P0500RESULTS OF A PHASE 1 TRIAL TO INVESTIGATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF BION-1301 IN HEALTHY VOLUNTEERS

Abstract

Abstract Background and Aims IgA nephropathy (IgAN), the leading cause of primary glomerulonephritis, is an autoimmune disease with no approved treatments. Slow progression to end-stage-renal disease occurs in up to 50% of patients with IgAN over approximately 20-25 years, resulting in the need for dialysis or kidney transplant. A critical step in IgAN pathogenesis is the production of galactose-deficient IgA1 (Gd-IgA1) leading to the generation of anti-Gd-IgA autoantibodies and the formation of immune complexes that result in kidney inflammation and damage. Patients with IgAN have elevated levels of A proliferation-inducing ligand (APRIL), which may contribute to IgAN pathogenesis by regulating differentiation and proliferation of B cells. In a study of patients with IgAN, those with high plasma APRIL levels had higher levels of Gd-IgA1 and proteinuria and lower estimated glomerular filtration rates compared to those with lower plasma APRIL levels. BION-1301 is a first-in-class humanized antagonistic antibody targeting APRIL. BION-1301 reduced serum levels of IgA, IgM, and IgG with no drug-related toxicity in nonhuman primates and was well-tolerated with no dose-limiting toxicities in a Phase 1/2 first-in-human clinical study in patients with late-stage multiple myeloma. The Phase 1 trial described here will characterize the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of BION-1301 in healthy volunteers (HV) and patients with IgAN. Methods The protocol for this study (NCT03945318) is comprised of 3 parts, of which only Parts 1 and 2 are complete. Parts 1 and 2 assess BION-1301 in HV, and Part 3 will assess BION-1301 in patients with IgAN. Parts 1 and 2 are double-blind, randomized, placebo-controlled single and multiple ascending dose designs, respectively. Part 3 will assess a multiple dose regimen in IgAN patients. Part 1 enrolled 36 HV in 5 dose cohorts, randomized in a 3:1 ratio to receive a single dose of BION-1301 or placebo delivered by IV infusion. Part 2 enrolled 27 HV in 3 dose cohorts, randomized in a 2:1 ratio to receive 3 doses of BION-1301 or placebo delivered by IV infusion once every two weeks over a one month period. Dose escalation decisions were made by a Safety Review Team based on safety, tolerability, and PK-related stopping criteria. Results To-date, BION-1301 continues to be well tolerated. Its biological activity in the study is characterized by free APRIL, IgA, IgG, and IgM levels; unblinded safety, PK, and PD results for Parts 1 and 2 in Healthy Volunteers will be presented. Conclusion BION-1301, a humanized anti-APRIL antibody, may provide a novel avenue for the potential treatment of IgAN that offers potential advantages compared to currently used antihypertensive or immunosuppressive therapies.