Letermovir for CMV Prophylaxis in Transplant Patients

Overseen By Jamie Doyle, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Pennsylvania

Must not be taking: Ganciclovir, Valganciclovir, Foscarnet, others

Disqualifiers: Prior transplant, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 90 to 365 days

80 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to compare the effectiveness of letermovir (Prevymis) with valganciclovir in preventing CMV, a common viral infection, in heart or lung transplant recipients. Researchers seek to determine if letermovir can prevent CMV as effectively as, or better than, valganciclovir, while being gentler on the body and causing fewer side effects, such as low white blood cell counts. Heart or lung transplant recipients at risk for CMV may be suitable candidates, particularly if they can begin the medication soon after surgery. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you have received certain anti-CMV treatments or investigational drugs recently. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that letermovir is likely to be safe for humans?

Research has shown that letermovir is generally well-tolerated. Studies have found it to be a safe choice for preventing CMV (cytomegalovirus) infections. One study demonstrated that letermovir had a good safety record, with fewer cases of active CMV compared to other treatments. Another study found that letermovir resulted in fewer significant CMV infections than a placebo.

Some side effects have been reported, but they are uncommon. Specifically, in one study, only about 11% of children treated with letermovir showed signs of CMV activity several weeks later. Overall, letermovir is considered a promising and safe option for those at risk of CMV infections. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for preventing cytomegalovirus (CMV) in transplant patients, which often include drugs like ganciclovir or valganciclovir, Letermovir offers a unique mechanism by targeting the CMV terminase complex. This specific action not only helps in reducing the virus's ability to replicate but also comes with a lower risk of side effects commonly associated with other CMV drugs, such as bone marrow suppression. Researchers are excited about Letermovir because it promises to provide effective CMV prophylaxis with potentially improved safety and tolerability for those undergoing transplants.

What evidence suggests that letermovir might be an effective treatment for CMV prophylaxis in transplant patients?

Research has shown that letermovir, which participants in this trial will receive, effectively prevents CMV (cytomegalovirus) disease in transplant patients. One study found it successfully stopped CMV from appearing in patients after a transplant, with few side effects. Another study found that letermovir reduced the risk of CMV-related issues and death beyond 200 days post-transplant. It also did not cause neutropenia, a common issue with other treatments involving a low count of a type of white blood cell. Overall, letermovir appears to be a promising option for preventing CMV in heart and lung transplant patients. ^{3 4 6 7 8}

Are You a Good Fit for This Trial?

This trial is for heart or lung transplant recipients who are CMV seropositive, can start oral medication within 14 days post-transplant, and agree to use contraception. Excluded are those with prior transplants, treated CMV infections, severe organ dysfunction, certain drug sensitivities, uncontrolled infections, recent malignancies (except some skin cancers), pregnancy/breastfeeding intentions or participation in other investigational studies.

Inclusion Criteria

I agree to use birth control and not donate sperm for 90 days after my last treatment dose.

I agree to use effective birth control or practice true abstinence during and 90 days after the study.

I can start oral medication to prevent CMV infection within 2 weeks after my transplant.

Exclusion Criteria

Suspected or known hypersensitivity to active or inactive ingredients of letermovir formulations and/or acyclovir formulations

Previously participated or is currently participating in any study involving administration of a CMV vaccine or another CMV investigational agent, or is planning to participate in a study of a CMV vaccine or another CMV investigational agent during the course of this study.

Documented positive results for human immunodeficiency virus antibody (HIV-Ab) test at any time prior to enrollment, or for hepatitis C virus antibody (HCV-Ab) and with detectable HCV ribonucleic acid (RNA) within 90 days prior to enrollment, or hepatitis B surface antigen (HBsAg) within 90 days prior to enrollment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive letermovir for CMV prophylaxis following heart or lung transplantation

90 to 365 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, including CMV resistance and acute cellular rejection

180 days

What Are the Treatments Tested in This Trial?

Interventions

• Letermovir

Trial Overview The study tests the tolerability and effectiveness of Letermovir as a preventive treatment against CMV infection in transplant patients compared to historical data from Valganciclovir users. It aims to show that Letermovir has similar infection rates but fewer side effects like neutropenia and incorrect dosing issues.

How Is the Trial Designed?

Group I: Letermovir Experimental Treatment 1 Intervention

Will include those participants who receive letermovir for CMV prophylaxis as provided through the clinical trial. The "exposed" group will be ascertained prospectively over a one-year period (the "post-intervention" period).

