First-In-Human, Randomized, Placebo-Controlled, SAD and MAD Trial to Evaluate Safety, Tolerability, and PK/PD...

BK polyomavirus (BKPyV) affects 10%-30% of kidney-transplant recipients receiving immunosuppressive therapy, potentially leading to nephropathy, graft dysfunction, graft loss, and increased mortality. Despite the medical need, no targeted therapies exist. This first-in-human trial evaluated the safety, tolerability, pharmacokinetics, and immunogenicity of potravitug, a novel fully human antibody against BKPyV. This partially randomized, single-blinded, and placebo-controlled trial enrolled 40 healthy participants randomized (3:1) to receive either single or multiple ascending doses (SAD/MAD) of potravitug or placebo intravenously. In the SAD phase, 16 participants were enrolled in 4 cohorts (n = 4 each) with escalating doses of 100, 500, 1000, and 2000 mg. In the MAD phase, 24 participants were enrolled in 3 consecutive cohorts (n = 8 each) with escalating doses of 500, 1000, and 2000 mg administered four times at four-week intervals. The primary outcome was incidence, frequency, and severity of treatment-emergent adverse events (TEAEs). Secondary outcomes included pharmacokinetic parameters and incidence of anti-drug antibodies. The ex vivo neutralization capacity was an exploratory pharmacodynamic outcome. In SAD cohorts, 17 TEAEs occurred in 7 (58.3%) active and 3 in 2 (50.0%) placebo recipients. In MAD cohorts, 49 TEAEs occurred in 13 (72.2%) active and 21 in 5 (83.3%) placebo recipients. No dose-limiting toxicities or anti-drug antibodies were detected, indicating a favorable safety profile. Dose-proportional increases in C_max and AUC, with a half-life characteristic of monoclonal antibodies, were observed. Based on pharmacokinetic-pharmacodynamic modeling, a 1000 mg intravenous dose administered four times at four-week intervals is expected to maintain sufficient drug concentrations and receptor occupancy of VP1 (BKPyV major capsid protein) in both the blood and kidney for at least 1 year.