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

16 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an interventional, open-label, single center, pilot study with historical controls to test the efficacy of letermovir (LET) for the prevention of CMV infection and disease in adult lung transplant recipients (LTRs) with idiopathic pulmonary fibrosis (IPF).

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.

What data supports the effectiveness of the drug Letermovir for CMV prevention after lung transplant?

Letermovir has been shown to be effective in reducing CMV infections in lung transplant recipients, with a significant decrease in CMV viral load in 82.1% of patients in a study. It is also used successfully for CMV prevention in other types of transplants, like stem cell transplants, due to its good safety profile and effectiveness. ^{1 2 3 4 5}

Is Letermovir safe for humans?

Letermovir has been used safely in patients who have received stem cell transplants to prevent CMV infections, with ongoing studies monitoring its safety and effectiveness. It is approved in several countries, including the USA and Canada, for this purpose, and interim safety data from Japan supports its use. ^{1 6 7 8 9}

How is the drug Letermovir unique for CMV prevention after lung transplant?

Letermovir is unique because it is a novel antiviral drug specifically targeting the CMV-terminase complex, making it effective for CMV prevention in lung transplant patients, especially those with resistance to other treatments like ganciclovir. It is used off-label in this population and has shown rapid response in reducing CMV viral load, with mild side effects. ^{1 3 5 10 11}

Research Team

Fernanda Silveira

Principal Investigator

University of Pittsburgh

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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 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 (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 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 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, 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, 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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Cytomegalovirus prevention in thoracic organ transplantation: A single-center evaluation of letermovir prophylaxis. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Extended duration letermovir in allogeneic hematopoietic stem cell transplant. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Letermovir in lung transplant recipients with cytomegalovirus infection: A retrospective observational study. [2023]

4. United States 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. [2023]

5. United States 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. [2021]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Letermovir: First Global Approval. [2019]

7. New Zealand 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. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Letermovir and its role in the prevention of cytomegalovirus infection in seropositive patients receiving an allogeneic hematopoietic cell transplant. [2020]

9. Greece pubmed.ncbi.nlm.nih.gov

Letermovir Prophylaxis for CMV Reactivation in Allogeneic Stem Cell Recipients: A Retrospective Single Center Analysis. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Letermovir use to treat complex cytomegalovirus reactivations in two heart transplant recipients. [2022]

11. United States 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. [2021]