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Abstract: TH-PO814

VIS649 Reduces Serum IgA Levels in NHPs Dose Dependently: PK/PD Exposure-Response Modeling for Translation to Treatment of IgA Nephropathy

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Sloan, Susan E., Visterra, Inc., Waltham, Massachusetts, United States
  • Engler, Frank A., Certara USA Inc., Parsippany, New Jersey, United States
  • Szretter, Kristy J., Visterra, Inc., Waltham, Massachusetts, United States
  • Myette, James R., Visterra, Inc., Waltham, Massachusetts, United States
  • Narayan, Kristin, Visterra, Inc., Waltham, Massachusetts, United States
  • Sundaresh, Bharathi L., Visterra, Inc., Waltham, Massachusetts, United States
  • Pereira, Brian J.G., Visterra, Inc., Waltham, Massachusetts, United States
Background

VIS649 is a humanized IgG2 monoclonal antibody that targets A PRoliferation-Inducing Ligand (APRIL), a cytokine that is implicated in IgA nephropathy (IgAN) pathogenesis. Targeting APRIL activity to reduce levels of aberrantly glycosylated circulating IgA1 may alter IgAN disease progression.

Methods

Cynomolgus monkeys (NHP; n=4/grp) were IV administered vehicle or VIS649 (0.5, 2.5 and 10 mg/kg) once weekly for 4 weeks, and followed for 8 weeks without treatment. Study endpoints included serum VIS649 and immunoglobulin (Ig) levels and peripheral lymphocytes (flow cytometry). Temporal changes in IgA concentration after VIS649 administration were described with a population pharmacokinetic/pharmacodynamic (popPK/PD) model using an indirect response model.

Results

At the 0.5 and 2.5 mg/kg dose levels there was a ~50% reduction in serum IgA levels. VIS649 administration at 10 mg/kg levels resulted in a ~70% serum IgA reduction. This maximal effect of ~70% reduction was confirmed in parallel studies at doses of up to 100 mg/kg and indicates that additional mechanisms support basal levels of IgA production. The effect of VIS649 on reducing IgA levels was reversible and observed after discontinuation of VIS649 treatment during the no-dose period with dose-dependent time to recovery. There was a lesser effect on serum IgG/IgM levels and peripheral lymphocytes were not affected. In a parallel study, a reduction in IgA+ mononuclear cells in GALT and tonsil tissues was observed, consistent with APRILs effect on Ig class switching and plasma cell survival in the mucosal compartment. These data were used to develop a popPK/PD model. Model simulation of single dose VIS649 in humans, in the range of 1-3 mg/kg, predicts a maximal (~70%) reduction in IgA levels followed by a dose-dependent return to baseline. Model simulation of repeated monthly doses suggest dose levels in the 0.3 to 3 mg/kg range will maintain a reduction in IgA levels below 50% of baseline.

Conclusion

VIS649 treatment reduces serum IgA levels in NHPs in a dose proportional manner. These data point to a clear potential therapeutic use of VIS649 in humans with IgAN.

Funding

  • Commercial Support