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Background and Aims IgA nephropathy (IgAN), the leading cause of primary glomerulonephritis, is an autoimmune disease with no approved treatments.1 Progression to end-stage-renal disease occurs in up to 45% of IgAN patients, requiring dialysis or kidney transplant to manage.2-4 A critical step in IgAN pathogenesis is the production of galactose-deficient IgA1 (Gd-IgA1) leading to the generation of anti-Gd-IgA1 autoantibodies and the formation of immune complexes that result in kidney inflammation and damage.5 A Proliferation-Inducing Ligand (APRIL), a soluble factor that regulates B cell differentiation, proliferation and survival of plasma cells, and IgA class-switching is elevated in patients with IgAN6, 7. IgAN patients with high plasma APRIL levels are reported as having higher levels of Gd-IgA1 and proteinuria and lower estimated glomerular filtration rates compared to those with lower plasma APRIL levels.7 BION-1301 is a novel humanized blocking antibody targeting APRIL that has been evaluated in a Phase 1 study of healthy volunteers (HV). In Parts 1 and 2 of the Phase 1 study in HV, we previously reported that BION-1301 was well-tolerated with no serious adverse events (SAEs), a pharmacokinetic (PK) half life >30 days and demonstrated dose-dependent pharmacodynamic (PD) effects characterized by durable reductions in serum levels of free April (fAPRIL), IgA and Gd-IgA1, IgM, and to a lesser extent IgG8. Here we present interim results from Part 3 of the Phase 1 and the Phase 2 Open-Label Extension (OLE) trials that characterize the safety, PK and PD profile, and preliminary efficacy of BION-1301 in patients with IgAN. Method The Phase 1 study (NCT03945318) comprises 3 parts. Parts 1 and 2 assessed single- and multiple ascending doses of BION-1301 in HV from 10mg to 1350mg and 50mg to 450mg once every 2 weeks for one month, respectively. Part 3 is an ongoing, open-label, two cohort design in approximately 20 IgAN patients with BION-1301 at a starting dose and regimen of 450mg once every 2 weeks for a total of 3 months. Key eligibility criteria for Part 3 include: (1) urine protein ≥0.5 g/24h or baseline UPCR ≥0.5 g/g, (2) stable/optimized dose of ACE-I/ARB or be intolerant to ACE-I/ARB, and (3) biopsy-verified diagnosis of IgAN within the past 10 years. Patients completing Part 3 are eligible to enroll in the Phase 2 OLE study (NCT04684745) to receive BION-1301 for up to an additional 2 years. To evaluate PK and PD effects of BION-1301, serum levels of BION-1301, free APRIL (fAPRIL), anti-drug antibodies (ADA), neutralizing antibodies (NAbs), and Gd-IgA1 were quantitated using ELISA-based immunoassays. Serum levels of IgA, IgG, and IgM were measured by immunoturbidimetry. UPCR was assessed from 24-hour urine collections. Results In Part 3 of Phase 1 and the Phase 2 OLE trial to date, BION-1301 has been well tolerated in IgAN patients receiving a 450mg dose every two weeks for 12+ weeks with no SAEs observed. Consistent with PD responses previously reported in HVs, durable reductions in serum levels of fAPRIL and immunoglobulins were also observed in IgAN patients. Clinically meaningful reductions in proteinuria were observed as early as 12 weeks and were associated with the reduction in IgA. Additional data from patients receiving long-term treatment will be updated. Conclusion BION-1301 is a novel humanized anti-APRIL monoclonal antibody being developed as a potential treatment for patients with IgAN. BION-1301 offers disease modifying potential by directly targeting the underlying multi-hit immune pathogenesis of IgAN, which is not addressed with the current standard of care treatment. Promising early biomarker and clinical activity responses support the continued development of BION-1301 in IgAN.

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BACKGROUND AND AIMS Immunoglobulin A nephropathy (IgAN) is the leading cause of primary glomerulonephritis worldwide with limited treatment options, especially for high-risk patients [1]. BION-1301 is a novel humanized monoclonal antibody that blocks a proliferation-inducing ligand (APRIL), a soluble factor that has been shown to be elevated in patients with IgAN and is correlated with poorer outcomes, including increased proteinuria and decreased eGFR [2, 3]. APRIL promotes IgA class switching, the survival of IgA-secreting plasma cells and the excess production of a galactose-deficient variant form of IgA1 (Gd-IgA1), which is an initiating step in IgAN pathogenesis. This leads to the generation of anti-Gd-IgA1 autoantibodies, considered to be the first ‘hit’ in the multi-hit pathogenesis of IgAN, and the formation of nephritogenic immune complexes that deposit in the kidney, resulting in inflammation and damage [2–4]. Blocking APRIL with BION-1301 is a novel approach to address the underlying pathogenesis of IgAN by reducing circulating levels of Gd-IgA1 and preventing the formation of pathogenic immune complexes. In a Phase 1/2 study of BION-1301 in healthy volunteers (HV), BION-1301 was well-tolerated with no serious adverse events (SAEs), demonstrated a pharmacokinetic (PK) half-life > 30 days and durable dose-dependent reductions in free APRIL (fAPRIL), Gd-IgA1, IgA and IgM, with a lesser effect on IgG [5]. Here we present updated interim results from Part 3 of the study that characterize the safety, PK/PD profile and preliminary efficacy of BION-1301 initially administered intravenously (IV), then subcutaneously (SC), in patients with IgAN. METHOD Parts 1 and 2 of the Phase 1/2 study (NCT03945318) assessing single and multiple ascending doses of BION-1301 in HV are complete. Part 3 is an ongoing, open-label, multicohort design in patients with IgAN treated with BION-1301 for up to 1 year. Key eligibility criteria for Part 3 include: (i) biopsy-verified diagnosis of IgAN within the past 10 years, (ii) baseline urine protein excretion ≥ 0.5 g/24 h or UPCR ≥ 0.5 g/g and (iii) stable/optimized dose of ACE-I/ARB (or intolerant). Cohort 1 receives 450 mg of BION-1301 administered IV every 2 weeks. After at least 24 weeks of IV dosing, patients’ transition to 600 mg of BION-1301 administered SC every 2 weeks. Cohort 2 receives 600 mg of BION-1301 SC every 2 weeks. To evaluate PK/PD effects of BION-1301, serum levels of BION-1301, fAPRIL, anti-drug antibodies (ADA), neutralizing antibodies (NAbs) and Gd-IgA1 were quantitated using ELISA-based immunoassays. RESULTS Updated data from Cohort 1 will be reported. BION-1301 was well-tolerated in patients with IgAN receiving a 450 mg IV dose every 2 weeks for at least 24 weeks, with no SAEs or early terminations due to AEs. Durable reductions in serum levels of fAPRIL and immunoglobulins were observed in patients with IgAN. Clinically meaningful reductions in proteinuria were seen as early as 12 weeks and were associated with the reduction in Gd-IgA1 levels. CONCLUSION BION-1301 offers disease-modifying potential by directly targeting the initiating mechanisms underlying the multi-hit immune pathogenesis of IgAN, which is not addressed with currently available treatments. Promising early mechanistic biomarker and clinical activity responses support the therapeutic potential of BION-1301 in IgAN.

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