Letermovir for CMV Prevention After Lung Transplant

Overseen By Kailey Hughes Kramer, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Fernanda P Silveira, MD, MS

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

Disqualifiers: Previous transplants, HIV, HCV, 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: 6-12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether letermovir can prevent CMV (cytomegalovirus) infections in individuals who recently underwent a lung transplant due to idiopathic pulmonary fibrosis, a lung disease that causes scarring. Researchers are testing letermovir against historical data from individuals treated with another drug, valganciclovir. This study may suit those who have had a lung transplant within the last 72 hours for idiopathic pulmonary fibrosis and are either CMV positive or will receive a lung from a CMV positive donor. Participants must be able to travel for follow-up visits for 15 months post-transplant. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant medical advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot use certain antiviral drugs like ganciclovir, valganciclovir, foscarnet, or cidofovir at the time of transplant.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that letermovir is a newer drug used to prevent CMV (cytomegalovirus) infections. The FDA has already approved it for use in kidney transplant patients, indicating a good safety record. Some studies suggest that letermovir may cause fewer blood-related side effects compared to valganciclovir, making it an appealing choice for preventing CMV in lung transplant patients, although specific data on lung transplants remains limited. Overall, existing evidence suggests letermovir is generally well-tolerated, but further research will help confirm its safety in different transplant situations. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Letermovir is unique because it offers a different approach to preventing CMV infections in lung transplant recipients. Unlike the standard of care, which typically involves the antiviral drug valganciclovir, letermovir specifically targets the CMV DNA terminase complex, an essential part of the virus's replication process. This targeted action may lead to fewer side effects and better tolerance, especially since letermovir doesn't affect the blood cells as much as valganciclovir does. Researchers are excited about letermovir because it has the potential to improve patient outcomes by reducing CMV complications without the common drawbacks of existing treatments.

What evidence suggests that letermovir might be an effective treatment for CMV prevention after lung transplant?

Research shows that letermovir helps prevent CMV (cytomegalovirus) infections in transplant patients. Studies have found that letermovir works better than a placebo in stopping CMV infections in individuals who have undergone stem cell transplants. In heart transplant patients, letermovir was well tolerated and effectively prevented CMV infections, with only a few cases of infection occurring. This trial will administer letermovir to lung transplant patients to assess its long-term effectiveness in reducing CMV infections. These findings suggest that letermovir could be a strong option for preventing CMV in lung transplant recipients with idiopathic pulmonary fibrosis. ^{2 6 7 8 9}

Who Is on the Research Team?

Fernanda Silveira

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

This trial is for adults over 18 with idiopathic pulmonary fibrosis who've had or will have a lung transplant and are CMV seropositive, or receive an organ from a CMV positive donor. They must be able to visit UPMC post-transplant for at least 15 months, provide consent, use contraception during the study and not have HIV/HCV, severe liver issues, need conflicting meds, or be pregnant.

Inclusion Criteria

Be willing to use a contraceptive method while receiving LET and for at least 90 days following last dose of LET

Able to provide informed consent

I can travel to UPMC for follow-up visits for at least 15 months after my transplant.

Exclusion Criteria

I have tested positive for hepatitis C.

Donor HCV NAT positive

Known or suspected hypersensitivity to LET or acyclovir

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive letermovir prophylaxis for 6 to 12 months depending on CMV serostatus

6-12 months

Follow-up

Participants are monitored for CMV infection or disease after completion of prophylaxis

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Letermovir

Trial Overview The study tests Letermovir's effectiveness in preventing Cytomegalovirus infection after lung transplantation compared to historical data. It's open-label (participants know what treatment they're getting) and involves patients who meet specific CMV criteria.

How Is the Trial Designed?

