AON-D21 – Complement C5a-neutralizing human/mouse cross-reactive L-aptamer from bench to phase 2 clinical trial

Using mirror-image in vitro selection by exponential enrichment (SELEX), nuclease-resistant aptamers targeting human and mouse C5a were identified. These aptamers bind C5a and inhibit signaling through both C5a receptors. A crystal structure provides insights into the contact points between aptamer and C5a. Non-clinical studies of the initially identified L-aptamer (NOX-D19) and its affinity-enhanced variants (NOX-D20, NOX-D21/AON-D21) have demonstrated efficacy in several mouse models of human diseases, including bacterial pneumonia (with and without mechanical ventilation), syngeneic lung cancer (in combination with anti-PD1 therapy), cholesterol crystal embolism, and asthma sensitization. Following preclinical development in mice and marmoset monkeys, a single- and a multiple ascending dose trial were conducted in healthy volunteers. Pharmacokinetic/pharmacodynamic (PK/PD) modeling enabled the design of a dosing regimen for repeated administration aimed at sustained C5a inhibition. Currently, AON-D21 is being evaluated in the Phase 2 ADCAP trial, which is assessing its safety and efficacy in 150 ICU-admitted patients with severe community-acquired pneumonia (viral or bacterial) across 28 sites in five European countries. Initial pharmacodynamic results confirm inhibition of circulating C5a in treated patients. The final study results are expected in 2026. This will be a review of preclinical and clinical work of a currently active complement therapeutics program with multiple references.