PGT121 is a recombinant human IgG1 mAb that targets a V3 glycan-dependent epitope region of HIV Env. PGT121 is a potent neutralizing antibody in vitro and has been shown to prevent and treat simian-human immunodeficiency virus in rhesus monkeys. Here we present safety, pharmacokinetic (PK) and antiviral efficacy data from the first-in-human phase 1 clinical trial of PGT121 conducted in the United States.
The first part of the study was a randomized, double blinded, dose escalation, placebo-controlled trial of PGT121 in adults who were HIV-uninfected (HIV-, N=20) and HIV-infected on ART (HIV+/ART+, N=15). PGT121 was given once at 3, 10, and 30 mg/kg IV and 3 mg/kg SC (N=5/group, 4:1 Ab/placebo). The second part of the study was an open label trial of PGT121 given once at 30 mg/kg IV in HIV-infected adults not on ART with high VL (3.3-4.8 log cp/ml, N=9) and low VL (2-2.6 log cp/ml, N=3). All participants were monitored for reactogenicity for 3 days and adverse events (AEs) for 56 days. PK and virologic assessments were performed through 6 months. The lower limit of quantification (LLOQ) of VL was 1.6 log cp/ml.
PGT121 was safe and well-tolerated with no related mod/severe AEs. The elimination half-life of PGT121 was ~22 days in HIV- and HIV+/ART+ groups, with variation by dose and route. In viremic HIV+ individuals not on ART, PGT121 showed antiviral efficacy in 5/9 participants in the high VL group with a median drop in VL of 1.7 log cp/ml (1.3-2.1) by d10. These individuals showed PGT121 sensitive virus at baseline but developed rebound by d28 with emergence of resistance. In the low VL group, PGT121 decreased VL to <LLOQ by d7 in 3/3 participants. Two of these individuals showed prolonged ART-free virologic suppression following 1 infusion with PGT121, with 1 individual experiencing rebound only at 6 months. The second individual’s VL is still <LLOQ at 6 months, despite PGT121 levels that have declined to <0.86 ug/ml.
In this Phase 1 study, PGT121 was safe and well-tolerated with a favorable PK profile. PGT121 led to a median 1.7 log drop in VL in viremic HIV+ participants with PGT121-sensitive virus and high VL at baseline. Surprisingly, a single infusion of PGT121 led to >5 months of viral suppression to <lower limit of quantification in 2 participants with the lowest VL at baseline. Follow up is ongoing to determine PGT121-induced changes to host immunity, as well as the ultimate duration of ART-free virologic remission in suppressed participants.