Nomacopan: A Comprehensive Monograph on a Dual-Action C5 and LTB4 Inhibitor

1.0 Executive Summary

Nomacopan is an investigational, second-generation biopharmaceutical agent representing a novel class of immunomodulators with a unique, dual-action mechanism. Originating from a protein found in the saliva of the Ornithodoros moubata tick, this recombinant small peptide is engineered to simultaneously inhibit two distinct and potent inflammatory pathways: the terminal complement component C5 and the lipid mediator leukotriene B4 (LTB4). This bifunctional activity distinguishes it from all currently approved complement inhibitors and forms the basis of its therapeutic rationale across a wide spectrum of autoimmune and inflammatory diseases.

Pharmacologically, Nomacopan prevents the cleavage of C5, thereby blocking the generation of the pro-inflammatory anaphylatoxin C5a and the formation of the cell-lysing Membrane Attack Complex (MAC). Concurrently, it employs a unique "ligand capture" mechanism to sequester and neutralize LTB4, a powerful chemoattractant for neutrophils. This combined blockade offers a more comprehensive approach to suppressing inflammation than targeting either pathway alone.

The clinical development of Nomacopan, led by Akari Therapeutics, has been characterized by a strategic evolution. Initial investigations demonstrated significant efficacy and a favorable safety profile in Paroxysmal Nocturnal Hemoglobinuria (PNH) and the autoimmune blistering skin disease Bullous Pemphigoid (BP). However, a portfolio reprioritization has shifted the company's focus toward indications with the highest unmet medical need and a clearer path to market. The lead clinical programs are now in Hematopoietic Stem Cell Transplant-Associated Thrombotic Microangiopathy (HSCT-TMA), a rare and often fatal condition with no approved treatments, and Geographic Atrophy (GA), a leading cause of blindness.