SAR443809, a selective inhibitor of the alternative complement pathway, has demonstrated strong potential for the treatment of disorders mediated by complement activity such as paroxysmal nocturnal hemoglobinuria (PNH), according to a study published in Blood Advances.
Dysregulation of the alternative complement pathway has been implicated in a number of disorders, including inflammatory conditions. Much effort has been devoted to inhibiting aberrant pathways of the complement system. An example of this is the development of the drug eculizumab, a monoclonal antibody against C5, which has demonstrated remarkable efficacy in the fight against PNH.
Nevertheless, much of the complement pathway remains a mystery, and it is still a popular target for clinical research.
Recently, researchers reported the discovery of SAR443809, “a humanized monoclonal IgG4 antibody which selectively binds to Factor Bb (FBb), the active form of FB,” according to Rajagopal and colleagues. Rajagopal et al sought to conduct a study to investigate its merits in inhibiting the alternative pathway, both in vitro and in nonhuman primates.
Read more about PNH etiology
In nonhuman primate studies, female cynomolgus monkeys were treated with 15 mg/kg of SAR443809 intravenously injected into the cephalic vein or subcutaneously administered into the back interscapular region. Researchers then plotted the pharmacology of SAR443809 over the study course. They discovered that SAR443809 significantly inhibited the alternative complement pathway, peaking at 90% or higher 24 to 48 hours postdose. Likewise, in vitro studies demonstrated robust, dose-dependent inhibition of the alternative complement pathway.
These results indicate that SAR443809 may be used effectively in future therapies against PNH by producing a sustained inhibition of the alternative complement pathway. The authors of the study stress that SAR443809 has currently only undergone phase 1 of clinical studies.
The downside to complement inhibitors is that they may increase the risk of infections with encapsulated bacteria. Hence, should SAR443809 be therapeutically administered in the future, vaccination may be necessary, just as it is for individuals undergoing other complement-targeted therapies.
Rajagopal V, Leksa NC, Gorham RD, et al. SAR443809: a selective inhibitor of the complement alternative pathway, targeting complement Factor Bb. Blood Adv. Published online March 10, 2023. doi:10.1182/bloodadvances.2022009028