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Pharmacology: Mechanism of Action: PREVYMIS is an antiviral drug against CMV [see Pharmacodynamics as follows].
Pharmacodynamics: Cardiac Electrophysiology: The effect of letermovir on doses up to 960 mg given IV on the QTc interval was evaluated in a randomized, single-dose, placebo- and active-controlled (moxifloxacin 400 mg oral) 4-period crossover thorough QT trial in 38 healthy subjects. Letermovir does not prolong QTc to any clinically relevant extent following the 960 mg IV dose, with plasma concentrations approximately 2-fold higher than the 480 mg IV dose.
Pharmacogenomics: The impact of genetic variants in the OATP1B1 gene SLCO1B1 (rs4149056, rs2306283, rs4149032) and UGT1A1 (rs4148323 and the promoter TA repeat variants) on the pharmacokinetics of letermovir was evaluated in 299 study participants. There was no clinically relevant impact of these variants on letermovir exposures.
CLINICAL STUDIES: Adult CMV-seropositive Recipients [R+] of an Allogeneic Hematopoietic Stem Cell Transplant: To evaluate PREVYMIS prophylaxis as a preventive strategy for CMV infection or disease in transplant recipients at high risk for CMV reactivation, the efficacy of PREVYMIS was assessed in a multicenter, double-blind, placebo-controlled Phase 3 trial (P001) in adult CMV-seropositive recipients [R+] of an allogeneic HSCT. Subjects were randomized (2:1) to receive either PREVYMIS at a dose of 480 mg once daily adjusted to 240 mg when co-administered with cyclosporine, or placebo.
Randomization was stratified by investigational site and risk level for CMV reactivation at the time of study entry. Study drug was initiated after HSCT (Day 0-28 post-transplant) and continued through Week 14 post-transplant. Study drug was administered either orally or IV; the dose of PREVYMIS was the same regardless of the route of administration. Subjects were monitored through Week 24 post-transplant for the primary efficacy endpoint with continued follow-up through Week 48 post-transplant.
Among the 565 treated subjects, 373 subjects received PREVYMIS (including 99 subjects who received at least one IV dose) and 192 received placebo (including 48 subjects who received at least one IV dose). The median time to starting study drug was 9 days after transplantation. Thirty-seven percent (37%) of subjects were engrafted at baseline. The median age was 54 years (range: 18 to 78 years); 58% were male; 82% were White; 10% were Asian; 2% were Black or African; and 7% were Hispanic or Latino. At baseline, 50% of subjects received a myeloablative regimen, 52% were receiving cyclosporine, and 42% were receiving tacrolimus. The most common primary reasons for transplant were acute myeloid leukemia (38%), myeloblastic syndrome (15%), and lymphoma (13%). Twelve percent (12%) of subjects were positive for CMV DNA at baseline.
At baseline, 31% of subjects were in the high risk stratum as defined by one or more of the following criteria: Human Leukocyte Antigen (HLA)-related (sibling) donor with at least one mismatch at one of the following three HLA-gene loci: HLA-A, -B or -DR, haploidentical donor; unrelated donor with at least one mismatch at one of the following four HLA-gene loci: HLA-A, -B, -C and -DRB1; use of umbilical cord blood as stem cell source; use of ex vivo T-cell-depleted grafts; Grade 2 or greater Graft-Versus-Host Disease (GVHD), requiring systemic corticosteroids. The remaining 69% of subjects did not meet any of these high risk stratum criteria and were therefore included in the low risk stratum.
Efficacy: Clinically Significant CMV Infection: The primary efficacy endpoint of P001 was the incidence of clinically significant CMV infection through Week 24 post-transplant. Clinically significant CMV infection was defined as the occurrence of either CMV end-organ disease, or initiation of anti-CMV pre-emptive therapy (PET) based on documented CMV viremia (using the Roche COBAS AmpliPrep/COBAS TaqMan assay, LLoQ is 137 IU/mL, which is approximately 150 copies/mL) and the clinical condition of the subject. The Non-Completer=Failure (NC=F) approach was used, where subjects who discontinued from the study prior to Week 24 post-transplant or had a missing outcome at Week 24 post-transplant were counted as failures.
PREVYMIS demonstrated superior efficacy over placebo in the analysis of the primary endpoint, as shown in Table 1. The estimated treatment difference of -23.5% was statistically significant (one-sided p-value <0.0001). (See Table 1.)
