Kidney Week

Abstract: TH-PO045

Pharmacokinetics/Pharmacodynamics of VIS649, a First-in-Class Humanized IgG2 Targeting APRIL for the Treatment of IgA Nephropathy, in Healthy Cynomolgus Monkeys

Session Information

• Glomerular: Basic/Experimental Immunology and Inflammation - I
  November 02, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Glomerular

• 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

• Szretter, Kristy J, Visterra, Inc., Cambridge, Massachusetts, United States

Kristy J Szretter,

• Myette, James R., Visterra, Inc., Cambridge, Massachusetts, United States

James R. Myette,

• Helger, Emily A, Visterra, Inc., Cambridge, Massachusetts, United States

Emily A Helger,

• Sundaresh, Bharathi L, Visterra, Inc., Cambridge, Massachusetts, United States

Bharathi L Sundaresh,

• Deotale, Ketan, Visterra, Inc., Cambridge, Massachusetts, United States

Ketan Deotale,

• Trevejo, Jose, Visterra, Inc., Cambridge, Massachusetts, United States

Jose Trevejo,

• Sloan, Susan E, Visterra, Inc., Cambridge, Massachusetts, United States

Susan E Sloan,

• Pereira, Brian J.G., Visterra, Inc., Cambridge, Massachusetts, United States

Brian J.G. Pereira,

Background

VIS649 is a humanized IgG2 monoclonal antibody that targets A PRoliferation-Inducing Ligand (APRIL), a cytokine that is part of the TNF superfamily that has been implicated in IgA nephropathy (IgAN) pathogenesis and progression. Because of its role in IgA class switching and plasma cell survival, targeting APRIL in IgAN patients may substantially reduce circulating levels of aberrantly glycosylated IgA and alter disease progression.

Methods

Cynomolgus monkeys (NHP; n = 4/group) were administered VIS649 (25 mg/kg) or vehicle alone once weekly for eight weeks by intravenous injection, and were then followed for an additional 3 weeks without treatment. Study endpoints included serum VIS649 and immunoglobulin (Ig) levels. In order to characterize the temporal relationship between circulating VIS649 and IgA, a population pharmacokinetic/pharmacodynamic (popPK/PD) model was developed. Temporal changes in IgA concentration following VIS649 administration was described with an indirect response model.

Results

Treatment of NHP with VIS649 resulted in significantly lower serum levels of IgA (up to 70%) and IgG (~40%), and minimal modulation of serum IgM levels. The changes in serum Ig levels were not reversed during the 3 week no-dose period, which was attributed to the saturating levels of VIS649 at the dose administered. Analysis of the VIS649 pharmacokinetic data revealed that serum levels of VIS649 accumulated following weekly dose administrations at 25 mg/kg, and estimated the VIS649 half-life in NHP as 15 days. The popPK/PD model fit available PK and PD data well. Simulations were performed over a range of doses to inform dose selection and frequency in a follow-on study that will test lower VIS649 doses. Model simulations predict that approximately 50% reduction in IgA levels may be achieved with lower dose levels.

Conclusion

VIS649, a humanized IgG2 monoclonal antibody that targets APRIL, reduced serum IgA levels significantly in healthy NHP following 8 weekly doses at 25 mg/kg. The specific targeting of APRIL confirmed its important role in the homeostasis of IgA, and confirmed our rationale for targeting it for the treatment of IgAN.

Funding

• Commercial Support –