ORLANDO – A first-in-class antiviral drug was safe and effective when used to prevent clinically significant cytomegalovirus infections in adults undergoing hematopoietic cell transplantation.

At 24 weeks post-transplant, 38% (122/325) of those receiving the novel antiviral letermovir were considered treatment failures, compared with 61% (103/170) of those receiving placebo (P less than .0001). All-cause mortality was 10% (n=32/325) for patients receiving letermovir and 16%, (n=27/170) for the placebo group (log rank two-sided P = 0.0317).

Cytomegalovirus (CMV) particles glowing through the use of an immunofluorescent technique, magnified at 25X.

The placebo group’s results began to diverge by study week 4, and their clinically significant cytomegalovirus (CMV) rates neared 40% by week 10. In those receiving letermovir, fewer than 10% had clinically significant CMV rates at week 10.

The study findings show that “we [can] prevent patients from getting CMV infections from the beginning of the transplant and that [result can] confer a mortality benefit,” lead author Francisco Marty, MD, said in an interview.

“By preventing cytomegalovirus infection early on, we may be able to offset mortality conferred by CMV seropositivity over the long term,” Dr. Marty added. “This has been a quest of nearly 30 years’ duration, and now, for the first time, we have a drug that’s effective and rather safe to prevent CMV infection after bone marrow transplantation. We may finally be able to tackle the disadvantage that CMV-infected bone marrow transplant recipients have experienced.”

Dr. Marty said that letermovir has received fast-track status both from the Food and Drug Administration and from the European Medicines Agency.

HCT recipients who are CMV-positive but who do not have clinically significant disease are not preemptively treated in current practice. “Previously, there wasn’t a primary prevention strategy in bone marrow transplantation. When myelosuppressive drugs were tried such as ganciclovir, any benefit was offset by increased myelosuppression, with resulting increases in bacterial and fungal infections,” said Dr. Marty, professor of medicine at Harvard Medical School, Boston.

Letermovir was generally well-tolerated in the clinical trial; myelotoxicity and nephrotoxicity levels were comparable in patients receiving letermovir and placebo. Letermovir targets the terminase complex, which is a viral replication process specific to CMV and not otherwise present in humans. That fact may explain, in part, letermovir’s limited toxicity, Dr. Marty said. The primary outcome measure of the phase III randomized, double-blind, placebo-controlled trial was the stratum-adjusted proportion of patients who had clinically significant CMV at post-transplant week 24, examining only the patients in the trials who had no detectable CMV DNA at the time of randomization. If patients did not complete the study, or had missing data at week 24, they were considered to have failed the trial.

Overall, 31% of patients were considered at high risk for CMV disease. Half of the patients received myeloablative conditioning, and about a third (35%) received antithymocyte globulin. Donor sources, whose characteristics were balanced between study arms, included 14% mismatched unrelated donors, 13% haploidentical donors, and 4% cord blood.

The multinational study’s 24-week results were presented at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation.

“This was an international study, conducted at multiple sites in multiple countries. We used two-to-one randomization, and stratified participants by their risk of CMV disease and by study sites. We wanted to make sure the groups were balanced by disease risk and by study sites, to account for regional variations in bone marrow transplant procedures and CMV treatment patterns,” said Dr. Marty.

For the study, clinically significant CMV infection was defined as either CMV disease, such as pneumonia, colitis, or hepatitis, or CMV viremia that would trigger preemptive treatment.

Letermovir, which can be administered orally or intravenously, was dosed at 480 mg per day. Because of the risk for a drug-drug interaction, patients on cyclosporine received 240 mg of letermovir per day. Having intravenous dosing as an option helped patients who were not tolerating oral intake to stay on the study drug during the post-transplant period, he said.

The study drug was begun a median of 9 days post-transplant. Some patients received letermovir or placebo as early as the day of transplant; all patients began the study drug by 28 days post-transplant. The study drug was continued through week 14, or until at least 100 days post-transplant. Overall, 37% of patients had engrafted at the time they began the study drug.

Patients had weekly serum CMV assays performed until week 14, with biweekly sampling done through week 24. If patients developed clinically significant CMV, or if their serum samples yielded CMV DNA warranting preemptive treatment, they discontinued the study drug and began treatment for CMV.

The safety analysis, which was carried through week 48, tracked adverse events from the first dose of study drug until 14 days after discontinuation. Adverse events that were more common with letermovir than placebo included vomiting (19% versus 14%), edema (15% versus 9%), atrial arrhythmias (10% versus 5%), and having alanine aspartate levels more than five times the upper limit of normal (4% versus 2%). Graft versus host disease occurred in 39% of patients in each group; diarrhea and nausea occurred in approximately one fourth of patients in each group.

In response to a question after the presentation, Dr. Marty said, “The higher the risk of CMV disease, the higher the benefit in terms of survival.” Answering another question, about who should receive letermovir. Dr. Marty replied, “Like acyclovir, we should give it during times of risk. And CMV risk is different for different populations. It’s a matter of managing risks and benefits.”

Though letermovir was safe and well-tolerated in this trial, it’s different from acyclovir in that “it’s not a one dollar a day drug,” Dr. Marty acknowledged.

Merck, which plans to market letermovir, was the sponsor of the study and plans to submit applications for approval in both the United States and in the European Union in 2017. Dr. Marty reported receiving research grants from Merck as well as Astellas, Chimerix, and Shire. Additionally, he has received honoraria from Alexion, Chimerix, LFB, Merck, Roche Molecular Diagnostics, and Shire.

This article was updated 2/27/17.

koakes@frontlinemedcom.com

On Twitter @karioakes

Fewer post-transplant CMV infections with novel antiviral prophylaxis