Letermovir for Cytomegalovirus Prophylaxis in Kidney Transplant Recipients

Overseen By Gelila Abebe

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Virginia Commonwealth University

Must be taking: Valganciclovir

Must not be taking: Pimozide, Ergot alkaloids

Disqualifiers: Re-transplantation, Pregnancy, Hypersensitivity, 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 months

60 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is being done to compare the effectiveness of de novo Letermovir versus valganciclovir in preventing the development of cytomegalovirus viremia or symptomatic disease in African American kidney transplant recipients within the first year after transplantation. There are two arms in the study: Arm 1: Prophylaxis: This group includes freshly transplanted high risk (CMV D+/R-) African American Kidney recipients who will be on prophylactic Letermovir for 6 month. Arm 2: Prophylaxis: This group includes high-risk African American kidney transplant recipients who had already completed the 6 month prophylactic course with the standard of care Valganciclovir.

Will I have to stop taking my current medications?

If you are taking pimozide, ergot alkaloids, or pitavastatin/simvastatin with cyclosporine, you may need to switch to a different medication. The study team will work with your doctor to find a suitable alternative.

What data supports the effectiveness of the drug Letermovir for cytomegalovirus prophylaxis in kidney transplant recipients?

Letermovir has been shown to be effective in preventing cytomegalovirus (CMV) infection in patients who have received a hematopoietic stem cell transplant, and it has been used successfully in cases where other treatments were not effective due to resistance or side effects. This suggests it may also be beneficial for kidney transplant recipients at risk of CMV infection. ^{1 2 3 4 5}

Is Letermovir safe for use in humans?

Letermovir is considered to have a good safety profile, with fewer side effects compared to other treatments like valganciclovir, and it does not require dose adjustments for kidney function. ^{1 2 6 7 8}

How is the drug Letermovir different from other treatments for preventing cytomegalovirus in kidney transplant patients?

Letermovir is unique because it targets the viral terminase complex, which is different from other drugs that target viral polymerase, and it has a better safety profile with less risk of myelotoxicity (bone marrow suppression) and no need for dose adjustment in patients with kidney issues. ^{1 3 4 7 9}

Research Team

Gaurav Gupta, MD

Principal Investigator

Virginia Commonwealth University

Eligibility Criteria

This trial is for African American adults who've received a kidney transplant and are at high risk for Cytomegalovirus (CMV) because they got the virus from the donor. It's not open to those who have already been treated with valganciclovir for CMV or have certain transplant-related complications.

Inclusion Criteria

Ability to provide informed consent before any trial related activities

I have received a kidney transplant.

I am at high risk for CMV due to donor/recipient status.

Exclusion Criteria

Patients with hypersensitivity to Letermovir or any of its components

I am not taking pimozide, ergot alkaloids, or certain cholesterol medicines with cyclosporine.

Positive cytotoxic cross match at the time of transplant

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive prophylactic Letermovir or are assessed retrospectively for Valganciclovir use for CMV prophylaxis

6 months

Regular visits for monitoring and assessment

Follow-up

Participants are monitored for safety, effectiveness, and secondary outcomes such as leukopenia and allograft rejection

up to 1 year

Periodic visits for assessment and monitoring

Treatment Details

Interventions

• Letermovir

Trial Overview The study is testing if Letermovir, taken once daily, is effective in preventing CMV compared to Valganciclovir, following guidelines by the AST ID COP. Participants will be monitored and treated accordingly if they develop CMV viremia.

Participant Groups

Group I: Letermovir group (study group) Experimental Treatment 1 Intervention

Letermovir 480 mg once daily

Group II: Historical Control study group Experimental Treatment 1 Intervention

Historically matched AA kidney transplant recipients who received the standard of care 450mg once a day valganciclovir prophylaxis

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?

Virginia Commonwealth University

Lead Sponsor

Trials

732

Recruited

22,900,000+

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 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]

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]

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 Phase 1 trial with 24 subjects, letermovir was well tolerated and showed increased exposure in patients with moderate to severe renal impairment, indicating that kidney function affects how the drug is processed in the body.

Specifically, renal impairment led to a significant increase in the unbound fraction of letermovir, with exposure levels rising by 192% in moderate impairment and 142% in severe impairment compared to healthy subjects, suggesting careful monitoring may be needed for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of letermovir, a novel anti-human cytomegalovirus drug, in patients with renal impairment. Kropeit, D., Scheuenpflug, J., Erb-Zohar, K., et al.[2021]

In an observational study of 48 transplant recipients treated with Letermovir (LET) for cytomegalovirus (CMV) infection, patients with a viral load below 1000 IU/ml at the start of treatment showed promising virologic outcomes, with only 2 experiencing a significant increase in viral load by week 12.

For patients who started LET with a viral load above 1000 IU/ml, 60% achieved a lower viral load by the end of therapy, indicating that LET may still be beneficial even in cases of higher initial viral loads, although further research is needed to optimize treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir treatment of cytomegalovirus infection or disease in solid organ and hematopoietic cell transplant recipients. Linder, KA., Kovacs, C., Mullane, KM., 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 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, approved by the FDA for preventing CMV infection in stem cell transplant recipients, was used off-label for a heart transplant patient with ganciclovir-resistant CMV, showing its potential beyond initial indications.

The patient had previously experienced unacceptable toxicities from other treatments (cidofovir and foscarnet), highlighting letermovir as a safer alternative for managing resistant CMV infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir successfully used for secondary prophylaxis in a heart transplant recipient with ganciclovir-resistant cytomegalovirus syndrome (UL97 mutation). Chong, PP., Teiber, D., Prokesch, BC., et al.[2019]

In a retrospective study of 10 abdominal transplant recipients, letermovir was well tolerated and successful in preventing CMV infection when used as primary prophylaxis, with all patients achieving positive outcomes.

However, letermovir was less effective as secondary prophylaxis, failing in 62.5% of cases due to breakthrough CMV infections, highlighting the need for further research on its efficacy in solid organ transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Letermovir for Primary and Secondary Cytomegalovirus Prophylaxis in Abdominal Organ Transplantation: A Single Center Experience. Ibrahim, D., Byrns, J., Maziarz, E., et al.[2023]

References

1. 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]

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

Letermovir: First Global Approval. [2019]

3. England pubmed.ncbi.nlm.nih.gov

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

4. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of letermovir, a novel anti-human cytomegalovirus drug, in patients with renal impairment. [2021]

5. Denmark pubmed.ncbi.nlm.nih.gov

Letermovir treatment of cytomegalovirus infection or disease in solid organ and hematopoietic cell transplant recipients. [2021]

6. Greece pubmed.ncbi.nlm.nih.gov

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

7. 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]

8. Denmark pubmed.ncbi.nlm.nih.gov

Letermovir successfully used for secondary prophylaxis in a heart transplant recipient with ganciclovir-resistant cytomegalovirus syndrome (UL97 mutation). [2019]

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

Use of Letermovir for Primary and Secondary Cytomegalovirus Prophylaxis in Abdominal Organ Transplantation: A Single Center Experience. [2023]