Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial of RG7667, a Combination Monoclonal Antibody, for Prevention of Cytomegalovirus Infection in High-Risk Kidney Transplant Recipients

Abstract

Cytomegalovirus (CMV) infection is a significant complication after kidney transplantation. We examined the ability of RG7667, a combination of two monoclonal antibodies, to prevent CMV infection in high-risk kidney transplant recipients in a randomized, double-blind, placebo-controlled trial. CMV-seronegative recipients of a kidney transplant from a CMV-seropositive donor (DϩRϪ) were randomized to receive RG7667 (n ϭ 60) or placebo (n ϭ 60) at the time of transplant and 1, 4, and 8 weeks posttransplant. Patients were monitored for CMV viremia every 1 to 2 weeks posttransplant for 24 weeks. Patients who had seroconverted (DϩRϩ) or withdrawn before dosing were excluded from the analysis (n ϭ 4). CMV viremia occurred in 27 of 59 (45.8%) patients receiving RG7667 and 35 of 57 (61.4%) patients receiving placebo (stratum-adjusted difference, 15.3%; P ϭ 0.100) within 12 weeks posttransplant and in 30 of 59 (50.8%) patients receiving RG7667 and 40 of 57 (70.2%) patients receiving placebo (stratum-adjusted difference, 19.3%; P ϭ 0.040) within 24 weeks posttransplant. Median time to CMV viremia was 139 days in patients receiving RG7667 compared to 46 days in patients receiving placebo (hazard ratio, 0.53; P ϭ 0.009). CMV disease was less common in the RG7667 than placebo group (3.4% versus 15.8%; P ϭ 0.030). Adverse events were generally balanced between treatment groups. In high-risk kidney transplant recipients, RG7667 was well tolerated, numerically reduced the incidence of CMV infection within 12 and 24 weeks posttransplant, delayed time to CMV viremia, and was associated with less CMV disease than the placebo. (This study has been registered at ClinicalTrials.gov under registration no. NCT01753167.)

The pentameric complex drives immunologically covert cell–cell transmission of wild-type human cytomegalovirus

“…The role of neutralizing antibodies in vivo remains unclear in this context. A number of studies have documented an inverse correlation between neutralization titers and intrauterine transmission (74)(75)(76)(77), and virus-specific antibodies have been shown to confer a degree of protection in animal models (78,79) and human kidney transplant recipients (80). In contrast, the administration of polyclonal human IgG containing high titers of neutralizing antibodies failed to prevent congenital infection in a randomized clinical trial (37), and a correlation between anti-gB antibody titers and protection in vaccinated transplant recipients was found to be independent of neutralization activity (81).…”

The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

“…These results highlight the typical approach of analytic vaccinology in the development of a subunit vaccine [113]. A phase 2 randomized double-blind placebo-controlled trial with a combination (RG7667) of a human mAb to gH and a humanized murine mAb to PC was recently reported to reduce HCMV infection and disease in high-risk KTR [114].…”

A First-in-Human Study To Assess the Safety and Pharmacokinetics of Monoclonal Antibodies against Human Cytomegalovirus in Healthy Volunteers

“…It is safe and well tolerated but is less effective than other antiviral therapies. Preliminary data from a combination of anti-HCMV monoclonal antibodies, showed a modest, therapeutic benefit in renal transplant recipients (3)(4)(5)(6).…”