Letermovir for Congenital CMV Infection

Recruiting at 11 trial locations

Overseen By David W. Kimberlin

Age: < 18

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must be taking: Valganciclovir

Must not be taking: Carbamazepine, Nafcillin, Phenobarbital, Phenytoin

Disqualifiers: HIV exposure, Imminent demise, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

Duration: 2 weeks

12 Participants Needed

Trial Summary

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 take certain drugs like carbamazepine, nafcillin, phenobarbital, or phenytoin during the study.

What data supports the effectiveness of the drug Letermovir for congenital CMV infection?

Letermovir has been shown to be effective in preventing CMV infection in adults who have received stem cell transplants, and it has been used successfully in some cases to treat CMV infections that are resistant to other drugs. Additionally, research suggests that Letermovir can cross the placenta, which may make it a potential option for treating congenital CMV infection. ^{1 2 3 4 5}

Is Letermovir safe for humans?

Letermovir has been used safely in adults for preventing CMV infections, especially in those who have had stem cell transplants. Some people experienced mild side effects like stomach issues and skin rashes, but overall, it is considered safe. ^{1 3 6 7 8}

How is the drug Letermovir unique for treating congenital CMV infection?

Letermovir is unique because it works by inhibiting the CMV DNA terminase complex, which is different from other CMV treatments that often target viral DNA polymerase. It is also known for having fewer side effects compared to other CMV drugs, making it a potentially safer option for patients. ^{1 2 3 4 9}

What is the purpose of this trial?

This is a Phase 1 single-arm open-label study of letermovir in neonates with symptomatic congenital Cytomegalovirus (CMV) disease. There will be two groups enrolled. Group 1 will be comprised of 4 subjects. Following documentation study inclusion and signing of informed consent, Group 1 subjects will receive one dose of oral letermovir (Study Day 0), using the dose bands. A full pharmacokinetics (PK) profile will then be obtained over the next 24 hours, and blood specimens will be shipped immediately to the University of Alabama at Birmingham (UAB) Pharmacokinetic Lab and processed in real time. Within = 7 days, pharmacokinetics (PK) results will be conveyed to the study site. If the Area Under the Curve (AUC24) is =100,000 ngxhr/mL (see footnote a in Table 1), the subject will initiate a 14-day course of once-daily oral letermovir at the same dose as utilized on Dose Finding Day. This duration of letermovir therapy was selected based upon our earlier observation in this population that patients with symptomatic congenital Cytomegalovirus (CMV) disease who achieve viral suppression to =2.5 log by day 14 of valganciclovir therapy and then maintain it over the next 4 months are statistically more likely to have improved hearing across the first two years of life (22). If the observed letermovir exposure of the subject is \> 100,000 ngxhr/mL, the once-daily oral letermovir dose that will be used will be adjusted down in 2.5 mg increments. Oral valganciclovir (16 mg/kg/dose BID) will begin within the first month of life, as standard of care; initiation of valganciclovir can be concomitant with or prior to initiation of the 14-day course of letermovir (but will not start before obtaining the pharmacokinetics (PK) specimens following the single dose of letermovir on the Dose Finding Day). This is similar to the intensification approach that has been evaluated in the management of patients infected with human immunodeficiency virus (23-25). The day that the 14-day course of letermovir begins for Group 1 subjects will be known as Study Day 1. Serial blood samples will be obtained on Study Days 1, 5, 10, and 14 for safety chemistry and hematology labs and for Cytomegalovirus (CMV) viral loads. Cytomegalovirus (CMV) viral load will be followed as well on Study Days 21 and 42 to assess for rebound in Cytomegalovirus (CMV) following cessation of letermovir treatment on Study Day 14. Saliva and urine viral loads will be followed at these timepoint as well. Full pharmacokinetics (PK) profiles for both letermovir and ganciclovir will be obtained on Study Day 10. In addition, sparse pharmacokinetics (PK) sampling will be obtained on Study Days 1, 5, and 14. Adverse events will be assessed at each study visit during treatment, and at Study Days 21 and 42 (4 weeks after the last study drug dose). Subjects then will continue on oral valganciclovir as routine clinical care to complete an anticipated 6 month duration of total therapy. The primary Objective is to determine the systemic exposure (AUC24) of letermovir following administration of oral letermovir granules in infants with symptomatic congenital CMV disease.

Eligibility Criteria

This trial is for infants with symptomatic congenital CMV disease who are planned to be treated with oral valganciclovir for 6 months. Eligible infants must have confirmed CMV, weigh between 2.6 kg and <8.0 kg, be at least 32 weeks gestational age at birth, and show symptoms like thrombocytopenia or CNS involvement.

Inclusion Criteria

My doctor plans to treat my infant's CMV with oral medication for 6 months.

I have symptoms like easy bruising, liver enlargement, or hearing loss due to CMV.

I have symptoms of a congenital CMV infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 week

Dose Finding

Participants receive one dose of oral letermovir and undergo pharmacokinetic profiling

1 day

1 visit (in-person)

Treatment

Participants receive a 14-day course of once-daily oral letermovir with concurrent valganciclovir

2 weeks

4 visits (in-person) on Study Days 1, 5, 10, and 14

Follow-up

Participants are monitored for safety and effectiveness after treatment, including viral load assessments

4 weeks

2 visits (in-person) on Study Days 21 and 42

Long-term Follow-up

Participants continue on oral valganciclovir as routine clinical care to complete an anticipated 6-month duration of total therapy

6 months

Treatment Details

Interventions

• Letermovir

Trial Overview The study tests the safety of oral Letermovir in newborns with symptomatic congenital Cytomegalovirus (CMV). It's a Phase 1 trial where subjects receive one dose followed by a pharmacokinetics profile assessment over 24 hours to determine appropriate dosing for a subsequent 14-day treatment course.

