SAR443809: a selective inhibitor of the complement alternative pathway, targeting complement factor Bb

Area of Science:

• Immunology
• Pharmacology
• Drug Discovery

Background:

• Complement system dysregulation is linked to various diseases.
• Current complement inhibitors face challenges like high drug levels and incomplete effector function inhibition.

Purpose of the Study:

• To discover and characterize SAR443809, a novel inhibitor targeting the alternative complement pathway's C3/C5 convertase (C3bBb).
• To evaluate the therapeutic potential of SAR443809 in complement-mediated disorders.

Main Methods:

• Discovery of SAR443809, a selective inhibitor of the alternative pathway C3/C5 convertase.
• In vitro assays using patient-derived paroxysmal nocturnal hemoglobinuria erythrocytes.
• Ex vivo experiments assessing hemolysis and C3b deposition.
• Pharmacokinetic studies in nonhuman primates following intravenous and subcutaneous administration.

Main Results:

• SAR443809 selectively binds to factor Bb, inhibiting alternative pathway C3/C5 convertase activity.
• Proximal inhibition by SAR443809 abrogated both hemolysis and C3b deposition, unlike C5 blockade.
• Sustained complement inhibition was observed for several weeks post-administration in nonhuman primates.

Conclusions:

• SAR443809 demonstrates potent and selective inhibition of the alternative complement pathway.
• This novel therapeutic agent shows potential for treating diseases driven by alternative pathway activation.
• SAR443809 offers advantages over terminal pathway inhibitors by addressing both hemolysis and C3b deposition.