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Study results in adult hematopoietic stem cell transplantation (HSCT) in patients

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Prophylaxis through Week 14 (~100 days) post-HSCT in adults

Clinically significant CMV infection through Week 24 (~168 days) in adult HSCT patients

PREVYMIS demonstrated significant efficacy vs placebo in the primary endpoint: Clinically significant CMV infectiona through Week 24 (NC=F approach)b

PREVYMIS® (letermovir) in Adults Demonstrated Clinically Significant Efficacy Through Week 24

(a) Clinically significant CMV infection was defined as either the occurrence of CMV end-organ disease or initiation of anti-CMV PET, based on documented CMV viremia and the clinical condition of the patient. Viremia was determined using the Roche COBAS® AmpliPrep/COBAS TaqMan® assay; lower limit of quantification was 137 IU/mL, which is approximately 150 copies/mL.
(b) The Noncompleter=Failure (NC=F) approach was used in which patients 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.
(c) The categories of failure are mutually exclusive and based on the hierarchy of categories in the order listed.
(d) Through Week 14, 8% of subjects in the PREVYMIS group and 39% of subjects in the placebo group experienced clinically significant CMV infection.
(e) Reasons for discontinuation included adverse event (AE), death, lost to follow-up, physician decision, and withdrawal by subject.

Rate of clinically significant CMV infection in adults

Significantly lower rate of onset of clinically significant CMV infection for PREVYMIS vs placebo1

Rate of Clinically Significant CMV Infection After Treatment Compared to Placebo

From The New England Journal of Medicine, Marty, Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation, Volume No. 377, Page No. 8, Figure No. 2. Copyright © 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Factors associated with clinically significant CMV infection between Week 14 and Week 24 post-HSCT among adult PREVYMIS patients included:

  • High-risk stratum for CMV reactivation at baseline
  • Having GVHD
  • Steroid use at any time after randomization

Mortality analysis in HSCT

Lower all-cause mortality for PREVYMIS vs placebo in adult HSCT patients2-4 a,b

Graph Showing Mortality Analysis for Prevymis vs Placebo in Adult HSCT Patients

Per Ljungman, Michael Schmitt, Francisco M Marty, Johan Maertens, Roy F Chemaly, Nicholas A Kartsonis, Joan R Butterton, Hong Wan, Valerie L Teal, Kendra Sarratt, Yoshihiko Murata, Randi Y Leavitt, Cyrus Badshah, A Mortality Analysis of Letermovir Prophylaxis for Cytomegalovirus (CMV) in CMV-seropositive Recipients of Allogeneic Hematopoietic Cell Transplantation, Clinical Infectious Diseases, Volume 70, Issue 8, 15 April 2020, Pages 1525–1533, https://doi.org/10.1093/cid/ciz490

(a) Data through week 24 post-HSCT P=0.04.
(b) Data through week 48 post-HSCT P=0.21, not significant.

High- and low-risk strata

Efficacy results were consistent across high- and low-risk strata for CMV reactivation in adult patients.

Efficacy Results in the High-Risk Subgroup

Efficacy Results in the Low-Risk Subgroup

Copyright © 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.4

Overview of CMV-seropositive recipients [R+] status and additional risk factors at baseline

Baseline Data of CMV-Seropositive Adult Patients in the Phase 3 Trial

Baseline data collected at randomization in the phase 3 trial.

The majority of patients in the phase 3 trial in adults were R+ with no additional risk factors at baseline. Thirty percent of patients were R+ with ≥1 of the following additional risk factors and were placed in the high-risk stratum:

  • Related donor with human leukocyte antigen (HLA) mismatch
  • Haploidentical donor
  • Unrelated donor with HLA mismatch
  • Use of umbilical cord blood
  • Use of ex vivo T-cell–depleted grafts
  • GVHD requiring systemic corticosteroids
See study design

Prophylaxis from Week 14 (~100 days) through Week 28 (~200 days) post-HSCT in adults

PREVYMIS demonstrated significant efficacy vs placebo

Primary endpoint: Clinically significant CMV infectiona through Week 28 post-HSCT (OF approachb)

Eligible subjects who completed PREVYMIS prophylaxis through ~100 days post-HSCT were randomized to receive PREVYMIS or placebo from Week 14 through Week 28 post-HSCT

Efficacy results in HSCT recipients at risk for late CMV infection and disease

Efficacy Results in Adult HSCT Recipients at Risk for Late CMV Infection and Disease Taking PREVYMIS® (letermovir) vs Placebo

(a) Clinically significant CMV infection (csCMVi) 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.
(b) The Observed Failure (OF) approach was used, where subjects who discontinued prematurely from the study without viremia or were missing data at the timepoint were not counted as failures. The number of subjects who discontinued from the study before Week 28 without viremia was 14 (9.7%) in the PREVYMIS arm and 0 in the placebo arm. The number of subjects with a missing outcome in the Week 28 visit window was 3 (2.1%) in the PREVYMIS arm and 4 (5.4%) in the placebo arm, none had prior viremia.
(c) The categories of failure are mutually exclusive and based on the hierarchy of categories in the order listed.
(d) 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.

