Discovery and Development of the Oral Complement Factor D Inhibitor ACH-4471.

BACKGROUND: Complement plays a vital role in our innate immune defense against invasive microorganisms. Excessive complement activation or insufficient control of activation on host cells, however, is associated with several chronic disorders. Essential to the activation and amplification of the alternative pathway (AP) of complement, complement factor D (CFD) is a specific serine protease that cleaves its unique substrate, complement factor B (CFB) in complex with an activated form of complement component 3 (C3), to generate the AP C3 convertases C3(H2O)Bb and C3bBb. These convertases comprise a central component in eliciting effector responses following AP activation, and they also enable a powerful amplification loop for both the classical pathway (CP) and lectin pathway (LP) of complement.
RESULTS: This review provides an update on inhibitors of CFD, which have evolved from irreversible small molecules that demonstrate poor selectivity to reversible small molecules and monoclonal antibodies that demonstrate exceptional selectivity and potency. An overview the discovery, preclinical pharmacology, Phase 1 clinical studies in healthy volunteers, and Phase 2 clinical studies in paroxysmal nocturnal hemoglobinuria (PNH) patients is presented for the reversible small-molecule inhibitor ACH-4471.
CONCLUSION: ACH-4471 is well tolerated and demonstrates meaningful improvement in clinical efficacy endpoints for the treatment of PNH. Because CFD is not required for activation of either the CP or LP, selective CFD inhibition by ACH-4471 presents a favorable therapeutic approach to modulating complement activity that leaves intact the effector functions following CP and LP activation and thus poses a lower risk of bacterial infection than other complement-directed approaches. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.