Click on icon to see table/diagram/imageAt Week 24 post-transplant, the Kaplan-Meier (K-M) event rate for clinically significant CMV infection was 18.9% in the PREVYMIS group compared to 44.3% in the placebo group (nominal two-sided stratified log-rank p-value<0.0001) (see Figure 1). Factors associated with clinically significant CMV infection between Week 14 and Week 24 post-transplant among PREVYMIS-treated subjects included high risk for CMV reactivation at baseline, having GVHD, and steroid use at any time after randomization.
Of the 373 subjects treated with PREVYMIS in P001, 56 (15.0%) subjects were 65 years of age or older. Safety and efficacy were similar across older and younger subjects. (See Figure 1.)
Click on icon to see table/diagram/imageEfficacy consistently favored PREVYMIS across subgroups including low and high risk strata for CMV reactivation, conditioning regimens, and concomitant immunosuppressive regimens. (See Figure 2.)
Click on icon to see table/diagram/imageMortality: The K-M event rate for all-cause mortality in the letermovir vs. placebo groups was 12.1% vs. 17.2% at Week 24 post-transplant (nominal two-sided stratified log-rank p-value=0.0401), and 23.8% vs. 27.6% at Week 48 post-transplant (nominal two-sided stratified log-rank p-value=0.2117; see Figure 3).
Click on icon to see table/diagram/imageIn a post-hoc analysis of all-cause mortality through Week 48 post-transplant, among subjects with clinically significant CMV infection through Week 24, the mortality rate in the letermovir vs. placebo groups was 21.1% vs. 33.8%; and among subjects without clinically significant CMV infection through Week 24, the mortality rate in the letermovir vs. placebo groups was 23.9% vs. 22.2%.
Pharmacokinetics: General Introduction: The pharmacokinetics of letermovir have been characterized following oral and IV administration in healthy subjects and HSCT recipients.
In healthy subjects, letermovir exposure increased in a greater than dose-proportional manner with both oral or IV administration following single and multiple doses of 240 mg and 480 mg. Letermovir was absorbed rapidly with a median time to maximum plasma concentration (Tmax) of 1.5 to 3.0 hours and declined in a biphasic manner. The geometric mean steady-state AUC and Cmax values were 71,500 ng•hr/mL and 13,000 ng/mL, respectively, with 480 mg once daily oral PREVYMIS. The post-absorption plasma concentration-time profile of letermovir following oral administration was similar to the profile observed with IV dosing. Letermovir clearance (CL) reached steady-state in 9 to 10 days with an accumulation ratio of 1.22 for AUC and 1.03 for Cmax.
In HSCT recipients, letermovir AUC was estimated using population pharmacokinetic analyses using Phase 3 data (see Table 2). Differences in exposure across treatment regimens are not clinically relevant; efficacy was consistent across the range of exposures observed in P001. (See Table 2.)
Click on icon to see table/diagram/imageAbsorption: In healthy subjects, absolute bioavailability of letermovir was estimated to be approximately 94% over the dose range 240 mg to 480 mg based on population pharmacokinetic analyses. In HSCT recipients, bioavailability of letermovir was estimated to be approximately 35% with 480 mg once daily oral PREVYMIS administered without cyclosporine. The inter-individual variability for bioavailability was estimated to be approximately 37%.
Effect of Cyclosporine: In HSCT recipients, co-administration of cyclosporine increased plasma concentrations of letermovir. Bioavailability of letermovir was estimated to be approximately 85% with 240 mg once daily oral PREVYMIS co-administered with cyclosporine. If PREVYMIS is co-administered with cyclosporine, the recommended dose of PREVYMIS is 240 mg once daily [see Dosage Adjustment in Adults under DOSAGE & ADMINISTRATION].
Effect of Food: Relative to fasting conditions, oral administration of 480 mg single dose of PREVYMIS with a standard high fat and high calorie meal did not have any effect on the overall exposure (AUC) and resulted in approximately 30% increase in peak levels (Cmax) of letermovir. PREVYMIS may be administered orally with or without food [see General under DOSAGE & ADMINISTRATION].
Distribution: Based on population pharmacokinetic analyses, the mean steady-state volume of distribution is estimated to be 45.5 L following IV administration in HSCT recipients.
