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

Trial Summary

What is the purpose of this trial?

Open label study to determine tolerability and efficacy of letermovir for CMV prophylaxis in heart and lung transplant recipients and compare it to the efficacy of valganciclovir historical controls. The study hypotheses are: 1. Letermovir prophylaxis will be associated with similar rates of CMV infection as valganciclovir among heart and lung transplant recipients 2. Letermovir will be better tolerated than valganciclovir for CMV prophylaxis in heart and lung transplant recipients, with a higher proportion of days of completed therapy with correct dosing during the planned prophylaxis period 3. Letermovir will have a lower rate of neutropenia than valganciclovir when used for CMV prophylaxis in heart and lung transplant recipients 4. Incorrect renal dosing will occur less frequently with letermovir than with valganciclovir when used for CMV prophylaxis in heart and lung transplant recipients

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.

What data supports the effectiveness of the drug Letermovir for CMV prophylaxis in transplant patients?

Letermovir is effective in preventing CMV reactivation and disease in transplant patients, with studies showing it has a good safety profile and fewer side effects compared to other treatments. It has been successfully used in cases where other drugs were not effective due to resistance or side effects. ^{1 2 3 4 5}

Is Letermovir safe for use in humans?

Letermovir has been approved for use in preventing CMV infections in transplant patients in several countries, including the USA, Canada, and Japan, indicating it has been evaluated for safety. Post-marketing surveillance in Japan involving 461 patients is ongoing to further assess its safety and effectiveness. ^{1 4 5 6 7}

What makes the drug Letermovir unique for CMV prevention in transplant patients?

Letermovir is unique because it specifically targets the CMV virus by inhibiting its DNA terminase complex, which is different from other antiviral drugs that often target viral DNA polymerase. This makes it a novel option for preventing CMV in transplant patients, as it can be more effective and have fewer side effects compared to traditional treatments. ^{8 9 10 11 12}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

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

2. 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]

3. 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]

4. Greece pubmed.ncbi.nlm.nih.gov

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

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

Letermovir: First Global Approval. [2019]

6. Denmark pubmed.ncbi.nlm.nih.gov

Risk factor analysis for cytomegalovirus reactivation under prophylaxis with letermovir after allogeneic hematopoietic stem cell transplantation. [2022]

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

Tolerability of HIV postexposure prophylaxis with tenofovir/emtricitabine and lopinavir/ritonavir tablet formulation. [2022]

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

HIV prevention among men who have sex with men: tenofovir alafenamide combination preexposure prophylaxis versus placebo. [2023]

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

Multicompartmental pharmacokinetic evaluation of long-acting cabotegravir in healthy adults for HIV preexposure prophylaxis. [2022]

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

How could HIV-1 drug resistance impact preexposure prophylaxis for HIV prevention? [2023]

12. England pubmed.ncbi.nlm.nih.gov

Cabotegravir in the treatment and prevention of Human Immunodeficiency Virus-1. [2020]