Group I: Letermovir Experimental Treatment 1 Intervention

Participants who are CMV seropositive (CMV R+) will receive letermovir prophylaxis for 6 months, and participants who are CMV donor seropositive/recipient seronegative (CMV D+/R-) will receive letermovir prophylaxis for 12 months. Letermovir will be administered at a dose of 480 mg IV or oral once daily. IV administration will occur only for those patients unable to swallow tablets. If letermovir is co-administered with cyclosporine A, the dosage of letermovir will be decreased to 240 mg once daily.

Group II: Valganciclovir Active Control 1 Intervention

Historical controls will be lung transplant recipients for idiopathic pulmonary fibrosis from 2010-2019 who are CMV R+ or CMV D+/R-. CMV prophylaxis in the historical controls was with valganciclovir for 6 months for CMV R+ and for 12 months for CMV D+/R-.

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?

Fernanda P Silveira, MD, MS

Lead Sponsor

Trials

2

Recruited

400+

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

In a study of 80 CMV-seropositive adult patients receiving letermovir as secondary prophylaxis after hematopoietic cell transplantation, the treatment was well tolerated and showed a low rate of breakthrough infections (5.5%), indicating its potential effectiveness in preventing CMV reactivation in high-risk patients.

Letermovir was administered for a median of 118 days, providing a crucial bridge between initial CMV treatment and immune recovery, although further research is needed to confirm these findings and assess long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir for Secondary Prophylaxis of Cytomegalovirus Infection and Disease after Allogeneic Hematopoietic Cell Transplantation: Results from the French Compassionate Program. Robin, C., Thiebaut, A., Alain, S., et al.[2021]

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]

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]

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]

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 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]

In a study of 87 allogeneic hematopoietic cell transplant recipients, extending letermovir prophylaxis beyond 100 days resulted in a lower rate of CMV reactivation (19%) compared to the standard duration group (28%).

The study suggests that longer letermovir prophylaxis may be beneficial in reducing CMV reactivation without increasing all-cause mortality, indicating a potential strategy for improving outcomes in CMV seropositive patients post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended duration letermovir in allogeneic hematopoietic stem cell transplant. Hinman, B., Cox, J., Umoru, G., et al.[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]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S2950133424000983

Letermovir use for cytomegalovirus prophylaxis following ... In a double-blinded randomized trial of hematopoietic stem cell transplant patients, letermovir was found to be more effective than placebo in preventing ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9121640/

Cytomegalovirus Prevention in Thoracic Organ Transplantation Letermovir was well tolerated and effective during extended prophylactic courses with only one case of breakthrough CMV infection in this cohort ...

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

Tolerability and clinical efficacy of letermovir for primary ... We studied the tolerability and clinical effectiveness of LET for primary CMV prophylaxis after heart transplant (HT) and compared rates of ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06066957

Open Label Trial of Oral Letermovir for CMV Prophylaxis in ... The study hypotheses are: Letermovir prophylaxis will be associated with similar rates of CMV infection as valganciclovir among heart and lung transplant ...

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

Letermovir Prophylaxis Guided by Cytomegalovirus Cell ... In people who received lung transplants, CMV-CMI–guided antiviral prophylaxis significantly reduced CMV infection within 18 months compared ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39884651/

Letermovir should be first-line cytomegalovirus prophylaxis ... Letermovir, a newer anti-CMV agent, is an attractive alternative for first-line prophylaxis in many lung transplant recipients.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05041426

Letermovir for CMV Prevention After Lung Transplantation This is an interventional, open-label, single center, pilot study with historical controls to test the efficacy of letermovir (LET) for the prevention of ...

8. jhltonline.org jhltonline.org/article/S1053-2498(25)02281-8/abstract

Letermovir: An enticing new CMV prophylaxis option with ... Letermovir should be first-line cytomegalovirus prophylaxis in lung transplant recipients. Am J Transplant. 2025; 25:908-915. Full Text · Full ...

9. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1111/tid.14279

Evaluating the efficacy and safety of letermovir compared ... Off-label use of letermovir (LET) may avert myelotoxicity associated with valganciclovir (VGCV), but data in lung transplantation are limited.