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 (D+R−) were randomized to receive RG7667 (n = 60) or placebo (n = 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 Patients who had seroconverted (D+R+) or withdrawn before dosing were excluded from the analysis (n = 4).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 = 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 = 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 = 0.009). CMV disease was less common in the RG7667 than placebo group (3.4% versus 15.8%; P = 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.)
INTRODUCTION
Cytomegalovirus (CMV) is a significant cause of morbidity and mortality in immunocompromised individuals, including solid-organ transplant (SOT) and hematopoietic stem cell transplant recipients (1). While prophylactic antiviral medication has decreased the incidence of CMV infection and disease in the early posttransplant period (2–4), these agents have clinically significant toxicities (5). Furthermore, late-onset CMV disease, which is associated with allograft failure and mortality (6–8), has been increasingly recognized as an important complication (9).
Kidneys are the most commonly transplanted solid organs (10), and CMV-seronegative recipients from a CMV-seropositive donor (D+R−) are the subgroup at highest risk for CMV infection and disease (11). CMV intravenous immunoglobulin (CMV-IVIG) decreases the incidence of CMV disease in D+R− kidney transplant recipients (12) and has been approved for prevention of CMV disease in SOT and kidney transplant recipients by U.S. and Canadian regulatory agencies, respectively (13, 14). However, prophylactic use of CMV-IVIG is uncommon (15, 16), likely due to the availability of oral antivirals and cost (17–19).
Compared to polyclonal antibody preparations and small-molecule antivirals, a monoclonal antibody-based therapy may offer several advantages, including higher target specificity, the potential for greater potency with the ability to administer higher doses of antibody, and lower toxicity (17, 20, 21). RG7667 is a combination of two monoclonal antibodies (MCMV5322A and MCMV3068A) that binds two distinct antigens on the surface of CMV and inhibits its entry into relevant host cells (21). In a phase 1 study, RG7667 was safe and well tolerated in healthy adults (21). This phase 2 trial evaluates the safety and activity of RG7667 for the prevention of CMV infection in D+R− kidney transplant recipients.
(This study was presented in part as an oral presentation at the Interscience Conference on Antimicrobial Agents and Chemotherapy [ICAAC]/International Congress of Chemotherapy and Infection [ICC], San Diego, CA, 17 to 21 September 2015 [22].)
RESULTS
Study population.Of the 120 patients randomized to receive study drug, 116 patients were included in the modified intention-to-treat (mITT) population (59 RG7667, 57 placebo) (Fig. 1). One hundred eighteen patients were included in the safety population (60 RG7667, 58 placebo), and 98 patients completed the study (48 RG7667, 50 placebo).
Screening, randomization, and follow-up of patients. D+R+, CMV-seropositive recipient of kidney transplant from CMV-seropositive donor; mITT, modified intention to treat.
The majority of patients were male (70%) and white (81.7%). Patients randomized to receive RG7667 and placebo were similar in terms of their baseline age, sex, race, ethnicity, weight, height, region, induction immunosuppression, and donor type (Table 1). The RG7667 group had a higher proportion of glomerulonephritis and a lower proportion of polycystic kidney disease as the reason for transplant. There was a higher proportion with two HLA-DR mismatches and a lower proportion with one HLA-DR mismatch in the RG7667 than the placebo group.
Participant characteristics
Efficacy.The proportion of patients exhibiting the primary endpoint of CMV viremia within 12 weeks posttransplant was lower in the RG7667 group (27 of 59 [45.8%]) than in the placebo group (35 of 57 [61.4%]) (Table 2). However, the stratum-adjusted difference (15.3%) was not significant at the unadjusted 5% level of significance (95% confidence interval [CI], −2.8% to 32.2%; P = 0.100). The primary endpoint was also observed less frequently in the RG7667 than the placebo group within subgroups stratified by region and induction immunosuppression (see Table S1 in the supplemental material). CMV viremia within 24 weeks posttransplant occurred significantly less frequently in the RG7667 (30 of 59 [50.8%]) than placebo (40 of 57 [70.2%]) group (stratum-adjusted difference, 19.3%; 95% CI, 1.4% to 35.6%; P = 0.040).
Efficacy endpoints
The median time to CMV viremia was significantly delayed in patients receiving RG7667 compared to placebo (139 versus 46 days; hazard ratio, 0.53 relative to placebo group; 95% CI, 0.33 to 0.86; P = 0.009) (Table 2 and Fig. 2). Delayed median time to CMV viremia in the RG7667 group compared with the placebo was also observed in subgroups stratified by region and induction immunosuppression (Table S2). Among those with a detectable viral load, the median viral load at initial detection was 342 copies/ml (311 IU/ml) in the RG7667 group and 1,051 copies/ml (956 IU/ml) in the placebo group. The median peak viral load was 2,965 copies/ml (2,698 IU/ml) in the RG7667 group and 6,397 copies/ml (5,821 IU/ml) in the placebo group. Receipt of preemptive anti-CMV therapy within 12 and 24 weeks posttransplant in the RG7667 (29 of 59 [49.2%] and 32 of 59 [54.2%], respectively) and placebo (36 of 57 [63.2%] and 40 of 57 [70.2%], respectively) groups closely mirrored the incidence of CMV viremia (Table 2)