ASRS 2025: ASRS 2025: Suprachoroidal avoralstat stops vascular leakage in a well-established rabbit model

At ASRS 2025 in Long Beach, Dilsher Dhoot, MD, of California Retina Consultants presented promising preclinical data on avoralstat, a plasma kallikrein inhibitor being explored as a novel treatment for diabetic macular edema (DME). In his talk, Dhoot highlighted that while anti-VEGF therapies have significantly advanced DME treatment, up to 40% of patients—according to studies such as Protocol T—still experience persistent fluid and edema, suggesting the involvement of alternative biological pathways.

Avoralstat targets the plasma kallikrein-bradykinin pathway, which is distinct from the VEGF pathway and has been implicated in vascular leakage. The molecule is a potent and small (513 daltons) inhibitor of plasma kallikrein. In preclinical studies using the DL-AAA rabbit model, avoralstat effectively reduced vascular leakage. Dhoot emphasized the molecule's durability, noting that therapeutic levels (EC90) were sustained for up to six months, an encouraging sign for long-term disease control.

Importantly, avoralstat is being delivered via suprachoroidal injection, which may enhance its bioavailability and retinal penetration—a potential improvement over earlier kallikrein inhibitors that failed to meet primary endpoints in clinical trials. Dhoot speculated that limited efficacy in previous studies may have been due to insufficient drug levels reaching the retina.

The research is now advancing into a Phase 1b clinical trial in Australia, which has already begun enrolling patients. This 3x3 dose-escalation study will involve recently diagnosed DME patients and aims to further assess safety, durability, and early efficacy signals. Preliminary results are expected by late 2025 or early 2026.

Looking ahead, Dhoot suggested that avoralstat could offer a monotherapy option for patients unresponsive to anti-VEGF treatment, potentially reshaping the treatment landscape for DME. He expressed optimism that with better drug delivery and a novel mechanism of action, avoralstat may finally unlock the potential of plasma kallikrein inhibition in retinal disease