Letermovir was highly effective in a phase 3 trial at preventing infection with cytomegalovirus, or CMV, in patients who underwent allogeneic hematopoietic cell transplantation who were CMV–seropositive at the time of transplant. Additionally, the drug was well-tolerated overall, with most side effects comparable to placebo.
CMV is a common complication of hematopoietic cell transplantation (HCT) and has been the focus of a decades-long search for an effective prophylaxis, explained Francisco Marty, MD, associate professor of medicine at Harvard Medical School and attending physician in transplant and oncology infectious diseases at Dana-Farber Cancer Institute and Brigham and Women’s Hospital.
“People who are CMV–seropositive do worse than people who are CMV–seronegative at the time of transplant,” Marty told Infectious Disease News. “So, the question has been, ‘Can these patients do better if we can provide a safe and effective primary antiviral prophylaxis?’ That has been the quest for the last 10 years with maribavir [ViroPharma/Shire], brincidofovir [Chimerix] and letermovir [AiCuris/Merck].”
Marty and colleagues compared letermovir with placebo for the prevention of clinically significant CMV (CS-CMV) infection in CMV–seropositive HCT patients aged 18 years or older who had undetectable plasma CMV DNA within 5 days of randomization.
From June 2014 to March 2016, patients were randomly assigned 2:1 to receive either 480 mg per day of letermovir — or 240 mg per day if on cyclosporine — or placebo orally or intravenously for 14 weeks after HCT. Marty and colleagues assessed the participants each week for the first 14 weeks, biweekly through week 24 and then every other month through week 48. Those who developed CS-CMV were discontinued from the study and treated for their infection.
Among 565 participants, 31% were at high risk for CMV disease, 50% received myeloablative conditioning and 35% received rabbit anti-thymocyte globulin (ATG), Marty and colleagues said. The donors included 14% mismatched unrelated, 13% haploidentical and 4% cord blood. The subjects began the study a median of 9 days after transplant, and only 37% had engrafted prior to the start of treatment.
Among 495 treated subjects with undetectable CMV DNA at randomization (the primary efficacy study population), 38% of the patients treated with letermovir developed clinically significant CMV or were considered failures by week 24 compared with 61% of patients in the placebo arm (stratum adjusted treatment difference, –23.5% (95% CI, –32.5 to –14.6; P < .0001).
The most common adverse events in each arm were graft-versus-host disease, diarrhea and nausea. The all-cause mortality was 10% in patients who received letermovir and 15% in the placebo arm.
Marty said 71% of the patients completed 100 days of treatment, a very high proportion in this population.
Marty will be presenting detailed results of the trial on Sunday, Feb. 26, in Orlando, Florida, during the late-breaking abstract session of the Tandem BMT meetings organized by the American Society of Blood and Marrow Transplantation and the Center of International Blood and Marrow Transplantation Research.
“At the clinician level, the important thing is that it was highly effective at preventing CMV reactivation or CMV disease during treatment, and that benefit persisted at week 24,” Marty said. “Not only did we prevent CMV reactivation and CMV disease, we also noticed a lower mortality in the people who received letermovir compared with those who received placebo.”
According to Merck, letermovir has been granted orphan drug status in Europe, Japan and the United States for the prevention of CMV infection and disease in at-risk populations, and the FDA has given the drug a fast-track designation in the United States.
Marty said the researchers are just finishing up some of the 48-week analyses and will probably submit to the FDA later this year. – by Gerard Gallagher
Marty FM, et al. A phase III randomized, double-blind, placebo-controlled trial of letermovir (LET) for prevention of cytomegalovirus (CMV) infection in adult CMV–seropositive recipients of allogeneic hematopoietic cell transplantation (HCT). Presented at: BMT Tandem Meetings; Feb. 22-26, 2017; Orlando, Florida.
Disclosure: Marty reports receiving research grants from Astellas, Chimerix, Merck and Shire. He has also received honoraria from Alexion, Chimerix, LFB, Merck, Roche Molecular Diagnostics, and Shire.