Letermovir is extensively bound (98.7%) to human plasma proteins in vitro. Blood to plasma partitioning of letermovir is 0.56 and independent of the concentration range (0.1 to 10 mg/L) evaluated in vitro.
In preclinical distribution studies, letermovir is distributed to organs and tissues with the highest concentrations observed in the gastrointestinal tract, bile duct and liver and low concentrations in the brain.
Elimination: The mean apparent terminal half-life for letermovir is approximately 12 hours with 480 mg IV PREVYMIS in healthy subjects.
Metabolism: The majority of drug-related component in plasma is unchanged parent (96.6%). No major metabolites are detected in plasma. Letermovir is partly eliminated by glucuronidation mediated by UGT1A1/1A3.
Excretion: Based on population pharmacokinetic analyses, letermovir steady-state CL is estimated to be 4.84 L/hr following IV administration in HSCT recipients. The inter-individual variability for CL is estimated to be 24.6%.
After oral administration of radio-labeled letermovir, 93.3% of radioactivity was recovered in feces. The majority of drug was excreted as unchanged parent with a minor amount (6% of dose) as an acyl-glucuronide metabolite in feces. Urinary excretion of letermovir was negligible (<2% of dose).
Specific Populations: Pediatric Population: The pharmacokinetics of letermovir in pediatric patients less than 18 years of age have not been evaluated.
Geriatric Population: Based on population pharmacokinetic analyses, there is no effect of age on letermovir pharmacokinetics. No dose adjustment is required based on age.
Gender: Based on population pharmacokinetic analyses, there is no difference in letermovir pharmacokinetics in females compared to males.
Weight: Based on population pharmacokinetic analyses, letermovir AUC is estimated to be 18.7% lower in subjects weighing 80-100 kg compared to subjects weighing 67 kg. This change is not clinically relevant.
Race: Based on population pharmacokinetic analyses, letermovir AUC is estimated to be 33.2% higher in Asians compared to Whites. This change is not clinically relevant.
Renal Impairment: Letermovir AUC was approximately 1.9- and 1.4-fold higher in subjects with moderate (eGFR greater than or equal to 30 to 59 mL/min/1.73 m2) and severe (eGFR less than 30 mL/min/1.73 m2) renal impairment, respectively, compared to healthy subjects. The changes in letermovir exposure due to renal impairment are not clinically relevant.
Hepatic Impairment: Letermovir AUC was approximately 1.6- and 3.8-fold higher in subjects with moderate (Child-Pugh Class B [CP-B], score of 7-9) and severe (Child-Pugh Class C [CP-C], score of 10-15) hepatic impairment, respectively, compared to healthy subjects. The changes in letermovir exposure in subjects with moderate hepatic impairment are not clinically relevant.
Clinically relevant increases in letermovir exposure are anticipated in patients with severe hepatic impairment or in patients with moderate hepatic impairment combined with moderate or severe renal impairment.
Drug Interaction Studies: Drug interaction studies were performed in healthy subjects with PREVYMIS and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions (see Table 3 and Table 4).
In vitro results indicate that letermovir is a substrate of OATP1B1/3, P-gp, UGT1A1, and UGT1A3. Inhibitors of OATP1B1/3 transporters may result in increases in letermovir plasma concentrations. If PREVYMIS is co-administered with cyclosporine (a potent OATP1B1/3 inhibitor), the recommended dose of PREVYMIS is 240 mg once daily [see Dosage Adjustment in Adults under DOSAGE & ADMINISTRATION]. Changes in letermovir plasma concentrations due to inhibition of P-gp/BCRP by itraconazole were not clinically relevant. Inhibition of UGTs is not anticipated to have a clinically relevant effect on letermovir plasma concentrations. Induction of drug enzymes (e.g., UGTs) and/or transporters (e.g., P-gp) by rifampin may result in clinically relevant decreases in letermovir plasma concentrations; therefore, co-administration of strong and moderate inducers with letermovir is not recommended [see Effects of Other Drugs on PREVYMIS under INTERACTIONS], Table 6, and Table 3. Although CYP3A, CYP2D6 and CYP2J2 were identified as enzymes capable of mediating the metabolism of letermovir in vitro, oxidative metabolism is considered to be a minor elimination pathway based on in vivo human data.
