Merck PREVYMIS bags USFDA nod for cytomegalovirus disease prevention in high-risk adult kidney transplant recipients

PREVYMIS is an antiviral agent that was initially approved by the FDA in 2017 for prophylaxis of CMV infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). PREVYMIS is administered once-daily as an oral tablet or as an injection for intravenous infusion.

PREVYMIS is contraindicated in patients receiving pimozide or ergot alkaloids. Increased pimozide concentrations due to concomitant administration of PREVYMIS may lead to QT prolongation and torsades de pointes. Increased ergot alkaloids concentrations due to concomitant administration of PREVYMIS 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 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," the company stated.

“PREVYMIS has been an important addition to the care of high-risk adult CMV-seropositive patients who have received allogeneic stem cell transplants to help prevent CMV infection and disease. We are delighted that PREVYMIS is now approved to help prevent CMV disease in adult kidney transplant patients at high risk,” said Dr. Elizabeth Rhee, vice president, global clinical development, Merck Research Laboratories. “At Merck, we are proud to continue to bring innovative medicines to people to address serious infectious diseases.”

The FDA approval of PREVYMIS for CMV disease prophylaxis in adult kidney transplant recipients was supported by a Phase 3, randomized, multicenter, double-blind, active comparator-controlled non-inferiority trial (P002, NCT03443869) in 589 adult kidney transplant recipients at high risk (CMV D+/R-). Participants were randomized (1:1) to receive either PREVYMIS concomitantly with acyclovir (n=292), or valganciclovir concomitantly with a placebo to acyclovir (n=297). Study drug was initiated between Day 0 and Day 7 post-kidney transplant and continued through Week 28 (~200 days) post-transplant. Study drug was administered either orally or IV; the dose of PREVYMIS was the same regardless of the route of administration. Three participants received IV PREVYMIS for a mean duration of 1.7 days. Participants were monitored through Week 52 post-transplant. The median age was 51 years (range: 18 to 82 years); 72% were male; 84% were White; 9% were Black; 3% were multiple; 2% were Asian; 1% Alaskan native or American Indian; 17% were Hispanic or Latino; and 60% received a kidney from a deceased donor. The most common primary reasons for transplant were congenital cystic kidney disease (17%), hypertension (16%), and diabetes/diabetic nephropathy (14%).

The study demonstrated that PREVYMIS was non-inferior to valganciclovir, the current standard of care, for the primary endpoint of incidence of CMV disease (CMV end-organ disease or CMV syndrome, confirmed by an independent adjudication committee) through Week 52 post-kidney transplant. The proportion of study participants with CMV disease through Week 52 post-kidney transplant was 10% with PREVYMIS and 12% with valganciclovir (stratum-adjusted treatment difference = -1.4, [95% confidence interval, -6.5, 3.8], meeting the pre-specified non-inferiority margin of 10%). The incidence of CMV syndrome (defined as evidence of CMV in blood by viral isolation, rapid culture, antigenemia, or nucleic acid testing, and two or more of the following: 1) fever ≥38°C for at least 2 days, 2) new or increased malaise/fatigue, 3) leukopenia or neutropenia on two separate measurements at least 24 hours apart, 4) ≥5% atypical lymphocytes, 5) thrombocytopenia, 6) elevation of ALT or AST to 2x the upper limit of normal) was 8% vs 11%, respectively. The incidence of CMV end organ disease was 2% vs less than 1%, respectively. For purposes of these analyses, participants who discontinued prematurely from the study for any reason or were missing data at the timepoint were not counted as failures. The number of participants who discontinued from the study before Week 52 was 32 (11%) in the PREVYMIS arm and 28 (9%) in the valganciclovir arm. The number of participants with a missing outcome in the Week 52 visit window was 24 (8%) in the PREVYMIS arm and 25 (8%) in the valganciclovir arm.

Efficacy was comparable across all subgroups. This included the subgroups that used or did not use highly cytolytic, anti-lymphocyte immunotherapy during induction, which was a stratification factor at randomization.

In an exploratory analysis of the incidence of CMV disease through Week 28 post-transplant, the difference (PREVYMIS – valganciclovir) was -1.7% with a 95% CI of (-3.4, 0.1). No subjects in the PREVYMIS group experienced CMV disease through Week 28 post-transplant (end of treatment period) compared with five subjects in the valganciclovir group.

The safety of PREVYMIS was also evaluated in the Phase 3 (P002) study.

The Phase 3 study also collected information on laboratory abnormalities reported through week 28 post-transplant. Selected laboratory abnormalities were as follows:

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