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Monday, April 10, 2017

3 Questions on…Designing Drugs to Prevent CMV Infections in Patients Undergoing Bone Marrow Transplant

With Francisco M. Marty, MD, of Harvard Medical School, Dana-Farber Cancer Institute, and Brigham and Women's Hospital

By Sarah DiGiulio

Cytomegalovirus (CMV) infection is the most common viral infection in patients who undergo allogeneic hematopoietic stem cell transplant—and it is associated with higher rates of mortality, even when currently available preemptive antiviral therapies are used (Blood 2016:127;2427-2438).

But researchers have been developing a new drug they hope will be more effective in preventing CMV infection in transplant patients. New phase III trial data shows the drug—letermovir—was associated with lower all-cause mortality in patients 6 months after they had undergone stem cell transplant.

Results from the study were presented in February at the Bone Marrow Transplant Tandem Meetings (the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation) (Abstract LB2).

The study included 565 patients who underwent allogeneic stem cell transplant and were not viremic with CMV at the start of the study. The efficacy analysis included 325 patients who had undergone allogeneic hematopoietic stem cell transplant who were CMV-seropositive and received the new drug, letermovir—and 170 patients who had undergone transplant, were CMV-seropositive, and received a placebo.

The patients receiving letermovir had minimal toxicity to the drug. Significantly fewer patients developed clinically significant CMV infections (or died or left the study for other reasons) who had received letermovir (37.5%) compared with the patients who had received the placebo (60.6%). And the data found a 9.8 percent all-cause mortality rate after 6 months for the patients receiving letermovir, compared with a 15.9 percent mortality rate for patients who received the placebo.

These results show letermovir is a highly-effective drug, said study author Francisco M. 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, Boston. In an interview with Oncology Times, Marty elaborated on why this new drug and these recent findings are important.

1. Why are the results of this trial significant and what does it mean for managing patients who undergo bone marrow transplant?

"For the first time in nearly 30 years, we have a potent, reliable, and safer anti-CMV antiviral we can use to prevent CMV reactivation after transplant and protect patients when they are the most susceptible to

CMV infection. Available antivirals to date are consistently myelosuppressive or nephrotoxic.

"A primary prophylaxis strategy early after bone marrow transplantation had been attempted in previous trials, but was never implemented because any benefits were offset by the side effects of the drugs and their consequences. This trial confirmed letermovir was not myelosuppressive at all—and there was not nephrotoxicity associated with its use.

"Not only did letermovir protect patients from developing CMV infection who require preemptive treatment, but the prophylactic strategy led to lower all-cause mortality when patients were followed for 24 weeks post-transplant. So, a strategy of primary prophylaxis posttransplant seems to be better than our current standard and suggests for the first time that the survival disadvantage of patients who are CMV-seropositive at the time of transplant can be abrogated."

2. How is letermovir different than other drugs that try to prevent CMV infections?

"Mechanistically, letermovir targets a different process in the replication of CMV by blocking the activity of the terminase complex that is in charge of cutting the CMV genomes being synthesized and packaging into the preformed virus capsids.

"The current standard approach to preventing CMV disease consists of preemptive therapy in which weekly surveillance with blood CMV testing by PCR or other methods is linked to antiviral treatment against CMV. The strategy has been successful in terms of preventing clinical CMV endorgan damage, but we have confirmation from large, recent cohort studies that patients who go into bone marrow transplantation having had CMV infection pre-transplant (being CMV-seropositive) fair worse in terms of all-cause mortality compared to patients in the same circumstances who have not been infected with CMV pre-transplant (CMV-seronegative).

"Letermovir is not myelosuppressive or nephrotoxic. We did observe some mild increases over placebo (≤5%) in terms of vomiting, nausea, peripheral edema, headaches, and atrial arrhythmias, but they were rarely serious or led to discontinuation of treatment."

3. The drug is currently being submitted to the FDA for regulatory approval. Are any trials still in the works? And what else should doctors who treat patients who undergo stem cell transplant know about the drug?

"There will be a comparative trial of prophylaxis in patients undergoing certain solid organ transplants to further assess the benefits of letermovir in other transplant populations. I hope the drug can be tested soon in children who undergo transplantation and in children affected by CMV early in life.

"This phase III trial demonstrates that letermovir is a highly-effective prophylaxis in the prevention of CMV reactivation after HCT in patients who are CMV-seropositive and had an overall favorable safety profile. The treatment differences were more pronounced in most patients at higher risk of CMV disease and associated with a lower all-cause mortality suggesting that for the first time we may be able to better tame the 'troll of transplantation' in this patient population."​