Letermovir is a time-dependent inhibitor and inducer of CYP3A in vitro. Co-administration of PREVYMIS with midazolam resulted in increased exposure of midazolam, indicating that the net effect of letermovir on CYP3A is moderate inhibition (see Table 4). Based on these results, co-administration of PREVYMIS with CYP3A substrates may increase the plasma concentrations of the CYP3A substrates [see CONTRAINDICATIONS, Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions under PRECAUTIONS, and Effects of PREVYMIS on Other Drugs, and Established and Other Potential Drug Interactions under INTERACTIONS] and Table 6. Letermovir is a reversible inhibitor of CYP2C8 in vitro. Physiologically based pharmacokinetic modeling predicts an increase in plasma concentrations of CYP2C8 substrates when co-administered with PREVYMIS [see Table 6, Established and Other Potential Drug Interactions under INTERACTIONS]. Co-administration of PREVYMIS reduced the exposure of voriconazole, most likely due to the induction of voriconazole elimination pathways, CYP2C9 and CYP2C19. Co-administration of PREVYMIS with CYP2C9 and CYP2C19 substrates may decrease the plasma concentrations of the CYP2C9 and CYP2C19 substrates [see Table 6, Established and Other Potential Drug Interactions under INTERACTIONS]. Letermovir is an inducer of CYP2B6 in vitro; the clinical relevance is unknown.
Letermovir inhibited efflux transporters P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), OAT3, and hepatic uptake transporter OATP1B1/3 in vitro. Co-administration of PREVYMIS with substrates of OATP1B1/3 transporters (e.g., atorvastatin, a known substrate of CYP3A, OATP1B1/3, and potentially BCRP) may result in a clinically relevant increase in plasma concentrations of OATP1B1/3 substrates [see Table 6, Established and Other Potential Drug Interactions under INTERACTIONS]. There were no clinically relevant changes in plasma concentrations of digoxin, a P-gp substrate, or acyclovir, an OAT3 substrate, following co-administration with PREVYMIS in clinical studies (see Table 4). The effect of letermovir on BCRP, BSEP, and MRP2 substrates was not evaluated in clinical studies; the clinical relevance is unknown. (See Tables 3 and 4.)
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Click on icon to see table/diagram/imageToxicology: ANIMAL TOXICOLOGY: General Toxicity: Testicular toxicity was noted only in rats at systemic exposures (AUC) ≥3-fold the exposures in humans at the RHD. This toxicity was characterized by seminiferous tubular degeneration, and oligospermia and cell debris in the epididymides, with decreased testicular and epididymides weights. The No-Observed Adverse Effect Level (NOAEL) for testicular toxicity in rats was observed at exposures (AUC) in rats similar to the exposures in humans at the RHD. This testicular toxicity appears to be species-specific; testicular toxicity was not observed in mice and monkeys at the highest doses tested at exposures up to 4-fold and 2-fold, respectively, the exposures in humans at the RHD. The relevance to humans is unknown. In the Phase 3 trial in HSCT recipients, there was no evidence of letermovir-related testicular toxicity [see Clinical Trials Experience under ADVERSE REACTIONS].
The toxicity profile of letermovir was generally similar in oral and intravenous studies in rats and monkeys, with the exception of vacuolation noted in the kidneys of rats administered IV letermovir formulated with 1500 mg/kg/day of the cyclodextrin excipient hydroxypropyl betadex. It is known that hydroxypropyl betadex can cause kidney vacuolation in rats when given intravenously at doses greater than 50 mg/kg/day{1}.
Carcinogenesis: A 6-month oral carcinogenicity study in RasH2 transgenic (Tg.RasH2) mice showed no evidence of human-relevant tumorigenesis up to the highest dose tested, 150 mg/kg/day and 300 mg/kg/day in males and females, respectively.
Mutagenesis: Letermovir was not genotoxic in a battery of in vitro or in vivo assays, including microbial mutagenesis assays, chromosomal aberration in Chinese Hamster Ovary cells, and in an in vivo mouse micronucleus study.
Reproduction: In the fertility and early embryonic development studies in the rat, there were no effects of letermovir on female fertility at the highest dose tested, 240 mg/kg/day (approximately 5-fold the AUC in humans at the RHD). In male rats, reduced sperm concentration, reduced sperm motility, and decreased fertility were observed at systemic exposures ≥3-fold the AUC in humans at the RHD [see General Toxicity as previously mentioned].