Participant Groups

Group I: Group 2 Experimental Treatment 1 Intervention

Neonates (\</= 90 days) with symptomatic congenital Cytomegalovirus (CMV) disease will initiate a 14-day course of once-daily oral letermovir, using weight dose banding. All subjects also will receive valganciclovir as standard of care. A dose escalation safety evaluation will occur to ensure the safety data support subjects proceeding. If the median of observed letermovir exposures of subjects in Group 1 is below 34,400 ngxhr/mL (or above 100,000 ngxhr/mL), then the subjects enrolled in Group 2 will receive once-daily oral letermovir at a dose that has been adjusted upward (or downward) in 2.5 mg increments. N=8

Group II: Group 1 Experimental Treatment 1 Intervention

Neonates (\</= 83 days) with symptomatic congenital Cytomegalovirus (CMV) disease will receive one dose of oral letermovir, using weight dose banding. All subjects also will receive valganciclovir as standard of care. A dose safety evaluation will occur to ensure the safety data support subjects proceeding. If the observed letermovir exposure is \</= 100,000 ngxhr/mL, the subject will initiate a 14-day course of once-daily oral letermovir at the same dose as utilized on the Dose Finding Day. If the observed letermovir exposure of the subject is \> 100,000 ngxhr/mL, the once-daily oral letermovir dose that will be used will be adjusted down in 2.5 mg increments from the dose utilized on the Dose Finding Day. N = 4

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?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Findings from Research

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 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]

Letermovir (LMV) is effective for preventing cytomegalovirus (CMV) infection in patients receiving hematopoietic stem cell transplants, but resistance can develop quickly, as shown in a case where a patient developed a mutation associated with high-level LMV resistance after secondary prophylaxis.

Monitoring viral loads and conducting genotyping for resistance mutations is crucial when using LMV, especially in patients with detectable CMV, to prevent the rapid selection of resistant strains.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fast breakthrough of resistant cytomegalovirus during secondary letermovir prophylaxis in a hematopoietic stem cell transplant recipient. Jung, S., Michel, M., Stamminger, T., et al.[2020]

Letermovir (LMV) and Maribavir (MBV) can effectively cross the placenta, achieving fetal concentrations significantly higher than the levels needed to inhibit cytomegalovirus (CMV), suggesting their potential for treating congenital CMV infection.

The study demonstrated that both drugs have favorable transfer rates and retention in the placenta, indicating they could be viable options for maternal treatment to benefit infected fetuses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placental transfer of Letermovir & Maribavir in the ex vivo human cotyledon perfusion model. New perspectives for in utero treatment of congenital cytomegalovirus infection. Faure Bardon, V., Peytavin, G., Lê, MP., et al.[2020]

In a study of 204 adult CMV-seropositive allo-SCT recipients treated with letermovir for CMV prophylaxis, the cumulative incidence of clinically significant CMV infection was low, at 5.4% by day +100 and 18.1% by day +168, indicating letermovir's efficacy in a real-world setting.

The treatment was generally safe, with low to mild adverse events reported in 40.7% of patients, primarily gastrointestinal issues and skin rashes, suggesting that letermovir is a well-tolerated option for CMV prevention in high-risk transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir Prophylaxis for Cytomegalovirus Infection in Allogeneic Stem Cell Transplantation: A Real-World Experience. Martino, M., Pitino, A., Gori, M., et al.[2021]

In a phase III trial, letermovir significantly reduced the rate of clinically significant CMV infection in adult CMV-seropositive patients after hematopoietic stem cell transplantation, demonstrating its efficacy as a prophylactic treatment.

The study found no significant relationship between letermovir exposure and the incidence of adverse events or the timing of CMV infection onset, supporting the current dosing recommendations for the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure-Response Analyses of Letermovir Following Oral and Intravenous Administration in Allogeneic Hematopoietic Cell Transplantation Recipients. Prohn, M., Cho, CR., Viberg, 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, 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]

References

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

Letermovir: First Global Approval. [2019]

2. 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]

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

Fast breakthrough of resistant cytomegalovirus during secondary letermovir prophylaxis in a hematopoietic stem cell transplant recipient. [2020]

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

Placental transfer of Letermovir & Maribavir in the ex vivo human cotyledon perfusion model. New perspectives for in utero treatment of congenital cytomegalovirus infection. [2020]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Letermovir Prophylaxis for Cytomegalovirus Infection in Allogeneic Stem Cell Transplantation: A Real-World Experience. [2021]

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

Exposure-Response Analyses of Letermovir Following Oral and Intravenous Administration in Allogeneic Hematopoietic Cell Transplantation Recipients. [2022]

8. Greece pubmed.ncbi.nlm.nih.gov

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

9. Japan pubmed.ncbi.nlm.nih.gov

Successful Treatment with Letermovir in a Heart Transplant Recipient with UL97 Mutation Ganciclovir-Resistant Cytomegalovirus Colitis and Viremia. [2023]