnet+ Ganciclovir/Valganciclovir | 7 (6) | n/a | ||||||||||||||||||||||||||||||
| Transplant type, n (%) | ||||||||||||||||||||||||||||||||
| HSCT | 48 (41) | 93 (40) | ||||||||||||||||||||||||||||||
| SOTd | 69 (59) | 142 (60) | ||||||||||||||||||||||||||||||
| Kidneye | 32 (46) | 74 (52) | ||||||||||||||||||||||||||||||
| Lunge | 22 (32) | 40 (28) | ||||||||||||||||||||||||||||||
| Hearte | 9 (13) | 14 (10) | ||||||||||||||||||||||||||||||
| Multiplee | 5 (7) | 5 (4) | ||||||||||||||||||||||||||||||
| Livere | 1 (1) | 6 (4) | ||||||||||||||||||||||||||||||
| Pancrease | 0 | 2 (1) | ||||||||||||||||||||||||||||||
| Intestinee | 0 | 1 (1) | ||||||||||||||||||||||||||||||
| CMV DNA levels category as reported by central laboratory, n (%)f | ||||||||||||||||||||||||||||||||
| High | 7 (6) | 14 (6) | ||||||||||||||||||||||||||||||
| Intermediate | 25 (21) | 68 (29) | ||||||||||||||||||||||||||||||
| Low | 85 (73) | 153 (65) | ||||||||||||||||||||||||||||||
| Baseline symptomatic CMV infectiong | ||||||||||||||||||||||||||||||||
| No | 109 (93) | 214 (91) | ||||||||||||||||||||||||||||||
| Yesg | 8 (7) | 21 (9) | ||||||||||||||||||||||||||||||
| CMV syndrome (SOT only), n (%)e,g,h | 7 (88) | 10 (48) | ||||||||||||||||||||||||||||||
| Tissue invasive disease, n (%)g,e,h | 1 (13) | 12 (57) | ||||||||||||||||||||||||||||||
CMV = cytomegalovirus, DNA = deoxyribonucleic acid, HSCT = haematopoietic stem cell transplant, IAT = investigator assigned anti-CMV treatment, max = maximum, min = minimum, N = number of patients, SD = standard deviation, SOT = solid organ transplant.
a Baseline was defined as the last value on or before the first dose date of study-assigned treatment, or date of randomisation for patients who did not receive study-assigned treatment.
b Age was calculated as the difference between date of birth and date of informed consent, truncated to years.
c Percentages are based on the number of subjects in the Randomized set within each column. Most recent anti-CMV agent, used to confirm refractory eligibility criteria.
d The most recent transplant.
e Percentages are based on the number of patients within the category.
f Viral load was defined for analysis by the baseline central specialty laboratory plasma CMV DNA qPCR results as high (≥91,000 IU/mL), intermediate (≥9,100 and <91,000 IU/mL), and low (<9,100 IU/mL).
g Confirmed by Endpoint Adjudication Committee (EAC).
h Patients could have CMV syndrome and tissue invasive disease.
The primary efficacy endpoint was confirmed CMV viraemia clearance (plasma CMV DNA concentration below the lower limit of quantification (< LLOQ; i.e., <137 IU/mL) at Week 8 regardless of whether either study-assigned treatment was discontinued before the end of the stipulated 8 weeks of therapy. The key secondary endpoint was CMV viraemia clearance and CMV infection symptom control at Week 8 with maintenance of this treatment effect through Study Week 16. CMV infection symptom control was defined as resolution or improvement of tissue-invasive disease or CMV syndrome for symptomatic patients at baseline, or no new symptoms for patients who were asymptomatic at baseline.
For the primary endpoint, LIVTENCITY was superior to IAT (56% vs. 24%, respectively, p<0.001). For the key secondary endpoint, 19% vs. 10% achieved both CMV viraemia clearance and CMV infection symptom control in the LIVTENCITY and IAT group, respectively (p=0.013) (See Table 4).
