Triplex is a broadly-recognized, multi-antigen vaccine engineered to induce a virus-specific T-cell response to control CMV in recipients of allogeneic hematopoietic stem cell transplant (“HSCT”) and solid organ transplant (“SOT”) recipients. To our knowledge, Triplex is the only vaccine in clinical development incorporating a recombinant viral vector with genes expressing three immuno-dominant proteins linked to CMV in the post-transplant setting [e.g., UL83 (pp65), UL123 (IE1), UL122 (IE2)]. The vaccine comprises the Modified Vaccinia Ankara (MVA) vector, which has been dosed safely in over 120,000 patients (young and old) and has been shown to be prolifically expressed and highly immunogenic. A recent study further demonstrated that use of MVA was safe in HSCT recipients (for more information, see http://www.ncbi.nlm.nih.gov/pubmed/23482644). Triplex is being developed for control of CMV in allogeneic HSCT and SOT recipients. Triplex was recently investigated in a Phase 1b dose-escalation study in 24 healthy volunteers at three dosing levels conducted at a single site, City of Hope National Medical Center in Duarte California. Patients received two intermuscular injections of Triplex vaccine four weeks apart starting on Day 28 after transplant. The study demonstrated that Triplex is both safe and highly immunogenic, inducing robust expansion of CD4+ and CD8+ T-cells specific for each immuno-dominant CMV protein. More specifically, healthy volunteers receiving Triplex showed robust and durable post-vaccination increases in CMV pp65-, IE1- and IE2-specific T-cells. CMV-specific T-cell responses were particularly pronounced in CMV-seropositive healthy volunteers with low pre-vaccination levels of CMV-specific T-cells. The results of the Triplex Phase 1b study were accepted for poster presentation at the 2015 Annual Meeting of the American Society of Hematologists (“ASH”) (see abstract https://ash.confex.com/ash/2015/webprogram/Paper81450.html; and published in Blood, see http://www.bloodjournal.org/content/126/23/3108?sso-checked=true.).
Based on the encouraging safety and immunogenicity data generated in the aforementioned Phase 1b, Helocyte commenced a multi-center, randomized (1:1), double-blinded, placebo-controlled Phase 2 study of Triplex in 102 HSCT CMV-seropositive recipients with matched related and unrelated donors who received at least the first of two intermuscular injections (on Days 28 and 56 respectively). The Phase 2 trial was conducted at three major U.S.-based cancer centers: City of Hope National Medical Center, Dana-Farber Cancer Institute and MD Anderson Cancer Center. The primary endpoints in the study were safety and reduction in “CMV Events” through Day 100. The protocol defines a “CMV Event” as: CMV viremia, initiation of preemptive antiviral therapy; and/or evidence of CMV disease. Secondary analyses include CMV-specific T-cell response, duration of viremia, time on antivirals, graft versus host disease and relapse-free survival. The Phase 2 study was supported by grants from the National Cancer Institute. For more information regarding the Phase 2 study of Triplex in Recipients of Allogeneic HSCT, see https://clinicaltrials.gov/ct2/show/NCT02506933?term=triplex+cmv&rank=1.
The Phase 2 clinical trial evaluating the vaccine in allogeneic hematopoietic stem cell transplant (“HSCT”) recipients with matched related and unrelated donors concluded in 4Q 2018. The study met its primary endpoint of reduction in CMV Events through day 100.
An independent data monitoring committee confirmed that Triplex was safe and well tolerated with no significant difference in adverse events between arms. Further, Triplex had no adverse impact on any transplant-related outcome (such as GvHD, relapse and survival). In the trial, subjects who received at least one injection of Triplex on day 28 after HSCT were observed to have 50% fewer CMV Events through day 100 than those who received placebo. There were five subjects with CMV events in the vaccine arm versus 10 in the placebo arm (p=0.08). The trial was designed to have 90% power at a one-sided significance level of 0.10 based on the Cox proportional-hazard model (time-to-event analysis). Thus, the trial exceeded the pre-specified, one-sided 0.10 standard for positivity, deemed appropriate for an initial Phase 2 study.
The Triplex Phase 2 trial results were presented orally at the 45th Annual Meeting of the European Society for Blood and Marrow Transplantation in March 2019. Additional information, including the presentation abstract, “Multi-antigen vaccine (triplex) based on attenuated poxvirus prevents cytomegalovirus viremia in a multi-center placebo-controlled, double blinded, randomized phase 2 clinical trial in allogeneic HCT recipients,” can be accessed at: https://www.professionalabstracts.com/ebmt2019/iplanner/#/session/132.
Triplex is currently the subject of multiple ongoing and planned studies, including one involving vaccination of the donor (followed by the recipient) in higher-risk stem cell transplant patients, potentially introducing CMV immunity sooner and positioning Triplex ahead of prophylactic antivirals in the standard of care.