PREVYMIS Film-coated tablet Ref.[8782] Active ingredients: Letermovir

Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals
ATC code: J05AX18

Mechanism of action

Letermovir inhibits the CMV DNA terminase complex which is required for cleavage and packaging of viral progeny DNA. 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 confirmed in cell culture. EC₅₀ values for recombinant CMV mutants expressing the substitutions map to pUL51 (P91S), pUL56 (C25F, S229F, V231A, V231L, V236A, T244K, T244R, L254F, L257F, L257I, F261C, F261L, F261S, Y321C, L328V, M329T, A365S, N368D), and pUL89 (N320H, D344E) were 1.6- to <10-fold higher than those for wild-type reference virus; these substitutions are not likely to be clinically relevant. EC₅₀ values for recombinant CMV mutants expressing pUL51 substitution A95V or pUL56 substitutions N232Y, V236L, V236M, E237D, E237G, L241P, K258E, C325F, C325R, C325W, C325Y, R369G, R369M, R369S and R369T were 10- to 9 300-fold higher than those for the wild-type reference virus; some of these substitutions have been observed in patients who have experienced prophylaxis failure in clinical trials (see below).

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 adult 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 adult subjects in the FAS population who experienced prophylaxis failure and for whom samples were a vailable for analysis. Two subjects had letermovir resistant GVs detected, both with substitutions mapping to pUL56. One subject had the substitution V236M and the other subject had the substitution E237G. One additional subject, who had detectable CMV DNA at baseline (and was therefore not in the FAS population), had pUL56 substitutions, C325W and R369T, detected after discontinuing letermovir.

In a Phase 3 trial (P040), DNA sequence analysis of the entire coding regions of UL51, UL56 and UL89 was performed on samples obtained from 32 adult subjects (regardless of treatment group) who experienced prophylaxis failure or who discontinued early with CMV viremia. There were no letermovir resistance-associated substitutions detected above the validated assay limit of 5%.

In a Phase 3 trial (P002), DNA sequence analysis of the entire coding regions of UL51, UL56 and UL89 was performed on samples obtained from 52 letermovir-treated adult subjects who experienced CMV disease or who discontinued early with CMV viremia. There were no letermovir resistance-associated substitutions detected above the validated assay limit of 5%.

In a Phase 2b trial (P030), DNA sequence analysis of the entire coding regions of UL51, UL56 and UL89 was performed on samples obtained from 10 letermovir-treated paediatric subjects at a visit for evaluation of CMV infection. A total of 2 letermovir resistance-associated substitutions both mapping to pUL56 were detected in 2 subjects. One subject had the substitution R369S and the other subject had the substitution C325W.

Cross-resistance

Cross-resistance is not like ly with medicinal products with a different mechanism of action. 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.

Cardiac electrophysiology

The effect of letermovir on doses up to 960 mg given intravenous ly on the QTc interval was evaluated in a randomi sed, single-dose, placebo- and active-controlled (moxifloxacin 400 mg oral) 4-period crossover thorough QT trial in 38 healthy adult subjects. Letermovir does not prolong QTc to any clinically relevant extent following the 960 mg intravenous dose with plasma concentrations approximately 2-fold higher than the 480 mg intravenous dose.

Clinical efficacy and safety

Adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant

P001: Prophylaxis through Week 14 (~100 days) post-HSCT

To evaluate letermovir prophylaxis as a preventive strategy for CMV infection or dise ase, the efficacy of letermovir was assessed in a multicentre, double-blind, placebo-controlled Phase 3 trial (P001) in adult CMV-seropositive recipients [R+] of an allogeneic HSCT. Subjects were randomi sed (2:1) to receive either letermovir at a dose of 480 mg once daily adjusted to 240 mg when co-administered with cyclosporine, or placebo. Randomisation was stratified by investigational site and risk (high vs. low) for CMV reactivation at the time of study entry. Letermovir was initiated after HSCT (Day 0-28 post-HSCT) and continued through Week 14 post-HSCT. Letermovir was administered either orally or intravenously; the dose of letermovir was the same regardless of the route of administration. Subjects were monitored through Week 24 post-HSCT for the primary efficacy endpoint with continued follow-up through Week 48 post-HSCT.

Subjects received CMV DNA monitoring weekly until post-HSCT week 14 and then every two weeks until post-HSCT week 24, with initiation of standard-of-care CMV pre-emptive therapy if CMV DNAemia was considered clinically significant. Subjects had c ontinued follow-up through Week 48 post-HSCT.

Among the 565 treated subjects, 373 subjects received letermovir (including 99 subjects who received at least one intravenous dose) and 192 received placebo (including 48 subjects who received at least one intravenous dose). The median time to starting letermovir 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); 56 (15.0%) subjects were 65 years of age or older: 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 myelo id leukaemia (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 at high risk for reactivation as defined by one or more of the following criteria: Human Leucocyte 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.

