Pharmacokinetics and Exposure-Response Analysis of RG7667, a Combination of Two Anticytomegalovirus Monoclonal Antibodies, in a Phase 2a Randomized Trial To Prevent Cytomegalovirus Infection in High-Risk Kidney Transplant Recipients

Abstract

RG7667, a novel combination of two anticytomegalovirus (anti-CMV) monoclonal IgG1 antibodies (MCMV5322A and MCMV3068A), was designed to block CMV entry into host cells. It was developed as a potential therapy for preventing CMV infection and disease in transplant recipients. RG7667 was assessed for preventing CMV infection in a phase 2a trial with CMV-seronegative recipients of kidney transplants from CMV-seropositive donors. The patients received 4 intravenous doses of RG7667 (10 mg/kg of body weight of each antibody, n = 60) or placebo (n = 60) at the time of the transplant and at 1, 4, and 8 weeks after the transplant. Serum samples were collected for pharmacokinetic (PK) analysis and antidrug antibody (ADA) evaluation. To guide future dose selection, the relationships between RG7667 exposure and pharmacological activity were evaluated. MCMV5322A and MCMV3068A exposures were confirmed in all RG7667-treated patients. Mean clearances for MCMV5322A and MCMV3068A were 2.97 and 2.65 ml/day/kg, respectively, and the terminal half-lives of MCMV5322A and MCMV3068A were 26.9 and 27.4 days, respectively. The ADA incidence was low and was not associated with lower drug exposure. Patients with RG7667 or component antibody exposures greater than the respective median values had a lower incidence of viremia at 12 weeks and 24 weeks after transplantation and a longer delayed time to detectable CMV viremia than patients with exposures less than the median values. MCMV5322A and MCMV3068A exhibited expected IgG1 PK profiles in high-risk kidney transplant recipients, consistent with the earlier PK behavior of RG7667 in healthy subjects. Higher drug exposure was associated with better anti-CMV pharmacological activity. (This study has been registered at ClinicalTrials.gov under identifier NCT01753167.).

Keywords: RG7667; cytomegalovirus; kidney transplantation; monoclonal antibodies; pharmacokinetics.

FIG 1

Observed concentrations of MCMV5322A (A) and MCMV3068A (B) versus time in a phase 2a overlay with predictions from a simulation using a two-compartment population PK model based on phase 1 PK data. Black circles, observed phase 2a data; blue shaded areas, 95% confidence interval; gray dashed lines, median; blue dashed lines, target concentration for each antibody. The 95% confidence intervals and medians were derived on the basis of the simulated concentrations for 1,000 subjects.

FIG 2

MCMV5322A (A) and MCMV3068A (B) serum concentration-time profiles for ADA-positive patients (red lines) and ADA-negative patients (black lines).

FIG 3

Incidence of viremia (viral load ≥ 150 copies/ml [137 IU/ml]) at 12 weeks (primary efficacy endpoint) (A) and 24 weeks (secondary efficacy endpoint) (B) posttransplantation stratified by the median C_{min_wk_12} of either or both antibodies.

FIG 4

Time to detectable CMV viremia stratified by the median C_{min_wk_12} (A, C, E) and the median AUC_56–84 (B, D, F). (A, B) MCMV5322A; (C, D) MCMV3068A; (E, F) RG7667.