OcuNexus Clinical Candidates and Indications

Peptagon™

The active drug substance in Peptagon™ is the Hemichannel Blocking peptidomimetic Peptide5 consisting of 12 amino acids derived from the second extracellular loop of the human Connexin43 (Cx43) protein. Peptide5 closes pathological Cx43 hemichannels, so inhibiting release of ATP and activation of the inflammasome pathway of inflammation.This reduces the release of inflammatory cytokines, thereby preventing further tissue damage. The continuing cycle of inflammation through activation of the inflammasome mediated inflammation otherwise results in vascular leak, edema, microvascular dropout and neovascularization due to the resulting ischemia. Some aspect of all of these clinical manifestations are hallmarks of both Age-Related Macular Degeneration (AMD) and Diabetic Eye Disease characterized by Diabetic Retinopathy (DR) and Diabetic Macular Edema (DME).

Peptagon™, with the active Peptide5, is formulated as a solution to facilitate intravitreal injection for the treatment of serious inflammatory back of the eye diseases such as AMD, DR and DME.

Extensive pre-clinical models of both AMD and DR have been developed and have been shown to support the mechanism of action of Peptide5 in inhibiting the release of ATP, inhibiting the inflammasome pathway of inflammation, whilst in addition demonstrating a surprising level of neuroprotection in the various models.

 

Peptagon™ in a Model of Diabetic Retinopathy

As mentioned previously the hallmarks of the activated inflammasome are seen clinically in diabetic retinopathy. One model which mimics the ultimate ischemia is the retina ischemia reperfusion model. In this model the retina is rendered ischemic through protracted (one hour) maintenance of extremely high intra ocular pressure to inhibit retinal blood flow, followed by reperfusion.  The resultant ischemia-reperfusion leads to neural cell (retinal ganglion cell) death.

In this model when animals were treated with Peptagon™, (intraperitoneal injection or intravitreally) vs placebo controls, there was significant difference in Cx43 levels with overexpression in the controls and significantly increased vessel leak in controls vs the treated eyes. Similarly there was significant sparing of neural retinal cells vs the placebo controls.

Furthermore donor human retinas with diabetic retinopathy contain significantly higher levels of Cx43 than retinas which do not have retinopathy along with vessel leak as expected with the activated and recycling inflammasome pathway of inflammation.