Among subjects in the PREVYMIS group, the cumulative rate of clinically significant CMV infection increased from 1.6% at the end of prophylaxis (Week 28) to 15.6% at Week 38. In the placebo group, the cumulative rate of clinically significant CMV infection increased from 17.6% at Week 28 to 19.0% at Week 38. There were no additional cases of clinically significant CMV infection in either group between Weeks 38 and 48.

Risk factors for late CMV infection and disease

Common Risk Factors Demonstrated in a Study for Late CMV Infection in Adults

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 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
  • 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
See study design

References

  1. Marty FM, Ljungman P, Chemaly RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med. 2017;377(25):2433–2444. doi:10.1056/NEJMoa1706640
  2. Ljungman P, Schmitt M, Marty FM, et al. A mortality analysis of letermovir prophylaxis for cytomegalovirus (CMV) in CMV seropositive recipients of allogeneic hematopoietic cell transplantation. Clin Infect Dis. 2020;70(8):1525-1533. Accessed February 5, 2025. https://pmc.ncbi.nlm.nih.gov/articles/instance/7146004/bin/ciz490_suppl_supplementary_figure_1.pdf
  3. Ljungman P, Schmitt M, Marty FM, et al. A mortality analysis of letermovir prophylaxis for cytomegalovirus (CMV) in CMV seropositive recipients of allogeneic hematopoietic cell transplantation. Clin Infect Dis. 2020;70(8):1525-1533. Accessed February 5, 2025. https://pmc.ncbi.nlm.nih.gov/articles/instance/7146004/bin/ciz490_suppl_supplementary_figure_2.pdf
  4. Ljungman P, Schmitt M, Marty FM, et al. A mortality analysis of letermovir prophylaxis for cytomegalovirus (CMV) in CMV seropositive recipients of allogeneic hematopoietic cell transplantation. Clin Infect Dis. 2020;70(8):1525-1533. doi:10.1093/cid/ciz490

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INDICATIONS

PREVYMIS® (letermovir) is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult and pediatric patients 6 months of age and older and weighing at least 6 kg who are CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).

 

PREVYMIS is indicated for prophylaxis of CMV disease in adult and pediatric patients 12 years of age and older and weighing at least 40 kg who are kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]).

SELECTED SAFETY INFORMATION

  • PREVYMIS is contraindicated in patients receiving pimozide or ergot alkaloids.
      • Increased pimozide concentrations may lead to QT prolongation and torsades de pointes.
      • Increased ergot alkaloids concentrations may lead to ergotism.
  • PREVYMIS is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Significantly increased pitavastatin or simvastatin concentrations may lead to myopathy or rhabdomyolysis.
  • The concomitant use of PREVYMIS and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (PREVYMIS or concomitant drugs) or reduced therapeutic effect of PREVYMIS or the concomitant drug.
  • Intravenous formulation of PREVYMIS contains the excipient hydroxypropyl betadex. PREVYMIS injection should be used only in patients unable to take oral therapy and patients should be switched to oral PREVYMIS as soon as they are able to take oral medications. If possible, intravenous administration should not exceed 4 weeks.
  • In patients with renal impairment, accumulation of hydroxypropyl betadex may occur. In adult patients with CLcr less than 50 mL/min and in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function) receiving PREVYMIS injection, closely monitor serum creatinine levels.
  • Animal studies have shown the potential for hydroxypropyl betadex to cause ototoxicity. The active ingredient, letermovir, is not known to be associated with ototoxicity.
  • The rate of adverse events occurring in at least 10% of adult HSCT recipients treated with PREVYMIS and at a frequency at least 2% greater than placebo were nausea (27% vs 23%), diarrhea (26% vs 24%), vomiting (19% vs 14%), peripheral edema (14% vs 9%), cough (14% vs 10%), headache (14% vs 9%), fatigue (13% vs 11%), and abdominal pain (12% vs 9%).
  • Hypersensitivity reaction, with associated moderate dyspnea, occurred in one adult HSCT recipient following the first infusion of IV PREVYMIS after switching from oral PREVYMIS, leading to treatment discontinuation.
  • The most common adverse event occurring in at least 10% of adult kidney transplant recipients treated with PREVYMIS and at a frequency greater than valganciclovir was diarrhea (32% vs 29%).
  • The safety profile of PREVYMIS in pediatric subjects was consistent with the safety profile observed in clinical trials of PREVYMIS in adults.
  • If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily.
  • If PREVYMIS is co-administered with cyclosporine in pediatric HSCT patients less than 12 years of age, dose adjustment may be required.
  • Co-administration of PREVYMIS may alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of PREVYMIS. Consult the full Prescribing Information prior to and during treatment for potential drug interactions.
  • Closely monitor serum creatinine levels in patients with CLcr less than 50 mL/min using PREVYMIS injection.
  • PREVYMIS is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment.
  • The safety and effectiveness of PREVYMIS have not been established for:
      • HSCT recipients less than 6 months of age or weighing less than 6 kg, or
      • Kidney transplant recipients less than 12 years of age or weighing less than 40 kg.
  • For patients with creatinine clearance (CLcr) greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment of PREVYMIS is required based on renal impairment. The safety of PREVYMIS in patients with end-stage renal disease (CLcr less than 10 mL/min), including patients on dialysis, is unknown.

