Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VIS649 (Sibeprenlimab), an APRIL-Neutralizing IgG2 Monoclonal Antibody, in Healthy Volunteers

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.

Keywords: APRIL; IgA nephropathy; clinical trial; galactose-deficient IgA; glomerulonephritis; monoclonal antibody.

Graphical abstract

Figure 1

Participant disposition. ^a1 participant lost to follow-up, 1 participant withdrew. ^b1 participant lost to follow-up. PD, pharmacodynamics; PK, pharmacokinetics.

Figure 2

Mean serum VIS649 concentration over time after a single i.v. dose (pharmacokinetics sample). Values below LLQ (0.1 μg/ml) were imputed as the LLQ. LLQ, lower limit of quantification.

Figure 3

Mean percentage change from baseline and absolute serum concentration for (a) IgA, (b) IgG, (c) IgM, and (d) Gd-IgA₁, by treatment (pharmacodynamics sample). Normal ranges: IgA, 66–433 mg/dl; IgG, 635–1741 mg/dl; IgM, 45–281 mg/dl. Lower limit of quantification for Gd-IgA₁, 0.5 μg/ml. Gd, galactose-deficient.

Figure 4

Median (IQR) percentage change from baseline in serum (a) APRIL concentration and (b) BAFF concentration, by treatment (pharmacodynamics sample). BAFF, B cell activating factor; IQR, interquartile range.

Figure 5

(a) Tetanus and (b) diphtheria IgG titer levels (vaccinated safety sample). Vaccine administered at the week 4 visit (week 4 titers were prevaccination). Lower limit of quantification for diphtheria IgG, 0.1 IU/ml. ULQ for tetanus IgG, 16.0 IU/ml; for diphtheria IgG, 2.00 IU/ml. ULQ, upper limit of quantification.