MedicalResearch.com Interview with:
Roy F Chemaly, M.D., M.P.H., F.A.C.P., F.I.D.S.A
Professor, Department of Infectious Diseases,
Director, Infection Control and Employee Health, Division of Internal Medicine
Director of the clinical virology research program,Department of infectious diseases
Infection control and employee health
The University of Texas MD Anderson
MedicalResearch.com: Would you briefly explain the significance of CMV infections? What is the background for this study?
Response: Cytomegalovirus (CMV) is one of the most important causes of infectious complications following organ transplantation and is a significant cause of illness and death in patients who have undergone allogeneic hematopoietic cell transplantation (allo-HCT). For more than 20 years, we have been managing this infection and trying to develop effective strategies to control it, but to no one’s satisfaction; CMV infection is still associated with significant morbidity and mortality in this high-risk population.
Most transplant centers have adopted preemptive antiviral therapy as the strategy of choice for HCT patients.1 While anti-CMV drugs have decreased the incidence of CMV diseases, their use for prophylaxis has not been associated with improved outcomes.1
Demographic and transplant trends heighten the need for new anti-CMV agents. In the U.S, 83% of people aged 60 and older are CMV seropositive. These older patients received 8% of all hematopoietic-cell transplants in 2000-2006, a figure that jumped to 22% in 2007-2013. As Baby Boomers age, many more allogeneic transplant patients will be CMV seropositive.
Therefore, prophylactic antiviral compounds that could effectively control viral replication, and restrict some pathologic processes of CMV diseases, could potentially lessen the complications associated with CMV infection and possibly reduce all-cause mortality.
MedicalResearch.com: What are the main findings?
Response: Letermovir is a first-in-class antiviral drug that inhibits the CMV terminase complex. In this randomized Phase 3 international, multi-center study, significantly fewer patients receiving the antiviral letermovir (MK-8228, AIC246) as compared to placebo developed clinically significant CMV infection (38% vs. 61% respectively, P < .0001); fewer patients failed for other reasons. At the end of treatment, the overall failure rate was 19% in the letermovir arm and 50% in the placebo arm.
Prophylaxis with letermovir or placebo for the prevention of clinically significant CMV infection was defined as CMV disease or CMV viremia leading to preemptive treatment. The population included 495 adult CMV-seropositive allogeneic hematopoietic cell transplant recipients with undetectable plasma cytomegalovirus DNA, who started study drug by day 28 post-transplant.
Patients were randomized 2:1 to letermovir or placebo, orally or intravenously, through week 14 (day 100) post-transplant. Letermovir was dosed at 480 mg/d (or 240 mg/d if given with cyclosporine, due to drug-drug interaction). Those who developed clinically significant CMV discontinued the study drug and received anti-CMV treatment.
The primary endpoint was the proportion of subjects with clinically significant CMV through week 24 post-transplant among subjects with undetectable CMV DNA at randomization; those who discontinued the study for any reason or had missing data at week 24 were considered failures. The analysis was also performed at the end of treatment, i.e., week 14.
Of the 565 enrolled and received study drug, 31% were considered at high risk for CMV, 50% received myeloablative conditioning, 35% received antithymocyte globulin, and 60% had donors who were CMV-seropositive. Patients underwent peripheral blood or bone marrow transplant for a variety of conditions, the most common of which was acute myeloid leukemia (38%). Patients began the study drug a median of 9 days post-transplant; only 37% had engrafted prior to the start of the drug.
MedicalResearch.com: What should readers take away from your report
Response: Letermovir was highly effective at preventing CMV infection. By week 24, significantly fewer patients developed clinically significant CMV infections in the letermovir arm (38%), compared to the placebo arm (61%). Letermovir was also associated with lower all-cause mortality through Week 24 post-HCT. The drug was well tolerated – approximately 71% of patients completed 100 days of treatment, a very high proportion in this population.
MedicalResearch.com: What are the next steps in the development/testing of letermovir?
Response: 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. Merck has stated that it plans to submit regulatory applications for the approval of letermovir in the United States and European Union (EU) in 2017.
MedicalResearch.com: Is there anything else you would like to add?
Response: We are hopeful that new antivirals like letermovir may change the landscape of CMV treatment and create a paradigm shift in the prevention of CMV infection after stem cell transplant.
Disclosure: Chemaly reports receiving research grants from Chimerix, Merck and Novartis. He also has received honoraria from and served on advisory boards for Astellas, Chimerix, Merck, Novartis and Oxford Immunotec.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
Phase 3 trial outcomes demonstrate letermovir is effective as CVM prophylaxis in bone marrow transplant patients
Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.
More Medical Research Interviews on MedicalResearch.com