Letermovir is already approved in United States, European Union for the following indications:

Approved in United States as Prevymis for:

• Prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT)
• Prophylaxis of cytomegalovirus (CMV) disease in adult kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-])
• 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 of an allogeneic hematopoietic stem cell transplant (HSCT)
• Prophylaxis of cytomegalovirus (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-])

Approved in European Union as Prevymis for:

• Prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT)
• Prophylaxis of cytomegalovirus (CMV) disease in adult kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-])

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

Cabotegravir, an injectable HIV preexposure prophylaxis, showed effective concentrations in plasma and tissues associated with HIV transmission, remaining above the necessary levels for efficacy for up to 12 weeks after a single injection.

The study involved 19 healthy adults, with 16 completing the trial, and while injection-site reactions were common (88%), they were mostly mild (grade 1), indicating a favorable safety profile for this long-acting treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicompartmental pharmacokinetic evaluation of long-acting cabotegravir in healthy adults for HIV preexposure prophylaxis. Shaik, JS., Weld, ED., Edick, S., et al.[2022]

The highest risk of HIV-1 drug resistance from preexposure prophylaxis (PrEP) occurs when individuals start or continue PrEP after being unknowingly infected with HIV, particularly with oral TDF/emtricitabine or injectable cabotegravir.

The dapivirine ring shows a low risk of developing resistance to nonnucleoside reverse transcriptase inhibitors, and new investigational agents like islatravir and lenacapavir are promising for PrEP due to their potential for sustained delivery and minimal cross-resistance, although ongoing monitoring for resistance mutations is essential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How could HIV-1 drug resistance impact preexposure prophylaxis for HIV prevention? Parikh, UM., Mellors, JW.[2023]

Letermovir is highly effective in preventing cytomegalovirus (CMV) reactivation and disease in transplant recipients, showing similar efficacy to standard treatments like valganciclovir but with a significantly better safety profile, including reduced myelotoxicity and no need for renal dose adjustments.

Recent studies indicate that letermovir not only prevents CMV effectively but also improves overall clinical outcomes, such as reduced mortality and lower rates of graft versus host disease, making it a promising option for extended prophylaxis in hematopoietic stem cell and solid organ transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new direction for cytomegalovirus prophylaxis among transplant recipients: Benefits and nonviral outcomes of letermovir use as primary CMV prophylaxis. Moore, WJ., Boutin, CA., Tanna, S.[2023]

Letermovir, an antiviral agent typically used for preventing CMV infection in stem cell transplant recipients, was successfully used off-label to treat a patient with resistant CMV disease after renal transplant.

This case report is significant as it demonstrates the effectiveness of combining letermovir with hyperimmune CMV immunoglobulin for treating high viral load CMV infections, providing a potential alternative when standard treatments are inadequate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment of UL97 Mutation Ganciclovir-Resistant Cytomegalovirus Viremia in a Renal Transplant Recipient With Letermovir and Adjunct Hyperimmune Cytomegalovirus Immunoglobulin: A Case Report. Pearston, AP., Ingemi, AI., Ripley, K., et al.[2021]

In a study of 48 CMV-seropositive allogeneic stem cell transplant recipients, letermovir prophylaxis significantly reduced the incidence of CMV reactivation to 33.3% compared to 76.2% in the control group, highlighting its efficacy in preventing this serious complication.

Patients receiving letermovir also showed improved overall survival at 180 days (92.6% vs. 80.9% in the control group), suggesting that prolonged use of letermovir may provide additional survival benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir Prophylaxis for CMV Reactivation in Allogeneic Stem Cell Recipients: A Retrospective Single Center Analysis. Koch, K., Osswald, L., Miller, I., et al.[2022]

Letermovir (Prevymis™) is an effective prophylactic treatment for preventing cytomegalovirus (CMV) infection and disease in adult patients who are CMV-seropositive and have received an allogeneic hematopoietic stem cell transplant, with approvals in Canada and the USA.

The drug works by inhibiting the CMV DNA terminase complex and has received positive regulatory feedback in Europe, indicating its potential for broader international use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir: First Global Approval. Kim, ES.[2019]

In a retrospective analysis of patients who underwent allogeneic hematopoietic stem cell transplantation, letermovir prophylaxis significantly reduced the incidence of clinically significant CMV infections (30.2% vs. 71.6% in the control group) within 100 days, indicating its efficacy in preventing CMV reactivation.

The study also found that letermovir prophylaxis was associated with lower non-relapse mortality (4.7% vs. 19.8% at day 500), and identified that receiving a transplant from a CMV seronegative donor to a seropositive recipient increased the risk of CMV infection even with letermovir treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk factor analysis for cytomegalovirus reactivation under prophylaxis with letermovir after allogeneic hematopoietic stem cell transplantation. Mizuno, K., Sakurai, M., Kato, J., et al.[2022]

In a 6-year post-marketing surveillance study involving 461 Japanese patients who received allogenic hematopoietic stem-cell transplantation, letermovir was found to be safe, with 13.9% experiencing adverse drug reactions, primarily renal impairment and nausea.

