Summary Basis of Decision for Prevymis

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

Human cytomegalovirus (CMV) is a beta herpesvirus which is a frequent pathogen in humans and is usually associated with asymptomatic infection, followed by a state of viral persistence or latency. After allogeneic HSCT, there is a higher risk of active CMV infection specifically because of the delayed recovery of T- and B-cell functions. Recipients of allogenic HSCT are at a greater risk of infection complications because of a longer time to achieve engraftment (prolonged neutropenia) and the added risk of graft versus host disease (GVHD). Thus, the rate by which immune functions recover after hematopoietic reconstitution significantly influences the incidence of CMV infection and disease following stem cell transplantation (SCT). In a minority of CMV-seropositive patients, CMV disease can occur before engraftment, leading to a very high mortality. T-cell depletion of the graft is associated with a high rate of CMV reactivation, a rapid onset of CMV-related symptoms, and a higher rate of fatal infections that may occur during the first 30 days after SCT.

After engraftment, severe combined quantitative and functional deficiencies in the T- and B-lymphocyte compartment persist in patients with allogeneic SCT. These deficiencies manifest as disorders in helper T-cell function and immunoglobulin synthesis, but also as an impaired cytotoxic T-cell response. During this period, active CMV infection occurs in approximately 60-70% of CMV-seropositive patients or CMV-seronegative patients who receive transplants from a seropositive donor. If no preventive measures are taken, the risk of developing CMV disease equals 20-30%.

Direct clinical effects of CMV infection in HSCT recipients include a wide spectrum of CMV disease manifestations, associated with considerable morbidity and mortality. Gastroenteritis is the most common clinical presentation in HSCT recipients. Other manifestations include pneumonia, hepatitis, retinitis, and encephalitis. Active CMV infection may be accompanied by myelosuppression and fever.

Indirect clinical effects of CMV infection include an increased risk of all-cause mortality, non-relapse mortality, GVHD, and opportunistic bacterial and invasive fungal infections.

Letermovir, the medicinal ingredient in Prevymis, is a novel, specific inhibitor of human CMV. It acts by inhibiting the CMV deoxyribonucleic acid (DNA) terminase complex, which cleaves newly synthesized CMV DNA into individual viral genomes. The novel mechanism of action of letermovir is distinct from currently authorized CMV agents, which inhibit the viral DNA polymerase. In cell culture models of infection, letermovir potently inhibited laboratory and clinical CMV isolates, including several strains resistant to other anti-CMV agents, with low nanomolar values of 50% effective concentration (EC50). There is no human homologue for this process; thus, the mechanism of action of Prevymis is highly specific suggesting a limited potential for mechanism-based toxicity. There is no known cross-resistance between Prevymis and currently authorized drugs for treatment of CMV.

Prevymis has been shown to prevent CMV infection in adult CMV-seropositive recipients (R+) of an allogeneic HSCT. The market authorization of Prevymis was based on efficacy and safety data derived from one randomized, double-blind, placebo-controlled Phase III trial (P001). Supportive data stemmed from 28 Phase I trials and two Phase II clinical trials (P019 and P020).

In the Phase III trial, 570 CMV-seropositive recipients (R+) of an allogeneic HSCT were randomized in a 2:1 ratio to receive either Prevymis (480 mg once daily, or 240 mg once daily if given concomitantly with cyclosporin) or matching placebo through Week 14 post-transplant. Patients could receive either oral or intravenous formulation, without any dose adjustment. A total of 565 patients received a study medication, 373 of whom received Prevymis. Efficacy and safety was evaluated through Week 24 post-transplant. The primary efficacy 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 based on documented CMV viremia and the clinical condition of the subject. Results of this trial demonstrate that Prevymis is superior to placebo in prevention of clinically significant CMV infection. Prophylaxis with Prevymis resulted in an approximately 40% relative risk reduction in clinically significant CMV infection compared to placebo. Prevymis was generally well tolerated. There was no evidence of myelotoxicity, nephrotoxicity or hepatotoxicity. The most commonly reported adverse events were GVHD, nausea, vomiting, diarrhea, pyrexia and rash. The incidence of these adverse events was comparable to the placebo group.

The concomitant use of Prevymis and certain drugs may result in known or potentially significant drug interactions, some of which may lead to: possible clinically significant adverse reactions from greater exposure of concomitant drugs or Prevymis; or significant decrease of concomitant drug plasma concentrations which may lead to reduced therapeutic effect of the concomitant drug. Therefore, appropriate contraindications and a Serious Drug Interactions box are included in the Prevymis Product Monograph. In addition, the Prevymis Product Monograph lists established or potentially significant drug interactions with recommendations for close monitoring and/or dose adjustments.

A Risk Management Plan (RMP) for Prevymis was submitted by Merck Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Prevymis was accepted.

Prevymis has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Prevymis Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.