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dc.contributor.authorMathur, Mohit
dc.contributor.authorBarratt, Jonathan
dc.contributor.authorSuzuki, Yusuke
dc.contributor.authorEngler, Frank
dc.contributor.authorPasetti, Marcela F.
dc.contributor.authorYarbrough, Jill
dc.contributor.authorSloan, Susan
dc.contributor.authorOldach, David
dc.date.accessioned2022-03-17T11:51:03Z
dc.date.available2022-03-17T11:51:03Z
dc.date.issued2022-01-01
dc.identifier.urihttp://hdl.handle.net/10713/18280
dc.description.abstractIntroduction: 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.en_US
dc.description.sponsorshipAstellas Pharma USen_US
dc.description.urihttps://doi.org/10.1016/j.ekir.2022.01.1073en_US
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.relation.ispartofKidney International Reportsen_US
dc.subjectAPRILen_US
dc.subjectclinical trialen_US
dc.subjectgalactose-deficient IgAen_US
dc.subjectglomerulonephritisen_US
dc.subjectIgA nephropathyen_US
dc.subjectmonoclonal antibodyen_US
dc.titleSafety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VIS649 (Sibeprenlimab), an APRIL-Neutralizing IgG2 Monoclonal Antibody, in Healthy Volunteersen_US
dc.typeArticleen_US
dc.identifier.doi10.1016/j.ekir.2022.01.1073
dc.source.journaltitleKidney International Reports


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