RZ402 is a potential once-daily orally-administered small molecule plasma kallikrein inhibitor (PKI) in preclinical development for vision-threatening eye complications of diabetes including Diabetic Retinopathy (DR) and Diabetic Macular Edema (DME).

It is estimated that approximately 50 million individuals worldwide are suffering from vision-threatening complications of diabetes, including DR and DME, which are the main cause of vision loss in working-age adults globally. DME is expected to increase in incidence and prevalence beyond its current estimate of 750,000 individuals in the US and 21 million worldwide. In the US, current treatment approaches to DR/DME directly target the VEGF pathway and are dominated by anti-VEGF agents such as ranibizumab, bevacizumab and aflibercept, which must be injected into the eye by retinal specialists on a monthly or bimonthly basis. These agents are initially efficacious however optimal therapeutic outcomes have not been achieved, in part due to sub-optimal compliance resulting from their invasive route of administration.

Plasma kallikrein acting through bradykinin has been shown to be a key mediator of retinal and generalized increased vascular leakage in DME, while pharmacologic inhibition with PKIs or genetic knockout of plasma kallikrein can normalize vascular leakage and its mediators.

RZ402 has demonstrated potent target inhibition in vitro and in rat, monkey, and human plasma, while showing high selectivity against other plasma proteases. In addition, RZ402 has been shown to suppress retinal vascular leakage in multiple clinically-relevant animal models of macular edema as effectively as an anti-VEGF agent. With oral administration, efficacious concentrations were exceeded for the intended 24-hour dosing interval.  These results validate the activity of RZ402 in clinically-relevant in-vivo models at orally-achievable exposures, thereby increasing supporting its potential as a stand-alone therapy for patients with DME. In addition, it appears to be safe and well-tolerated, with broad therapeutic margins.

Rezolute is planning to file an IND with the FDA for RZ402 in Q4 2018.