Development of RA101348, a Potent Cyclic Peptide Inhibitor of C5 for Complement-Mediated Diseases

The involvement of complement in the pathogenesis of serious, life-threatening diseases underscores the importance in developing therapeutics to intervene in this cascade. Specifically, dysregulation of the complement system is central in multiple hematologic conditions. Antibody blockade of the C5 component of complement has been approved as a treatment for paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic-uremic syndrome (aHUS), validating C5 as a therapeutic target for these conditions.

Ra Pharma has developed a macrocyclic peptide platform capable of yielding potent inhibitors of protein-protein interactions. Recently, we developed a short cyclic peptide that binds complement C5 with high affinity (K_D = 2.6 nM) and inhibits its cleavage into C5a and C5b by a novel mechanism. At low nanomolar concentrations, RA101348 blocks the formation of the terminal complement complex (TCC) in vitro, as demonstrated in RBC lysis assays for both alternative and classical complement activation pathways.

Inhibition of in vivo complement activity was evaluated in cynomolgus monkeys following single- and multi-dose subcutaneous (SC) administration. RA101348 exhibited high SC bioavailability, and low, single doses inhibited complement activity by 90-100%. The effect is durable owing to an in vivo terminal half-life of approximately 72 hrs. Repeat dosing for 7 days was well tolerated in monkeys at up to 100-fold above projected human therapeutic doses and resulted in sustained inhibition of complement activity.

RA101348 is a novel therapeutic approach for inhibiting the activity of C5 for the treatment of disorders caused or associated with complement dysregulation. It offers the potential to enable self-administration of therapeutics for patients with PNH and other complement disorders.