Before prescribing PREVYMIS® (letermovir), please read the accompanying Prescribing Information. The Patient Information and Instructions for Use also are available.

INDICATIONS
SELECTED SAFETY INFORMATION

PREVYMIS® (letermovir) is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult and pediatric patients 6 months of age and older and weighing at least 6 kg who are CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).

 

PREVYMIS is indicated for prophylaxis of CMV disease in adult and pediatric patients 12 years of age and older and weighing at least 40 kg who are kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]).

SELECTED SAFETY INFORMATION

  • PREVYMIS is contraindicated in patients receiving pimozide or ergot alkaloids.
      • Increased pimozide concentrations may lead to QT prolongation and torsades de pointes.
      • Increased ergot alkaloids concentrations may lead to ergotism.
  • PREVYMIS is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Significantly increased pitavastatin or simvastatin concentrations may lead to myopathy or rhabdomyolysis.
  • The concomitant use of PREVYMIS and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (PREVYMIS or concomitant drugs) or reduced therapeutic effect of PREVYMIS or the concomitant drug.
  • Intravenous formulation of PREVYMIS contains the excipient hydroxypropyl betadex. PREVYMIS injection should be used only in patients unable to take oral therapy and patients should be switched to oral PREVYMIS as soon as they are able to take oral medications. If possible, intravenous administration should not exceed 4 weeks.
  • In patients with renal impairment, accumulation of hydroxypropyl betadex may occur. In adult patients with CLcr less than 50 mL/min and in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function) receiving PREVYMIS injection, closely monitor serum creatinine levels.
  • Animal studies have shown the potential for hydroxypropyl betadex to cause ototoxicity. The active ingredient, letermovir, is not known to be associated with ototoxicity.
  • The rate of adverse events occurring in at least 10% of adult HSCT recipients treated with PREVYMIS and at a frequency at least 2% greater than placebo were nausea (27% vs 23%), diarrhea (26% vs 24%), vomiting (19% vs 14%), peripheral edema (14% vs 9%), cough (14% vs 10%), headache (14% vs 9%), fatigue (13% vs 11%), and abdominal pain (12% vs 9%).
  • Hypersensitivity reaction, with associated moderate dyspnea, occurred in one adult HSCT recipient following the first infusion of IV PREVYMIS after switching from oral PREVYMIS, leading to treatment discontinuation.
  • The most common adverse event occurring in at least 10% of adult kidney transplant recipients treated with PREVYMIS and at a frequency greater than valganciclovir was diarrhea (32% vs 29%).
  • The safety profile of PREVYMIS in pediatric subjects was consistent with the safety profile observed in clinical trials of PREVYMIS in adults.
  • If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily.
  • If PREVYMIS is co-administered with cyclosporine in pediatric HSCT patients less than 12 years of age, dose adjustment may be required.
  • Co-administration of PREVYMIS may alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of PREVYMIS. Consult the full Prescribing Information prior to and during treatment for potential drug interactions.
  • Closely monitor serum creatinine levels in patients with CLcr less than 50 mL/min using PREVYMIS injection.
  • PREVYMIS is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment.
  • The safety and effectiveness of PREVYMIS have not been established for:
      • HSCT recipients less than 6 months of age or weighing less than 6 kg, or
      • Kidney transplant recipients less than 12 years of age or weighing less than 40 kg.
  • For patients with creatinine clearance (CLcr) greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment of PREVYMIS is required based on renal impairment. The safety of PREVYMIS in patients with end-stage renal disease (CLcr less than 10 mL/min), including patients on dialysis, is unknown.

Before prescribing PREVYMIS® (letermovir), please read the accompanying Prescribing Information. The Patient Information and Instructions for Use also are available.