EXN407, a novel topical therapeutic candidate with high retinal bioavailability for the treatment of diabetic macular oedema, inhibits ocular neovascularisation

Abstract

Purpose : Retinal vascular diseases are treated by intra-ocular injection of anti-VEGFs. SRPK1 inhibitors reduce angiogenic VEGF-A isoforms and choroidal neovascularisation (CNV) in vivo. To address the challenge posed by injections, we developed topical SRPK1 inhibitors with high retinal exposure and low systemic availability. Here we present EXN407, fully profiled preclinically through to in vivo efficacy, pharmacokinetics (PK) and safety/toxicology in large eyes.

Methods : SRPK1 inhibition and selectivity were shown by radiometric assays. VEGF-A isoform expression was analysed by ELISA. Ex vivo trans-scleral permeability was assessed in porcine eye tissue using mass spectrometry. Efficacy was evaluated in vivo after bi-daily administration of 0.05% EXN407 in (i) laser-induced CNV in C57/Bl6 mice at 7 days, and (ii) STZ-induced diabetic retinopathy in rats over 28 days. Ocular and systemic pharmacokinetic profiles for EXN407 were determined in (i) Hy79b rabbits administered a single eye drop for successive timepoints or dosed b.i.d for 6 days, (ii) Non-human primate (NHP) after 21 days b.i.d of dosing, up to 0.15%. Ocular toxicity and safety was assessed over 10 days t.i.d in rabbits or 21 days b.i.d in NHP administered EXN407.

Results : EXN407 is a potent, specific SRPK1 inhibitor (IC₅₀ 4nM), reduces pro-angiogenic VEGF-A (IC₅₀ 211nM) and shows exceptional ocular permeability, (>10x pazopanib and regorafenib) resulting in superior efficacy in vivo. EXN407 inhibits CNV after 0.2µg/ml bid eye drops (p<0.05 n=25, comparable to anti-VEGF injection) and diabetes-induced VEGF-A and vascular permeability after 0.05% bid eye drops. In rabbit and NHP, EXN407 reached retinal exposure levels at concentrations >10x that required for in vivo efficacy. It displays low systemic exposure and no toxicity.

Conclusions : EXN407 has superior retinal permeability ex vivo, correlating with high retina levels and low systemic exposure in rabbits and NHP. EXN407 potently reduces choroidal neovascularisation and permeability in vivo by blocking SRPK1 splicing of VEGF-A. EXN407 is an exemplar compound showing how improved retinal permeability can be identified through methodical rational drug design. The compound has the attributes to move into clinical development as a topical therapeutic to reduce intravitreal injections of anti-VEGF antibodies.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.