FB-7011: A Novel, Long-Duration siRNA Dual-Targeting Both Complement Factor B (CFB) and Mannan-Binding Lectin Serine Protease 2 (MASP2) Exhibits Therapeutic Potential for Treatment of IgAN

Background: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis, leading to end-stage renal disease in 30-40% of patients. Current therapies for IgAN are limited by safety, efficacy, and patient adherence issue. Developing specific treatments that target boh AP and LP holds significant potential to overcome the limitations of existing therapies. Here we report the discovery and development of FB-7011, a first-in-class, N-acetylgalactosamine (GalNAc)-conjugated, chemically linked small interfering RNA (siRNA) that targets both CFB and MASP2, the key proteases in the AP and LP, respectively, and inhibits AP and LP activation during the progression of IgAN. Methods: The HepG2/MASP2 stable cells, humanized MASP2 and CFB transgenic mice and cynomolgus macaques were used to evaluate the MASP2 and CFB mRNA/protein knockdown efficacy of FB-7011 both in vitro and in vivo. The pharmacodynamics of FB7011 were characterized in IgAN NHP model induced by BSA/CCl4/LPS. A single dose of FB-7011 was subcutaneously administrated after 10 weeks of the induction. The renal outcomes (uTP, uPCR, eGFR), histopathology (IgA deposition). The safety pharmacology, pharmacokinetics, and toxicology of FB-7011 were evaluated in a series of in vitro and in vivo nonclinical studies. Results: FB-7011 achieved >90% MASP2 and CFB mRNA suppression with an IC50 in the picomolar range in vitro.A single dose of FB-7011 led to simultaneous and effective knockdown of CFB mRNA and MASP2 mRNA and protein expression levels in CFB and MASP2 double transgenic mice and cynomolgus macaques. Upon a single dose of FB7011 treatment in the IgAN NHP model, the levels of uPCR, uTP, eGFR were significantly reversed. No off-target effects and immunotoxicity of FB-7011 were observed in vitro. FB-7011 was well tolerated in the in vivo studies. Conclusion: FB-7011 exhibits robust and durable inhibitions of AP and LP in complement system, resulting in reduced renal injury in the preclinical models. The pharmacodynamic profile of FB-7011 may support a twice-yearly dosing regimen in human, addressing both efficacy and dosing challenges in current treatment regimens. Clinical studies are warranted to validate these findings in IgAN patients.