In male mice, there were no effects on testicular toxicity by histopathologic evaluation at systemic exposures approximately 4-fold the AUC in humans at the RHD.
In a study dedicated to investigate effects on the male reproductive system of mature monkeys administered letermovir, there was no evidence of testicular toxicity based on histopathologic evaluation, measurement of testicular size, blood hormone analysis (follicle stimulating hormone, inhibin B and testosterone) and sperm evaluation (sperm count, motility and morphology) at systemic exposures approximately 2-fold the AUC in humans at the RHD.
Development: Letermovir was administered orally to pregnant rats at 0, 10, 50 or 250 mg/kg/day from gestation days 6 to 17. Maternal toxicity (including decrease in body weight gain) was noted at 250 mg/kg/day (approximately 11-fold the AUC at the RHD); in the offspring, decreased fetal weight with delayed ossification, slightly edematous fetuses, and increased incidence of shortened umbilical cords and of variations and malformations in the vertebrae, ribs, and pelvis were observed. No maternal or developmental effects were noted at the dose of 50 mg/kg/day (approximately 2.5-fold the AUC at the RHD).
Letermovir was administered orally to pregnant rabbits at 0, 25, 75 or 225 mg/kg/day from gestation days 6 to 20. Maternal toxicity (including mortality and abortions) was noted at 225 mg/kg/day (approximately 2-fold the AUC at the RHD); in the offspring, an increased incidence of malformations and variations in the vertebrae and ribs were observed. No maternal or developmental effects were noted at the dose of 75 mg/kg/day (at less than the AUC at the RHD).
In the pre- and post-natal developmental study, letermovir was administered orally to pregnant rats at 0, 10, 45 or 180 mg/kg/day from gestation day 6 to lactation day 22. There was no developmental toxicity observed up to the highest exposure tested (2-fold the AUC at the RHD).
Microbiology: Mechanism of Action: Letermovir inhibits the CMV DNA terminase complex, which is required for viral replication. Biochemical characterization and electron microscopy demonstrated that letermovir affects the formation of proper unit length genomes and interferes with virion maturation.
Antiviral Activity: The median EC50 value of letermovir against a collection of clinical CMV isolates in a cell-culture model of infection was 2.1 nM (range = 0.7 nM to 6.1 nM, n=74).
Viral Resistance: In Cell Culture: The CMV genes UL51, UL56, and UL89 encode subunits of CMV DNA terminase. CMV mutants with reduced susceptibility to letermovir have been selected in cell culture, and the substitutions map to pUL51 (P91S), pUL56 (C25F, S229F, V231A, V231L, N232Y, V236A, V236L, V236M, E237D, L241P, T244K, T244R, L254F, L257F, L257I, K258E, F261C, F261L, F261S, Y321C, C325F, C325R, C325W, C325Y, L328V, M329T, A365S, N368D, R369G, R369M, R369S), and pUL89 (N320H, D344E). EC50 values for recombinant CMV mutants expressing these substitutions are 1.6- to 9,300-fold higher than those for the wild-type reference virus.
In Clinical Studies: In a Phase 2b trial evaluating letermovir doses of 60, 120, or 240 mg/day or placebo for up to 84 days in 131 HSCT recipients, DNA sequence analysis of a select region of UL56 (amino acids 231 to 369) was performed on samples obtained from 12 letermovir-treated subjects who experienced prophylaxis failure and for whom samples were available for analysis. One subject (who received 60 mg/day) had a letermovir resistant genotypic variant (GV) (V236M).
In a Phase 3 trial (P001), DNA sequence analysis of the entire coding regions of UL56 and UL89 was performed on samples obtained from 40 letermovir-treated subjects in the FAS population who experienced prophylaxis failure and for whom samples were available for analysis. A total of 2 letermovir resistance-associated substitutions both mapping to pUL56 were detected in 2 subjects. One subject had the substitution V236M, and the other had E237G.
Cross Resistance: Cross resistance is not likely with drugs outside of this class. Letermovir is fully active against viral populations with substitutions conferring resistance to CMV DNA polymerase inhibitors (ganciclovir, cidofovir, and foscarnet). A panel of recombinant CMV strains with substitutions conferring resistance to letermovir was fully susceptible to cidofovir, foscarnet and ganciclovir with the exception of a recombinant strain with the pUL56 E237G substitution which confers a 2.1-fold reduction in ganciclovir susceptibility relative to wild-type.
