The recent first global approval of letermovir has been reviewed in detail in the First Global Approval report in Adis’ journal Drugs[1], based on the development milestones tracked in AdisInsight[2].

In early November 2017, letermovir (Prevymis™), developed by Merck & Co., Inc., under a global license from AiCuris Anti-infective Cures GmbH, received its first global approval in North America (Canada on the 1st of the month[1], then USA on the 8th [3]). These approvals were followed immediately (9th of the month) by a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP)[4]. In all regions letermovir was approved for the prophylaxis of Cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic haematopoietic stem cell transplant (HSCT). [1]

Letermovir is dispensed as once-daily oral tablets, and as a solution for intravenous infusion. It is a potent inhibitor of the CMV DNA terminase complex (pUL51, pUL56 and pUL89); this is required for the processing and packaging of viral DNA and ultimately prevents the formation of mature virions. This mechanism of action is unique and distinct from other marketed antiviral agents that also target viral DNA polymerase encoded by the CMV UL54 gene. [1]

In CMV-seropositive recipients of HSCT, the probability of developing CMV reactivation is estimated at ~80% in the absence of preventative medication. [1] In the EU it is estimated that 106,000 people are affected per year; therefore it is considered a rare disease. [4] That said, in this immune-compromised patient population, CMV reactivation can lead to serious morbidity and mortality. As medication for a rare disease, letermorvir received orphan designation from the CHMP in mid-2012. [4]

Dr. Roy Baynes, senior vice president, head of clinical development, and chief medical officer, Merck Research Laboratories stated that letermorvir was “the first new medicine for CMV infection approved in the U.S. in 15 years”.[5]

The approval of letermorvir was supported by the results of a phase III trial conducted in 570 enrolled patients from 20 countries worldwide.[6]

Dr. Francisco M. Marty, lead investigator of the trial, 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, “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.” [5]

It is thought that the novel mechanism of action of letermorvir will avoid the haematological adverse events and cross resistance associated with DNA polymerase agents. However, the prescribing information for letermorvir includes warnings relating to drug interactions with several other medications including cyclosporine, and especially those that are inhibitors of OATP1B1/3 transporters or are CYP3A substrates.[3]

Letermovir is also under regulatory review in Japan, and under phase III investigation in New Zealand, Turkey and Peru for the same indication.

For further information related to the first approval of letermorvir please visit Drugs[1], or to learn more about the overall development of letermorvir across all indications visit AdisInsight[2].

Image credit:  Antony-Xia

Leave a Reply