Primary efficacy endpoint:

The primary efficacy endpoint of clinically significant CMV infection in P001 was defined by the incidence of CMV DNAemia warranting anti-CMV pre-emptive therapy (PET) or the occurrence of CMV end-organ disease. The Non-Completer=Failure (NC=F) approach was used, where subjects who discontinued from the study prior to Week 24 post-HSCT or had a missing outcome at Week 24 post-HSCT were counted as failures.

Letermovir demonstrated superior efficacy over placebo in the analysis of the primary endpoint, as shown in Table 3. The estimated treatment difference of -23.5% was statistically significant (one-sided p-value <0.0001).

Table 3. P001: Efficacy results in HSCT recipients (NC=F Approach, FAS Population):

^† The categories of failure are mutually exclusive and based on the hierarchy of categories in the order listed.
^§ 95% CIs and p-value for the treatment differences in percent response were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (high or low risk). A 1-sided p-value ≤0.0249 was used for declaring statistical significance.
FAS=Full analysis set; FAS includes randomised subjects who received at least one dose of study medicine, and excludes subjects with detectable CMV DNA at baseline. Approach to handling missing values: Non-Completer=Failure (NC=F) approach. With NC=F approach, failure was defined as all subjects with clinically significant CMV infection or who prematurely discontinued from the study or had a missing outcome through Week 24 post-HSCT visit window.
N = number of subjects in each treatment group.
n (%) = Number (percent) of subjects in each sub-category.
Note: The proportion of subjects with detectable CMV viral DNA on Day 1 that developed clinically significant CMV infection in the letermovir group was 64.6% (31/48) compared to 90.9% (20/22) in the placebo group through Week 24 post-HSCT. The estimated difference (95% CI for the difference) was -26.1% (-45.9%, -6.3%), with a nominal one-sided p-value <0.0048.

Factors associated with CMV DNAemia after Week 14 post-HSCT among letermovir-treated subjects included high risk for CMV reactivation at baseline, GVHD, use of corticosteroids, and CMV negative donor serostatus.

Figure 1. P001: Kaplan-Meier plot of time to initiation of anti-CMV PET or onset of CMV end-organ disease through Week 24 post-transplant in HSCT recipients (FAS population):

There were no differences in the incidence of or time to engraftment between the letermovir and placebo groups.

Efficacy consistently favoured letermovir across subgroups including low and high risk for CMV reactivation, conditioning regimens, and concomitant immunosuppressive regimens (see Figure 2).

Figure 2. P001: Forest plot of the proportion of subjects initiating anti-CMV PET or with CMV end-organ disease through Week 24 post-HSCT by selected subgroups (NC=F approach, FAS population):

NC=F, Non-Completer=Failure. With NC=F approach, 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.

P040: Prophylaxis from Week 14 (~100 days) through Week 28 (~200 days) post-HSCT

The efficacy of extending letermovir prophylaxis from Week 14 (~100 days) through Week 28 (~200 days) post-HSCT in patients at risk for late CMV infection and disease was assessed in a multicentre, double-blind, placebo-controlled Phase 3 trial (P040) in adult CMV-seropositive recipients [R+] of an allogeneic HSCT. Eligible subjects who completed letermovir prophylaxis through ~100 days post-HSCT were randomised (2:1) to receive letermovir or placebo from Week 14 through Week 28 post-HSCT. Subjects were monitored through Week 28 post-HSCT for the primary efficacy endpoint with continued off-treatment follow-up through Week 48 post-HSCT.

Among the 218 treated subjects, 144 subjects received letermovir and 74 received placebo. The median age was 55 years (range: 20 to 74 years); 62% were male; 79% were white; 11% were Asian; 2% were Black; and 10% were Hispanic or Latino. The most common reasons for transplant were acute myeloid leukaemia (42%), acute lymphocytic leukaemia (15%), and myelodysplastic syndrome (11%).

At study entry, all subjects had risk factors for late CMV infection and disease, with 64% having two or more risk factors. The risk factors included: 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 foll owing 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; receipt of anti-thymocyte globulin; receipt of alemtuzumab; use of systemic prednisone (or equivalent) at a dose of ≥1 mg/kg of body weight per day.

Primary efficacy endpoint:

The primary efficacy endpoint of P040 was the incidence of clinically significant CMV infection through Week 28 post-HSCT. Clinically significant CMV infection was defined as the occurrence of either CMV end-organ disease, or initiation of anti-CMV PET based on documented CMV viremia and the clinical condition of the subject. The Observed Failure (OF) approach was used, where subjects who developed clinically significant CMV infection or discontinued prematurely from the study with viremia were counted as failures.

Letermovir demonstrated superior efficacy over placebo in the analysis of the primary endpoint, as shown in Table 4. The estimated treatment difference of -16.1% was statistically significant (one-sided p-value=0.0005). Efficacy consistently favored letermovir across subgroups based on subject characteristics (age, gender, race) and risk factors for late CMV infection and disease.