Table 4. Primary and key secondary efficacy endpoint analysis (randomised set) in Study 303:
| IAT (N=117) n (%) | LIVTENCITY 400 mg twice daily (N=235) n (%) | |
|---|---|---|
| rimary endpoint: CMV viraemia clearance response at week 8 | ||
| Overall | ||
| Responders | 28 (24) | 131 (56) |
| Adjusted difference in proportion of responders (95% CI)a | 32.8 (22.8, 42.7) | |
| p-value: adjusteda | <0.001 | |
| Key secondary endpoint: Achievement of CMV viraemia clearance and CMV infection symptom controlb at week 8, with maintenance through week 16b | ||
| Overall | ||
| Responders | 12 (10) | 44 (19) |
| Adjusted difference in proportion of responders (95% CI)a | 9.45 (2.0, 16.9) | |
| p-value: Adjusteda | 0.013 | |
CI = confidence interval; CMV = cytomegalovirus; HSCT = haematopoietic stem cell transplant; IAT = investigator-assigned anti-CMV treatment; N = number of patients; SOT = solid organ transplant.
a Cochran-Mantel-Haenszel weighted average approach was used for the adjusted difference in proportion (maribavir-IAT), the corresponding 95% CI, and the p-value after adjusting for the transplant type and baseline plasma CMV DNA concentration.
b CMV infection symptom control was defined as resolution or improvement of tissue-invasive disease or CMV syndrome for symptomatic patients at baseline, or no new symptoms for patients who were asymptomatic at baseline.
The treatment effect was consistent across transplant type, age group, and the presence of CMV syndrome/disease at baseline. However, LIVTENCITY was less effective against subjects with increased CMV DNA levels (≥50 000 IU/mL) and patients with absence of genotypic resistance (see table 5).
Table 5. Percentage of Responders by subgroup in Study 303:
| IAT (N=117) | LIVTENCITY 400 mg Twice Daily (N=235) | |||
|---|---|---|---|---|
| n/N | % | n/N | % | |
| Transplant type | ||||
| SOT | 18/69 | 26 | 79/142 | 56 |
| HSCT | 10/48 | 21 | 52/93 | 56 |
| Baseline CMV DNA viral load | ||||
| Low | 21/85 | 25 | 95/153 | 62 |
| Intermediate/High | 7/32 | 22 | 36/82 | 44 |
| Genotypic resistance to other anti-CMV agents | ||||
| Yes | 14/69 | 20 | 76/121 | 63 |
| No | 11/34 | 32 | 42/96 | 44 |
| CMV syndrome/disease at baseline | ||||
| Yes | 1/8 | 13 | 10/21 | 48 |
| No | 27/109 | 25 | 121/214 | 57 |
| Age Group | ||||
| 18 to 44 years | 8/32 | 25 | 28/55 | 51 |
| 45 to 64 years | 19/69 | 28 | 71/126 | 56 |
| ≥65 years | 1/16 | 6 | 32/54 | 59 |
CMV = cytomegalovirus, DNA = deoxyribonucleic acid, HSCT = hematopoietic stem cell transplant, SOT = solid organ transplant
The secondary endpoint of recurrence of CMV viraemia was reported in 57% of the maribavir treated patients and in 34% of the IAT treated patients. Of these, 18% in the maribavir group had recurrence of CMV viraemia while on-treatment compared to 12% the IAT group. Recurrence of CMV viraemia during follow up was seen in 39% of patients in the maribavir group and in 22% of the patients in the IAT group. Overall mortality: All-cause mortality was assessed for the entire study period. A similar percentage of subjects in each treatment group died during the trial (LIVTENCITY 11% [27/235]; IAT 11% [13/117]).
The European Medicines Agency has deferred the obligation to submit the results of studies with LIVTENCITY in one or more subsets of the paediatric population for treatment of cytomegalovirus infection (see section 4.2).
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.
Table 6. 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 (see section 4.4 and 5.3).
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 (see section 4.4 and 5.2).
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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