Regulatory Decision Summary for Prevymis
The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.
Antivirals for systemic use
Type of Submission:
Supplement to a New Drug Submission
Authorized; issued a Notice of Compliance in accordance with the Food and Drug Regulations
What was the purpose of this submission?
This Supplemental New Drug Submission (SNDS) for Prevymis was filed to obtain market authorization seeking a new indication for the prophylaxis of cytomegalovirus (CMV) disease in adult kidney transplant recipients who are at risk. Upon review of the data submitted, the indication for the prophylaxis of CMV disease in adult kidney transplant recipients who are at high risk (donor CMV seropositive [D+]/recipient CMV seronegative [R-]) was authorized.
This SNDS was filed and approved under Priority Review Policy.
Why was the decision issued?
The results of a pivotal Phase 3 study support the use of Prevymis for the prophylaxis of cytomegalovirus (CMV) disease in adult kidney transplant recipients who are at risk. The Phase 3 pivotal study P002MK8228 (P002) was a randomized, double-blind, active comparator-controlled clinical trial to evaluate the efficacy and safety of letermovir versus valganciclovir for the prevention of human CMV in 601 adult kidney transplant recipients who are at high risk, i.e., donor CMV seropositive [D+]/recipient CMV seronegative [R-]. Patients were randomized in a 1:1 ratio within 7 days post-kidney transplant to receive either letermovir (480 mg once daily [QD] or 240 mg QD if co-administered with cyclosporine) or valganciclovir (900 mg QD) through week 28 post-transplant. Patients in the letermovir group received acyclovir 400 mg twice daily (BID) for prophylaxis of herpes simplex virus (HSV) and varicella zoster virus (VZV); patients in the valganciclovir group received a matching placebo. Study medications were initiated between Day 0 and Day 7 post-kidney transplant and continued through Week 28 (~200 days) post-transplant. A total of 589 patients, 292 in the letermovir group and 297 in the valganciclovir group, received study medication. The safety and efficacy were evaluated through week 52 post-transplant.
The primary efficacy endpoint in study P002 was the incidence of CMV disease (CMV end-organ disease or CMV syndrome, confirmed by an independent adjudication committee) through Week 52 post-transplant. The Observed Failure (OF) approach was used, where subjects who discontinued prematurely from the study for any reason or were missing data at the timepoint were not considered failures. The number of subjects who discontinued from the study before Week 52 was 32 (11.1%) in the letermovir group and 28 (9.4%) in the valganciclovir group. The number of subjects with a missing outcome in the Week 52 visit window was 24 (8.3%) in the letermovir group and 25 (8.4%) in the valganciclovir group. Based on a pre-specified non-inferiority margin of 10%, 200 days of treatment with letermovir in study P002 was non-inferior to treatment with valganciclovir for the prevention of CMV disease through week 52 post-transplant in high-risk kidney transplant recipients. A total of 30 patients (10.4%) in the letermovir group (24 patients with CMV syndrome and 6 patients with CMV end-organ disease) and 35 patients (11.8%) in the valganciclovir group (34 patients with CMV syndrome and 1 patient with CMV end-organ disease) had confirmed CMV disease (stratum-adjusted treatment difference [95% CI] of -1.4 [-6.5, 3.8]).
No patient in the letermovir treatment group had adjudicated CMV disease through week 28 post-transplant compared to 5 patients (1.4%) in the valganciclovir group. The proportion of patients with CMV DNAemia through week 52 post-transplant was lower in the letermovir group (31.8%) compared to the valganciclovir group (37.7%). No patients in study P002 developed any mutation associated with letermovir resistance that was detected at a frequency of ≥ 5%.
Administration of letermovir for 200 days post-transplant in study P002 was generally well-tolerated. The frequency of serious adverse events (SAEs) was similar for the letermovir and valganciclovir groups, i.e., 36.3% vs. 38.0%. Drug-related adverse events (AEs) and SAEs were less frequent in the letermovir group (19.9% and 1.4%, respectively) compared to the valganciclovir group (35.0% and 5.1%, respectively). The proportion of participants who discontinued study intervention due to AEs was lower in the letermovir group compared with the valganciclovir group, i.e., 4.1% vs. 13.5%. Drug-related AEs experienced by ≥2% of patients were reported by a lower proportion of participants in the letermovir group compared with the valganciclovir group and included leukopenia (6.8% vs. 22.9%), neutropenia (2.1% vs. 8.1%) and white blood cell count decreased (1.0% vs. 4.0%). Deaths occurred in 5 patients in the letermovir group and 3 patients in the valganciclovir group but they were not considered related to either study drug.
Based on the review of the evidence submitted in this SNDS, Health Canada considers that the benefit-harm-uncertainty profile of Prevymis is favorable when used for the prophylaxis of CMV disease in adult kidney transplant recipients who are at high risk (donor CMV seropositive [D+]/recipient CMV seronegative [R-]). Therefore, the proposed indication was amended to specify that Prevymis is indicated for the prophylaxis of CMV disease in adult kidney transplant recipients who are at high risk (D+/R-)
For further details about Prevymis, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.
Date of Decision:
Manufacturer / Sponsor:
Drug Identification Number(s) Issued:
Available by prescription only