Merck & Co., Inc., known as MSD outside the United States and Canada, announced that the US Food and Drug Administration (FDA) has approved Prevymis (letermovir) once-daily tablets for oral use and injection for intravenous infusion.

Prevymis is indicated for prophylaxis (prevention) of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).

CMV is a common and potentially serious viral infection in allogeneic HSCT recipients. CMV-seropositive patients who undergo an HSCT are at high risk for CMV reactivation. Any level of CMV infection is associated with increased mortality in HSCT patients.

In the pivotal phase 3 clinical trial supporting approval, significantly fewer patients in the Prevymis group (38%, n=122/325) compared to the placebo group (61%, n=103/170) developed clinically significant CMV infection, discontinued treatment or had missing data through Week 24 post-HSCT [treatment difference: -23.5 (95% confidence interval -32.5 to -14.6), (p<0.0001)], the primary efficacy endpoint. All-cause mortality in patients receiving Prevymis was lower compared to placebo, 12% vs. 17%, respectively, at week 24 post-transplant. In this study, the incidence of bone marrow suppression in the Prevymis group was comparable to the placebo group. The median time to engraftment was 19 days in the Prevymis group and 18 days in the placebo group.

Prevymis is contraindicated in patients receiving pimozide or ergot alkaloids. Increased pimozide concentrations may lead to QT prolongation and torsades de pointes. Increased ergot alkaloids concentrations may lead to ergotism. Prevymis is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Significantly increased pitavastatin or simvastatin concentrations may lead to myopathy or rhabdomyolysis.

The concomitant use of Prevymis (letermovir) and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (Prevymis or concomitant drugs) or reduced therapeutic effect of Prevymis or the concomitant drug. Consider the potential for drug interactions prior to and during Prevymis therapy; review concomitant medications during Prevymis therapy; and monitor for adverse reactions associated with Prevymis and concomitant medications.

“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,” said Dr. Francisco M. Marty, 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.

The recommended dosage of Prevymis is 480 mg administered once daily, initiated as early as Day 0 and up to Day 28 post-transplantation (before or after engraftment), and continued through Day 100 post-transplantation. If Prevymis is co-administered with cyclosporine, the dosage of oral or intravenous Prevymis should be decreased to 240 mg once daily. Prevymis is available as 240 mg and 480 mg tablets, which may be administered with or without food. Prevymis is also available as 240 mg and 480 mg injection for intravenous infusion via a peripheral catheter or central venous line at a constant rate over one hour.

“Prevymis is the first new medicine for CMV infection approved in the US in 15 years,” said Dr. Roy Baynes, senior vice president, head of clinical development, and chief medical officer, Merck Research Laboratories. “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.”

Prevymis is expected to be available in December. The list price (wholesaler acquisition cost) per day for Prevymis tablets is $195.00 and for Prevymis injection is $270.00. Wholesaler acquisition costs do not include discounts that may be paid on the product.

The cardiac adverse event rate (regardless of investigator-assessed causality) was higher in patients receiving Prevymis than placebo (13% vs. 6%). The most common cardiac adverse events were tachycardia (reported in 4% Prevymis patients and 2% placebo patients) and atrial fibrillation (reported in 3% Prevymis patients and 1% placebo patients). These adverse events were reported as mild or moderate in severity. The rate of adverse events occurring in at least 10% of Prevymis-treated HSCT recipients and at a frequency at least 2% greater than placebo were nausea (27% vs. 23%), diarrhea (26% vs. 24%), vomiting (19% vs. 14%), peripheral edema (14% vs. 9%), cough (14% vs. 10%), headache (14% vs. 9%), fatigue (13% vs. 11%), and abdominal pain (12% vs. 9%). The most frequently reported adverse event that led to study drug discontinuation was nausea (occurring in 2% of Prevymis patients and 1% of placebo patients). Hypersensitivity reaction, with associated moderate dyspnea, occurred in one patient following the first infusion of IV Prevymis after switching from oral Prevymis, leading to treatment discontinuation.

To evaluate prophylaxis with Prevymis as a preventive strategy for CMV infection or disease in transplant recipients at high risk for CMV reactivation, the efficacy of Prevymis was assessed in a multicenter, double-blind, placebo-controlled Phase 3 trial in adult CMV-positive recipients [R+] of an allogeneic HSCT. Patients were randomized (2:1) to receive either Prevymis at a dose of 480 mg once daily adjusted to 240 mg when co-administered with cyclosporine, or placebo. Study drug was initiated after HSCT (at any time from Day 0-28 post-transplant) and continued through Week 14 post-transplant. Patients were monitored through Week 24 post-transplant for the primary efficacy endpoint, with continued follow-up through Week 48 post-transplant. The primary efficacy endpoint was the incidence of clinically significant CMV infection through Week 24 post-transplant, defined as the occurrence of either CMV end-organ disease, or initiation of anti-CMV pre-emptive therapy based on documented CMV viremia and the clinical condition of the patient. The Non-Completer equals Failure approach was used, where patients who discontinued from the trial prior to Week 24 post-transplant or had a missing outcome at Week 24 post-transplant were counted as failures.

Among the 565 treated patients, 34% were engrafted at baseline and 30% had one or more factors associated with additional risk for CMV reactivation. The most common primary reasons for transplant were acute myeloid leukemia (38%), myelodysplastic syndrome (16%), and lymphoma (12%).

Fewer patients in the Prevymis group had clinically significant CMV infection by Week 24 post-HSCT compared to the placebo group, 18% vs. 42%, respectively. Through the Week 14 post-HSCT treatment period, 8% of patients in the Prevymis group and 39% of patients in the placebo group experienced clinically significant CMV infection. Clinically significant CMV infection was defined as CMV end-organ disease or initiation of pre-emptive therapy based on documented CMV viremia and the clinical condition of the patient.

Prevymis is a member of a new class of non-nucleoside CMV inhibitors (3,4 dihydro-quinazolines) and inhibits viral replication by specifically targeting the viral terminase complex. Cross resistance is not likely with drugs outside of this class. Prevymis is fully active against viral populations with substitutions conferring resistance to CMV DNA polymerase inhibitors. These DNA polymerase inhibitors are fully active against viral populations with substitutions conferring resistance to Prevymis. Prevymis has no activity against other viruses. Letermovir has been granted orphan designation for the prevention of CMV disease in at-risk populations in the U.S., EU and Japan, and is under accelerated review in the EU and Japan.

Under an agreement signed in 2012, Merck (through a subsidiary) purchased worldwide rights to develop and commercialize letermovir from AiCuris GmbH & Co KG.