Translational Framework to Predict Clinical Responses to APRIL Blockade for Development of JADE101, an Anti-APRIL Monoclonal Antibody in IgAN

Background: IgA nephropathy (IgAN) is an autoimmune kidney disease characterized by mesangial deposition of immune complexes containing IgA and Gd-IgA1. Blocking A proliferation-inducing ligand (APRIL) is potentially disease modifying in IgAN by reducing IgA, Gd-IgA1 and proteinuria, ultimately stabilizing kidney function. JADE101 is a novel APRIL neutralizing monoclonal antibody (mAb) designed with high affinity and extended half-life. Biomarker responses to APRIL inhibition were leveraged to assess preclinical to clinical translation and the consistency of pharmacokinetic (PK) and pharmacodynamic (PD) responses in healthy volunteers (HV) and IgAN patients to support development of APRIL targeted therapies in IgAN. Methods: Translational PKPD models and statistical correlation were used to integrate preclinical data from the JADE101 development program with publicly available clinical data from anti-APRIL mAbs and other IgA-depleting agents (dual APRIL/BAFF inhibitors and anti-CD38 mAbs). Correlation coefficients (r) were used to estimate correlations between key pharmacologic properties and PKPD endpoints relevant to IgAN drug development. Results: In vitro APRIL binding affinity is predictive of in vivo IgA reduction in non-human primates (r=0.99) and humans (r=0.99). Clinical data reveal consistent anti-APRIL mAb PK with a direct relationship between PK and APRIL neutralization leading to predictable IgA reduction in HVs and IgAN patients with a strong association (r=0.93) across mechanisms. IgA and Gd-IgA1 reductions are correlated in IgAN patients (r=0.96). IgA reduction at 8 weeks of treatment in IgAN patients is correlated with proteinuria reduction after 36 weeks of treatment (r=0.89). The magnitude of APRIL neutralization and proteinuria reduction were correlated in IgAN patients (r=0.96). Conclusion: Tightly correlated biomarker responses to APRIL blockade enable preclinical and HV clinical data to potentially predict clinical responses in IgAN patients. Complete APRIL neutralization in HVs appears to ultimately predict deep IgA and Gd-IgA1 suppression and maximal proteinuria reductions in IgAN patients. These associations provide a foundation for JADE101 development, a potentially disease modifying therapy in IgAN with convenient, infrequent dosing. Funding: Commercial Support - Jade Biosciences