Table 4. P040: Efficacy results in HSCT recipients at risk for late CMV infection and disease (OF approach, FAS population):

^* The categories of failure are mutually exclusive and based on the hierarchy of categories in the order listed.
^† Clinically significant CMV infection was defined as CMV end-organ disease (proven or probable) or initiation of PET based on documented CMV viremia and the clinical condition of the subject.
^‡ 95% CIs and p-value for the treatment differences in percent response were calculated using stratum-adjusted Mantel -Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (haploidentical donor yes or no). A one -sided p-value ≤0.0249 was used for declaring statistical significance.
Approach to handling missing values: Observed Failure (OF) approach. With the OF approach, failure was defined as all subjects who developed clinically significant CMV infection or discontinued prematurely from the study with CMV viremia fro m Week 14 (~100 days) through Week 28 (~200 days) post-HSCT.
N=Number of subjects in each treatment group.
n (%)=Number (percent) of subjects in each sub-category.

P002: Adult CMV-seronegative recipients of a kidney transplant from a CMV-seropositive donor [D+/R-]

To evaluate letermovir prophylaxis as a preventive strategy for CMV disease in kidney transplant recipients, the efficacy of letermovir was assessed in a multicentre, double-blind, active comparator-controlled non-inferiority Phase 3 trial (P00 2) in adult kidney transplant recipients at high risk [D+/R-]. Subjects were randomi sed (1:1) to receive either letermovir or valganciclovir. Letermovir was given concomitantly with acyclovir. Valganciclovir was given concomitantly with a placebo to acyclovir. Randomisation was stratified by the use or non-use of highly cytolytic, anti-lymphocyte immunotherapy during induction. Letermovir or valganciclovir were initiated between Day 0 and Day 7 post-kidney transplant and continued through Week 28 (~200 days) post-transplant. Subjects were monitored through Week 52 post-transplant.

Among the 589 treated subjects, 292 subjects received letermovir and 297 received valganciclovir. The median age was 51 years (range: 18 to 82 years); 72% were male; 84% were White; 2% were Asian; 9% were Black; 17% were Hispanic or Latino; and 60% received a kidney from a deceased donor. The most common primary reasons for transplant were congenital cystic kidney disease (17%), hypertension (16%), and diabetes/diabetic nephropathy (14%).

Primary efficacy endpoint:

The primary efficacy endpoint of P002 was the incidence of CMV disease (CMV end-organ disease or CMV syndrome, confirmed by an independent adjudication committee) through Week 52 post-transplant. The OF approach was used, where subjects who discontinued prematurely from the study for any reason or were missing data at the timepoint were not considered failures.

Letermovir demonstrated non-inferiority to valganciclovir in the analysis of the primary endpoint, as shown in Table 5.

Table 5. P002 Efficacy results in kidney transplant recipients (OF approach, FAS population):

^* CMV disease cases confirmed by an independent adjudication committee.
^† The 95% CIs for the treatment differences in percent response were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (use/nonuse of highly cytolytic, anti-lymphocyte immunotherapy during induction).
^‡ Based on a non-inferiority margin of 10%, letermovir is non-inferior to valganciclovir.
Approach to handling missing values: Observed F ailure (OF) approach. With OF approach, participants who discontinue prematurely from the study for any reason are not considered failures.
Note: Subjects randomised to the letermovir group were given acyclovir for herpes simplex virus (HSV) and varicella zoster virus (VZV) prophylaxis. Subjects randomi sed to the valganciclovir group were given a placebo to acyclovir.
N=number of subjects in each treatment group.
n (%)=Number (percent) of subjects in each sub-category.

Efficacy was comparable across all subgroups, including sex, age, race, region, and the use/non-use of highly cytolytic, anti -lymphocyte immunotherapy during induction.

Paediatric population

P030: Paediatric recipients of an allogeneic hematopoietic stem cell transplant

To evaluate letermovir prophylaxis as a preventive strategy for CMV infection or disease in paediatric transplant recipients, the efficacy of letermovir was assessed in a multicentre, open-label, single-arm Phase 2b trial (P030) in paediatric recipients of an allogeneic HSCT. Study drug was initiated after HSCT (Day 0-28 post-HSCT) and continued through Week 14 post-HSCT. Study drug was administered either orally or intravenously; the dose of letermovir was based on age, body weight and formulation.

Among the 63 treated subjects, 8 were 0 to less than 2 years of age, 27 were 2 to less than 12 years of age and 28 were 12 to less than 18 years of age. At baseline, 87% of subjects received a myeloablative regimen, 67% were receiving cyclosporine, and 27% were receiving tacrolimus. The most common primary reasons for transplant were acute myeloid leukaemia (18%) a nd aplastic anaemia (10%) in the overall population, and combined immunodeficiency (37.5%) and familial haemophagocytic lymphohistiocytosis (25.0%) in children less than 2 years of age.

Secondary efficacy endpoint

The efficacy endpoints of P030 were secondary and included the incidence of clinically significant CMV infection through Week 14 post-HSCT and through Week 24 post-HSCT. Clinically significant CMV infection was defined as the occurrence of either CMV end-organ disease, or initiation of anti-CMV PET based on documented CMV viremia and the clinical condition of the subject. The incidence of clinically significant CMV infection was 7.1% and 10.7% through Week 14 post-HSCT and Week 24 post-HSCT, respectively.