Mechanism of Action

Prevymis (letermovir) is a CMV DNA terminase complex inhibitor. Letermovir inhibits the CMV DNA terminase complex (pUL51, pUL56 and pUL89) which is required for viral DNA processing and packaging. Biochemical characterization and electron microscopy demonstrated that letermovir affects the production of proper unit length genomes and interferes with virion maturation. Genotypic characterization of virus resistant to letermovir confirmed that letermovir targets the terminase complex.

Side Effects

Adverse effects associated with the use of Prevymis may include, but are not limited to, the following:

Nausea

Diarrhea

Vomiting

Peripheral edema

Cough

Headache

Fatigue

Abdominal pain

Dosing/Administration

Prevymis is supplied as a tablet for oral administration and as a solution for intravenous injection. The recommended dose is 480 mg administered once daily orally or as an intravenous (IV) infusion over one hour through 100 days post-transplant. Dosage adjustment: If Prevymis is co-administered with cyclosporine, the dosage of Prevymis should be decreased to 240 mg once daily.

Clinical Trial Results

FDA Approval

The FDA approval of Prevymis is based on a multicenter, double-blind, placebo-controlled phase 3 Trial in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). Subjects were randomized to receive either Prevymis at a dose of 480 mg once daily adjusted to 240 mg when coadministered with cyclosporine, or placebo. Randomization was stratified by investigational site and risk level for CMV reactivation at the time of study entry. Study drug was initiated after HSCT (at any time from Day 0 to Day 28 post-transplant) and continued through Week 14 post-transplant. Study drug was administered either orally or intravenously; the dose of Prevymis was the same regardless of the route of administration. Subjects received CMV DNA monitoring weekly until post-transplant Week 14 and then biweekly until post-transplant Week 24, with initiation of standard-of-care CMV pre-emptive therapy if CMV viremia was considered clinically significant. The data show that significantly fewer subjects taking the drug (38 percent) compared to those given a placebo (61 percent) developed clinically significant CMV infection, discontinued treatment or had missing data through Week 24 post-HSCT. In addition, all-cause mortality in patients receiving Prevymis was lower compared to placebo at 12 percent versus 17 percent, respectively, 24 weeks post-transplant.