Researchers wrote a review discussing current novel insights into the use of factor D inhibition in a number of complementopathies, including cold agglutinin disease (CAD), and published their findings in the International Journal of Molecular Sciences.
Complement-mediated diseases are scattered across the various medical disciplines, including hematology, rheumatology, and nephrology. Much research has been devoted to repairing pathological aspects of the complement pathway, including blocking targets, reducing complement-mediated effects, and introducing the use of C5 inhibitors, such as eculizumab and ravulizumab.
The complement system plays a primary role in regulating innate immunity. Complement activation can occur via 3 cascades: classical, lectin, and alternative. Unlike the classical and lectin cascades, the alternative pathways of complement are capable of auto-activation via a low-level steady process that takes place in the fluid phase. Studies have demonstrated that the amplification of alternate pathways is responsible for over 80% of C5 cleavage.
“Therefore, the continuous control of [alternative pathway] activation is absolutely critical for proper complement function and failure of this, for a variety of reasons, has been shown to be the cause of complementopathies,” the authors of the study wrote. “Moreover, in vivo studies using gene-targeted mice have provided strong evidence that two serine proteases, namely Factor D (FD) and Factor B (FB), are essential for [alternative pathway] activation.”
Read more about CAD epidemiology
FD has the lowest concentration of any complement protein, making it an attractive therapeutic target. FD possesses 2 important characteristics: its self-inhibitory mechanism and its substrate-induced activation. These properties make it a self-regulating enzyme with very high substrate specificity, opening the door for therapeutic intervention within the alternative pathway of complement.
Danicopan is an FD inhibitor that selectively inhibits proximally the alternative complement pathway. Early results demonstrate that it can impede intravascular hemolysis and restrict C3-mediated extravascular hemolysis. In addition, the use of danicopan has resulted in substantially elevated levels of hemoglobin.
“The miracle of complement inhibitors as ‘orphan drugs’ has dramatically improved morbidity and mortality in patients with otherwise life-threatening complementopathies,” the authors said. “Further studies and developments are warranted to address the unmet clinical needs in the field of complementopathies.”
Gavriilaki E, Papakonstantinou A, Agrios KA. Novel insights into factor D inhibition. Int J Mol Sci. 2022;23(13):7216. doi:10.3390/ijms23137216