Objectives: RO7434656 (IONIS-FB-LRx, ISIS 696844), a ligand-conjugated antisense oligonucleotide targeting complement factor B mRNA, was engineered for enhanced delivery to the liver as the primary site of factor B production. In a Phase 2 trial (NCT04014335), RO7434656 inhibited alternative complement pathway activation and demonstrated a clinically meaningful reduction in the urine protein-to-creatinine ratio (UPCR; Fig 1) and stabilization of the estimated glomerular filtration rate (eGFR) in patients with IgA nephropathy (IgAN). Methods: IMAGINATION (NCT05797610), a Phase 3, randomized, double-blind, placebo-controlled trial will evaluate the efficacy and safety of RO7434656 in adults with biopsy-confirmed primary IgAN (Fig 2). 428 patients will be divided into 2 cohorts: a primary cohort with eGFR ≥30 mL/min/1.73m2 and an exploratory cohort with eGFR 20-29 mL/min/1.73m2. Patients on maximally tolerated doses of ACEi/ARB will be randomized 1:1 to receive RO7434656 or placebo subcutaneously (SC) on Days 1, 15 and 29 and every 4 weeks (Q4W) thereafter for 105 weeks, with the option to continue double-blind or open-label treatment. The primary endpoint is change from baseline in 24h UPCR at Week 37. Key secondary endpoints include eGFR slope from baseline at Week 105, time to the composite kidney failure endpoint and patient-reported outcomes. Blood, urine and optional kidney biopsies will be collected throughout the study to assess biomarkers. Results: Expected upon study completion. Conclusions: The unique antisense modality and long tissue half-life of RO7434656 enables Q4W SC administration to inhibit the alternative complement pathway. IMAGINATION aims to evaluate the efficacy and safety of RO7434656 in adults with IgAN using a broad range of assessments over 105 weeks. Study and medical writing support funded by F. Hoffmann-La Roche Ltd. This abstract was submitted and accepted for presentation at ASN Kidney Week 2023 and 2024 ISN World Congress of Nephrology. The authors declare that re-submitting the abstract is permitted by the previous meetings.