The effectiveness of letermovir for CMV prophylaxis was confirmed, with CMV antigen positivity rates of 21.2% at Week 14 and 37.5% at Week 24 after transplantation, indicating its role in reducing CMV infection risk in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Effectiveness of Letermovir in Allogenic Hematopoietic Stem Cell Transplantation Recipients: Interim Report of Post-marketing Surveillance in Japan. Hiraishi, I., Ueno, R., Watanabe, A., et al.[2022]

In a study of 249 adults at high risk for HIV exposure, the combination of tenofovir/emtricitabine and lopinavir/ritonavir (TDF/FTC+LPV/r) was found to have good tolerability, with 58% of participants reporting good tolerability after 28 days of post-exposure prophylaxis (PEP).

The dropout rate due to adverse effects was significantly lower for TDF/FTC+LPV/r compared to other PEP regimens, indicating it may be a safer and more effective standard of care for HIV prevention after potential exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability of HIV postexposure prophylaxis with tenofovir/emtricitabine and lopinavir/ritonavir tablet formulation. Tosini, W., Muller, P., Prazuck, T., et al.[2022]

Cabotegravir (CAB) is an effective treatment for HIV-1 infection, showing efficacy both as part of combination therapy and as a long-acting injectable formulation administered every 4 to 8 weeks.

CAB is also being explored as a pre-exposure prophylaxis (PrEP) for high-risk individuals, with ongoing studies comparing its effectiveness to standard PrEP regimens, indicating its potential to reduce new infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabotegravir in the treatment and prevention of Human Immunodeficiency Virus-1. McPherson, TD., Sobieszczyk, ME., Markowitz, M.[2020]

Letermovir, an anti-CMV drug, was successfully used to treat ganciclovir-resistant CMV colitis in a heart transplant recipient, demonstrating its potential as a curative option.

In a second case, while letermovir was used as pre-emptive therapy for CMV reactivation, it did not prevent CMV esophagitis, indicating that while effective for secondary prophylaxis, it may not always prevent all forms of CMV-related complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir use to treat complex cytomegalovirus reactivations in two heart transplant recipients. Boignard, A., Augier, C., Kheng, M., et al.[2022]

In a comparison of tenofovir alafenamide and emtricitabine (TAF/FTC) versus placebo for HIV prevention, TAF/FTC showed a significant reduction in HIV infection risk, being 5.8 percentage points lower than placebo over 96 weeks.

The analysis utilized data from the DISCOVER and iPrEx trials, confirming that TAF/FTC is effective in preventing HIV infection, with a 12.5-fold lower risk compared to placebo after adjusting for demographic differences.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HIV prevention among men who have sex with men: tenofovir alafenamide combination preexposure prophylaxis versus placebo. Zivich, PN., Cole, SR., Edwards, JK., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9879759/

Real-World Outcomes Associated With Letermovir Use for ... Letermovir for CMV PP was effective in reducing the risk of CMV-related complications overall and mortality beyond day 200 among adult allo-HCT recipients.

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1071916425002842

Efficacy of Letermovir for Cytomegalovirus Prophylaxis in ... Cytomegalovirus (CMV) prophylaxis post–heart transplantation with letermovir appears to be effective in preventing CMV disease. •. Most patients ...

3. academic.oup.com academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaf410/8211939?searchresult=1

Letermovir Prophylaxis Guided by Cytomegalovirus Cell ... This study aimed to assess whether CMV-CMI–guided letermovir prophylaxis is more effective than a fixed-duration approach in reducing the ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa1706640

Letermovir Prophylaxis for Cytomegalovirus in ... Letermovir at a dose of 240 mg per day was highly effective in preventing CMV viremia after engraftment in transplant recipients and had little toxicity.

5. jhltonline.org jhltonline.org/article/S1053-2498(25)02257-0/abstract

Tolerability and clinical efficacy of letermovir for primary ... Thirty-two patients completed 3 or 6 months of LET prophylaxis. There were no episodes of neutropenia while on LET compared to 15% (30/204) in ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10918401/

Real-Life Data on the Efficacy and Safety of Letermovir for ... LMV prophylaxis was effective in preventing CMV reactivation with a favorable safety profile. CMV reactivation occurred mostly after LMV ...

7. ema.europa.eu ema.europa.eu/en/medicines/human/EPAR/prevymis

Prevymis | European Medicines Agency (EMA) Supportive data from this study indicated that around 11% (6 out of 56) of the treated children had signs of CMV becoming active 24 weeks after the stem cell ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT02137772

NCT02137772 | Letermovir (MK-8228) Versus Placebo in ... The study evaluated the efficacy and safety of letermovir (MK-8228) for the prevention of clinically-significant CMV infection in adult, CMV-seropositive ...