Letermovir Found to Reduce Clinically Significant CMV infection in HCT Patients

Letermovir found to prevent clinically significant CMV infection in HCT patients with CMV DNA when compared to placebo in recent phase 3 trial.

Cytomegalovirus (CMV) remains one of the most important complications after allogeneic hematopoietic stem cell transplantation (HCT). It can cause multiorgan disease in recipients of stem cell transplants, including pneumonia, hepatitis, gastroenteritis, retinitis, and encephalitis, and the disease can develop both early and late after the transplantation procedure.

Letermovir is an antiviral agent that inhibits CMV replication by binding to components of the terminase complex. Letermovir was developed in an area of need for effective antiviral agents that can be safely prescribed prophylactically after HCT.

Previously, a phase 3 trial evaluated letermovir in hematopoietic-cell transplantation (HCT) recipients and found at week 14, the prophylaxis was effective in preventing clinically significant CMV infections. Clinically significant CMV was defined as requiring antiviral preemptive therapy or having CMV disease. The trial also reported a favorable safety profile that was associated with lower all-cause mortality by week 24 compared to placebo.

Now, in an Oral Abstract Session at ID Week 2018 held this year in San Francisco, California, Francisco Marty, MD, associate professor of medicine at the Dana-Farber Cancer Institute, presented findings from the trial that evaluated letermovir prophylaxis for CMV-seropositive HCT recipients, with a focus on the outcomes of patients with detectable CMV DNA at randomization that had been excluded from the trial’s efficacy analyses.

In an exclusive interview with Contagion® Dr. Marty discussed the study as well as how CMV research is being conducted and how letermovir is used in the HCT recipient patient population (see video).

For the study, Dr. Marty and colleagues compared patients who were randomized 2:1 and were treated with letermovir or placebo who had detectable CMV DNA at randomization (70) to patients with undetectable CMV DNA (495), the primary efficacy population of the trial.

The investigators analyzed the incidence of clinically significant CMV infection, CMV viral load kinetics, and mortality. CMV viral load was 150 c/mL in 63 patients (range, 150-716) of the 70 patients with detectable CMV DNA at point of randomization (48 LET, 22 PBO). All of the patients had undetectable CMV viral load ≤5 days before randomization.

The findings indicate that the median drug exposure was 70 days (range, 1-113) in the letermovir group and 14 days (range, 7-99) in the placebo group. By week 14, clinically significant CMV infection occurred in 15 (31.3%) letermovir-treated patients and 17 (77.3%) in the placebo patients. Further, clinically significant CMV infection with imputed events were 22 (45.8%) in the letermovir group and 20 (90.9%) in the placebo group (difference —44.8%; 95% CI, –64.7% to –24.8%; p<.0001).

The baseline characteristics in this population were similar to the primary efficacy population, with the exception of patients with myeloablative conditioning (62.9% vs. 48.3%) and more median time following HCT to beginning letermovir drug (15 days vs. 8 days).

Median CMV virologic load at time of preemptive therapy was 413 c/mL (range, 150-31,847) and was reportedly similar between the 2 groups. Eight patients had quantifiable CMV virologic load (range, 171-1,728 c/mL) 1 week following start of the study drug; 6 did not receive preemptive therapy (5 LET [10.4%], 1 PBO [4.5%]).

For patients with detectable CMV DNA at randomization, the event rate for cause of mortality at week 24 was 15% in the letermovir group and 18.2% in the placebo group [95% confidence interval (CI) 4.8% to 25.3% and 2.1% to 34.3%, respectively]. HCT week 48 rates were 26.5% and 40.9% ([95% CI, 13.6%-38.5%] and [95% CI, 20.4% to 61.5%]), respectively.

The investigators conclude that letermovir prevented clinically significant CMV infection compared to placebo in patients with detectable CMV DNA at the point of randomization.

Dr. Marty also spoke with Contagion® about the versatility of letermovir—which can be administered intravenously or taken as an oral pill—and highlighted future research that will evaluate the treatment for other indications. (see video).

“The drug is available both as an IV and as an oral pill and for patients who cannot take a pill it is good to start with the IV,” Dr. Marty said, “The bioavailability of the oral medication is slower than the IV, so one thing that we’ve been doing is, for patients who start early after transplant in the hospital, we start them with IV for a few days to make sure they get to a steady state level quickly, and then we switch them to oral a few days later, to minimize any risks.”

Dr. Marty also indicated that letermovir is currently being evaluated in kidney transplant recipients and in the future there will be a pediatric development for children who received transplants.

Disclosures

F. M. Marty, Merck: Consultant and Investigator, Consulting fee, Research support, and Speaker honorarium. Astellas: Consultant and Investigator, Consulting fee and Research support. Chimerix: Consultant and Investigator, Consulting fee and Research support. Fate Therapeutics: Consultant, Consulting fee. GlaxoSmithKline: Consultant, Consulting fee. LFB: Consultant, Consulting fee. Roche Molecular Diagnostics: Consultant, Consulting fee. Shire: Consultant and Investigator, Consulting fee and Research support. Cidara: Investigator, Research support. Ansun: Investigator, Research support. Gilead: Investigator, Research support. WHISCON: Investigator, Research support; P. Ljungman, Merck: Investigator, Research support. AiCuris: Consultant, Consulting fee. Astellas: Investigator, Research support. Oxford Immunotec: Consultant and Investigator, Consulting fee and Research support; R. F. Chemaly, Merck: Consultant and Investigator, Consulting fee and Research support. Chimerix: Consultant and Investigator, Consulting fee and Research support. Astellas: Consultant, Consulting fee. Novartis: Investigator, Research support. Oxford Immunotec: Consultant, Consulting fee; H. Wan, Merck: Employee and Shareholder, Salary; V. L. Teal, Merck: Employee and Shareholder, Salary; J. Butterton, Merck: Employee and Shareholder, Salary; W. W. Yeh, Merck: Employee and Shareholder, Salary; R. Y. Leavitt, Merck: Employee and Shareholder, Salary; C. Badshah, Merck: Employee and Shareholder, Salary.