FB-7013: A Novel, Long-Duration siRNA Targeting 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. Recent studies indicate that the activation of lectin pathway (LP) in the complement system is a major pathogenic process in IgAN. Currently, no therapeutic agent specifically targeting LP is available for clinical use. Here we report the discovery and development of FB-7013, a first-in-class, N-acetylgalactosamine (GalNAc) -conjugated small interfering RNA (siRNA) targeting MASP2, the key proteases in the LP. FB7013 specifically inhibits LP activation during the progression of IgAN. Methods: The HepG2/MASP2 stable cells, humanized MASP2 transgenic mice and cynomolgus macaques were used to evaluate the MASP2 mRNA/protein knockdown efficacy of FB-7013 both in vitro and in vivo. The pharmacodynamics of FB7013 were characterized in IgAN NHP model induced by BSA/CCl4/LPS. A single dose of FB7013 was subcutaneously administrated after 10 weeks of the induction. The renal outcomes (uTP, uPCR, eGFR), histopathology (IgA deposition, mesangial cell number), and the expression levels of MASP2 in serum/liver were measured after treatment. The safety pharmacology, pharmacokinetics, and toxicology of FB-7013 were evaluated in a series of in vitro and in vivo nonclinical studies. Results: FB-7013 achieved >90% MASP2 mRNA suppression with an IC50 in the picomolar range in vitro.A single dose of FB-7013 in humanized MASP2 transgenic mice resulted in sustained MASP2 mRNA knockdown in the liver for two months. In Cynomolgus macaques, FB7013 elicited a sustained and statistically significant suppression of the MASP2 protein expression level that lasted for four months. Upon a single dose of FB-7013 treatment at 3 mpk and 9 mpk in the IgAN NHP model, the levels of uPCR, uTP, eGFR were significantly reversed. No off-target effects and immunotoxicity of FB-7013 were observed in vitro. FB-7013 was well tolerated in the in vivo studies. Conclusion: FB-7013 exhibits robust and durable inhibition of LP activation, resulting in reduced renal injury in IgAN model. Its pharmacodynamic profile may support twice-yearly dosing in human, addressing both efficacy and dosing challenges in current treatment regimens. Clinical studies are warranted to validate these findings in IgAN patients.