Letermovir for CMV in Transplant Recipients

Overseen By Sandesh Parajuli, MBBS

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: University of Wisconsin, Madison

Must not be taking: CMV vaccine

Disqualifiers: Ganciclovir-resistant CMV, Pregnancy, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: 12 weeks

90 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests letermovir (Prevymis) to determine if it can prevent the recurrence of cytomegalovirus (CMV) infection in individuals who have undergone a kidney or kidney/pancreas transplant. CMV can cause complications post-transplant, particularly when the immune system is weak. The trial focuses on transplant recipients who show signs of CMV infection and are at high risk for CMV. Participants will transition from their current CMV treatment to letermovir. This trial suits those who have had a transplant and require CMV treatment based on their doctor’s guidelines. As a Phase 3 trial, it represents the final step before FDA approval, allowing participants to contribute to the potential availability of a new treatment.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

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

Research shows that letermovir is generally well tolerated. In one study, researchers used letermovir to prevent CMV, a virus that can cause infections, in transplant patients. The results indicated that most participants did not experience severe side effects. Another study compared letermovir to valganciclovir for preventing CMV and found letermovir to be a safe alternative.

Since this trial is in a later phase, more evidence supports its safety for humans. Those with concerns about joining the trial should consult their doctor. ^{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 cytomegalovirus (CMV) in transplant recipients. Unlike standard treatments like ganciclovir or valganciclovir, which can cause bone marrow suppression, letermovir targets the CMV terminase complex, a key part of the virus's DNA replication process, without affecting human cells. This selective action means it has a lower risk of side effects, making it a promising option for patients who can't tolerate traditional therapies. Researchers are excited about letermovir because it could provide a safer and more effective way to keep CMV at bay in vulnerable transplant patients.

What evidence suggests that letermovir might be an effective treatment for CMV?

Studies have shown that letermovir effectively prevents cytomegalovirus (CMV) infections in transplant recipients. Research indicates it can reduce CMV-related complications and lower the risk of death in patients who have received a stem cell transplant. In this trial, participants will switch from ganciclovir derivatives to letermovir. Letermovir also shows promise as an alternative to valganciclovir for preventing CMV in heart and kidney transplant patients. It effectively prevents CMV infections without causing major side effects. Overall, letermovir is considered a strong option for controlling CMV in transplant recipients. ^{2 5 6 7 8}

Who Is on the Research Team?

Sandesh Parajuli, MBBS

Principal Investigator

University of Wisconsin, Madison

Are You a Good Fit for This Trial?

This trial is for adult kidney or kidney/pancreas transplant recipients at UW Health who are at risk of cytomegalovirus (CMV) infection. The study lasts about 6 months, and participants must meet specific health criteria to join.

Inclusion Criteria

I am at high risk for CMV infection after my transplant.

Patient must demonstrate proven or presumptive lack of cell-mediated immunity (CMI), either by CMI testing or risk factor screening

Patient must be able to provide informed consent to participate

Exclusion Criteria

Patient is currently participating in any study involving the administration of a CMV vaccine or another CMV investigational agent

Patient is unable or unwilling, in the opinion of the Investigator, to comply with the protocol

I have a CMV infection that did not respond to ganciclovir treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are converted from ganciclovir derivatives to letermovir for secondary prophylaxis of CMV infection

12 weeks

Weekly monitoring visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 90 days

Monthly visits

What Are the Treatments Tested in This Trial?

Interventions

• Letermovir

Trial Overview The effectiveness of Letermovir (Prevymis) in preventing the recurrence of CMV infections post-transplant is being tested. Participants will receive this medication over a period to assess its protective benefits.

How Is the Trial Designed?

Group I: Letermovir for CMV in Transplant Patients Experimental Treatment 1 Intervention

Enrolled participants will be converted from treatment with ganciclovir derivatives to letermovir

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 Wisconsin, Madison

Lead Sponsor

Trials

1,249

Recruited

3,255,000+

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

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 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 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, 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 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]

Letermovir, a new anti-CMV drug with fewer side effects, was successfully used off-label to treat a heart transplant recipient with ganciclovir-resistant CMV colitis, highlighting its potential as an alternative treatment.

The case suggests that monitoring CMV-pp65 antigenemia levels could be a useful additional marker for assessing the efficacy of letermovir treatment, alongside traditional CMV-DNA PCR levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment with Letermovir in a Heart Transplant Recipient with UL97 Mutation Ganciclovir-Resistant Cytomegalovirus Colitis and Viremia. Yanase, T., Hatano, M., Bujo, C., et al.[2023]

In a study of 6 transplant patients treated with letermovir for refractory CMV infection, 3 asymptomatic patients showed a significant decrease in viral load to below 200 IU/mL, indicating potential efficacy of the drug.

No treatment-related adverse effects were reported, suggesting that letermovir may be a safe option for treating CMV infections, although its effectiveness appears to vary and may be enhanced when used alongside other antiviral medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir as Salvage Therapy for Cytomegalovirus Infection in Transplant Recipients. Phoompoung, P., Ferreira, VH., Tikkanen, J., 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 ... Letermovir holds promise as an effective and safe alternative to valganciclovir for CMV prophylaxis in HT recipients.

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

Letermovir Prophylaxis Guided by Cytomegalovirus Cell ... Letermovir Prophylaxis Guided by Cytomegalovirus Cell-Mediated Immunity Improves the Outcomes of Allogeneic Hematopoietic Stem Cell Transplant ...

4. jamanetwork.com jamanetwork.com/journals/jama/fullarticle/2805945

Letermovir vs Valganciclovir for Prophylaxis of ... This trial compared letermovir vs valganciclovir prophylaxis in adult CMV-seronegative kidney transplant recipients who received an organ ...

5. 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.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38615067/

a multicenter, open-label, noncomparative Phase 3 study Letermovir was generally well tolerated, and the data support its use for the prevention of CMV disease/infection in adult Japanese KTRs.

7. academic.oup.com academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaf410/8211939

Letermovir Prophylaxis Guided by Cytomegalovirus Cell ... The study showed that a cytomegalovirus (CMV)–specific cell-mediated immunity–guided CMV prophylaxis strategy may help reduce the cumulative ...

8. merckconnect.com merckconnect.com/prevymis/hsct-study-design/

Phase 3 Study of Adult CMV-seropositive Recipients ... The safety and effectiveness of PREVYMIS have not been established for: HSCT recipients less than 6 months of age or weighing less than 6 kg, or; Kidney ...