Letermovir Granted FDA Approval for CMV Prophylaxis After Transplant

The FDA has approved letermovir (Prevymis) to prevent cytomegalovirus (CMV) infection in adult CMV-seropositive patients treated with an allogeneic hematopoietic stem cell transplant (HSCT), based on a significant reduction in CMV infection rates in a phase III study.

In the pivotal study that led to the approval, 37.5% of patients treated with letermovir developed CMV by week 24 post-HSCT compared with 60.6% of those in the placebo arm (P<.0001). Moreover, letermovir was associated with lower all-cause mortality versus placebo at 24 weeks (12% vs 17%). The median time to engraftment and bone marrow suppression rates were similar in each group.

“Prevymis is the first new medicine for CMV infection approved in the United States in 15 years,” Roy Baynes, MD, PhD, senior vice president, head of clinical development, and chief medical officer, Merck Research Laboratories, said in a statement. “Prevymis continues Merck’s longstanding tradition of bringing forward important new therapies to address serious infectious diseases. We are proud to add this breakthrough medicine to our existing offerings for physicians and patients.”

The study randomized 495 patients with baseline undetectable plasma CMV DNA in a 2:1 ratio to receive once-daily letermovir (n = 325) or placebo (n = 170) following HSCT. An additional 70 patients were enrolled and treated but tested positive for CMV DNA at entry and were excluded from the efficacy analysis. Letermovir was administered for 100 days at 480 mg/day or 240 mg/day for those on cyclosporine. Treatment was started on the day of transplant or up to day 28 post-transplant (median, day 9).

Of those enrolled, 31% were at high-risk of CMV. Treatment included myeloablative conditioning for 50% of patients and 35% received ATG. In addition to related donors, HSCT also consisted of mismatched unrelated donors (14%), haploidentical donors (13%), and cord blood (4%).

The primary endpoint of the study was clinically significant CMV infection through week 24 post-HSCT, which was defined as the onset of CMV, initiation of anti-CMV preemptive therapy, or treatment discontinuation and initiation of anti-CMV preemptive therapy. Developed of CMV was labeled as a treatment failure. Secondary endpoints focused CMV infection at various time points and mortality.

At the 24-week assessment, which was presented at the 2017 BMT Tandem Meetings in February, there were 122 failures in the letermovir arm (37.5%), which consisted of clinically significant CMV (n = 57; 17.5%), PET for CMV (n = 52; 16%), and CMV disease (n = 5; 1.5%). In the placebo arm, failures consisted of clinically significant CMV (n = 71; 41.8%), PET for CMV (n = 68; 37.6%), CMV disease (n = 3; 1.8%), although there was some overlap in these figures. Reduction in the risk of clinically significant CMV was observed for letermovir in those at high risk (P <.0001) and low risk for CMV stratum (P <.0001).

There were 56 early discontinuations in the letermovir arm (17.2%) versus 27 in the placebo group (15.9%). Discontinuation events in the letermovir and placebo arms, respectively, were related to adverse events (1.8% vs 0.6%), death without CMV (6.8% vs 7.1%), other reasons (6.8% vs 8.2%), and missing outcomes (2.8% vs 2.9%).

The most common adverse events in the letermovir and placebo arms, respectively, were GVHD (39.1% vs 38.5%), diarrhea (26.0% vs 24.5%), and nausea (26.5% vs 23.4%). Additionally, patients experienced vomiting (18.5% vs 13.5%), peripheral edema (14.5% vs 9.4%), and cough (14.2% vs 10.4%). The most common serious adverse events were infection (20.6% vs 18.8%), GVHD (9.9% vs 10.4%), and acute kidney injury (1.3% vs 4.7%).

“Our findings demonstrate that letermovir is a significant and welcomed advance in the prevention of clinically significant CMV infection and lowers mortality in this highly vulnerable patient population,” lead investigator of the phase III studwy 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 in Boston, said in a statement.

Letermovir is a non-nucleoside CMV inhibitor that targets the viral terminase complex to prevent replication. Merck plans to make the medication available in December 2017 at a list price of $195.00 for a tablet version and $270.00 for an injection formulation.

Marty FM, Ljungman PT, Chemaly RF, 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; February 23-26, 2017; Orlando, Florida.