First‐In‐Human, Randomized, Placebo‐Controlled, SAD and MAD Trial to Evaluate Safety, Tolerability, and PK/PD Modeling of Potravitug in Healthy Adults
ABSTRACT 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...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-08-01
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| Series: | Clinical and Translational Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1111/cts.70316 |
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| Summary: | ABSTRACT 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 Cmax 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. |
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| ISSN: | 1752-8054 1752-8062 |