Regulatory Decision Summary for Prevymis

Health Canada considers that the benefit/risk profile of Prevymis is favourable when used as directed for the prophylaxis of cytomegalovirus (CMV) infection in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).

Prevymis contains letermovir, a novel, specific inhibitor of human cytomegalovirus (CMV) which acts by inhibiting the viral DNA terminase complex. Prevymis can be administered orally or by intravenous [IV] infusion. To support the indication for Prevymis the sponsor had submitted 28 Phase 1 trials, two Phase 2 clinical trials, and a Phase 3 trial.

The primary efficacy and safety information in support of the Prevymis for the prevention of CMV infection in adult CMV- seropositive recipients [R+] of an allogeneic HSCT was derived from a single phase 3 pivotal clinical trial. In this trial, 570 CMV-seropositive recipients (R+) of an allogeneic HSCT were randomized in a 2:1 ratio to receive either letermovir (480 mg QD or 240 mg QD if given concomitantly with cyclosporin) or matching placebo through Week 14 post-transplant. The subject could receive either an oral or IV formulation, without any dose adjustment.

A total of 565 subjects received study medication. Efficacy and safety was evaluated through Week 24 post-transplant. The primary endpoint was the proportion of subjects with clinically significant CMV infection through Week 24 post-transplant, defined as the onset of CMV end-organ disease OR initiation of anti-CMV Pre-emptive Therapy (PET) based on documented CMV viremia and the clinical condition of the subject.

Results of this study demonstrate that Prevymis is superior to placebo in prevention of clinically significant CMV infection. The incidence of clinically significant CMV infection through Week 24 post-transplant was 37.5% in the letermovir group compared to 60.6% in the placebo group (difference: -23.5%; 1-sided p-value <0.0001). Prevymis prophylaxis resulted in ~40% relative risk reduction in clinically significant CMV infections compared to placebo. Prevymis was generally well tolerated. There was no evidence of myelotoxicity, nephrotoxicity or hepatotoxicity. The most commonly reported adverse events (AEs) were Graft-versus-host disease (GVHD), nausea, vomiting, diarrhea, pyrexia and rash. The incidence of these AEs was comparable to subjects receiving placebo.

Based on the data submitted, Health Canada considers that the anticipated benefits of Prevymis outweigh the potential risks under the conditions of use described in the Prevymis Product Monograph at this time.