Alonso A. Ricardo
SVP & Head of Research
Macrocyclic Peptide Inhibitors of Complement C5 for the Treatment of Systemic and CNS Immune Disorders
Complement component 5, C5, is a member of the terminal complement pathway, and its cleavage results in the formation of two fragments: C5a, an anaphylatoxin, and C5b, the precursor for the membrane attack complex formation, MAC or C5b-9. Abnormal activation of the terminal complement cascade leads to pathological conditions such as autoimmune disease, intravascular hemolysis, and vascular injury. More recently, excessive activation of C5 has also been associated with inflammasome formation and the development of neuroinflammation.
Using its proprietary Extreme Diversity™ platform, Ra Pharma discovered and developed zilucoplan, a 15-amino acid macrocyclic peptide, designed to bind and inhibit the cleavage of complement C5. Zilucoplan exhibits a favorable safety and tolerability profile and has achieved clinically meaningful and statistically significant efficacy endpoints in Phase 2 clinical studies in patients with generalized myasthenia gravis, gMG, and paroxysmal nocturnal hemoglobinuria, PNH.
In addition to zilucoplan, Ra Pharma has used its proprietary passive, permeable peptide platform to discover a new class of short macrocyclic peptide C5 inhibitors; these molecules are orally bioavailable and have achieved CNS exposure in rodents. Ra Pharma believes these results validate the enormous potential of Ra’s discovery engine for the identification of potent, selective, cell-permeable, and bioavailable peptides for the treatment of systemic disease.
AffiliationsChief Technology and Innovation Officer, Ra Pharmaceuticals