Safety, tolerability, pharmacokinetics, and pharmacodynamics of VIS649 (sibeprenlimab), an APRIL-neutralizing IgG2 monoclonal antibody, in healthy volunteers
Barratt, Jonathan
Barratt, Jonathan
Abstract
Introduction: VIS649 (sibeprenlimab), a humanized IgG2 monoclonal antibody that inhibits APRIL, is being developed as a potential treatment for IgA nephropathy (IgAN). This phase 1, first-in-human, randomized, double-blind, single ascending dose study aimed to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of VIS649 in healthy adults.
Methods: Participants were randomized to VIS649 (sequential i.v. dosing cohorts: 0.5, 2.0, 6.0, 12.0 mg/kg) or placebo; a further cohort received VIS649 6.0 mg/kg or placebo followed by a tetanus/diphtheria vaccine challenge.
Results: A total of 51 participants were randomized, dosed, and analyzed for safety (7 for each VIS649 dose; 8 for placebo; 10 for VIS649 + vaccine; 5 for placebo + vaccine). There were no serious adverse events (AEs) or AEs leading to study discontinuation. VIS649 had nonlinear PK: half-life increased with dose and drug exposure increased in a greater than dose-proportional manner. Serum APRIL, IgA, galactose-deficient (Gd) IgA1, IgG, and IgM were reversibly suppressed in a dose-dependent manner, with a dose-response in time to recovery. Tetanus and diphtheria serum IgG titers increased after recall vaccination.
Conclusion: VIS649 was safe, well tolerated, and reversibly suppressed APRIL and various immunoglobulins, without loss of antigen-specific vaccination response. Further clinical development of VIS649 for IgAN is warranted. Trial registration: ClinicalTrials.gov: NCT03719443.
MIDER Authors
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Date
2022-02-07
Type
Article
Subject
APRIL, IgA nephropathy, Clinical trial, Galactose-deficient IgA, Glomerulonephritis, Monoclonal antibody
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Citation
Mathur, M., Barratt, J., Suzuki, Y., Engler, F., Pasetti, M. F., Yarbrough, J., Sloan, S., & Oldach, D. (2022). Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VIS649 (Sibeprenlimab), an APRIL-Neutralizing IgG2 Monoclonal Antibody, in Healthy Volunteers. Kidney international reports, 7(5), 993–1003. https://doi.org/10.1016/j.ekir.2022.01.1073