Topical OT-717 confers superior retinal protection compared to intravitreal anti-VEGF in mouse retinal vein occlusion model

Abstract

Purpose : Retinal vein occlusion (RVO) and diabetic macular edema disrupt retinal blood supply, causing neurovascular injury and loss of vision. Up to 50% of patients do not respond to existing therapies, which do not target neurodegeneration from retinal ischemia. To address unmet need in treatment of retinal edema, we developed a topical eye-drop biologic caspase inhibitor (OT-717) and compared efficacy of OT-717 vs intravitreal anti-VEGF injections in a mouse model of RVO.

Methods : RVO was achieved in adult C57/Bl6 mice by laser photocoagulation. In vivo analyses—optical coherence tomography (OCT) and electroretinogram (ERG)—were conducted with the Micron IV system. Mice (n=16-25) received intravitreal injection with 0.4µg VEGF neutralizing antibody (R&D Systems) or vehicle 24hr prior to induction of RVO, and received eye-drops containing either 10µg OT-717 or vehicle immediately after RVO and again at 24hr post-RVO. Ocular tolerability of OT-717 was assessed in New Zealand white rabbits by a third party.

Results : Intravitreal anti-VEGF blocked induction of VEGF in retinal lysates 24hr post-RVO, and reduced inner retinal swelling. Posttreatment with OT-717 eye-drops conferred greater reduction of retinal edema compared to VEGF neutralization (p<0.01). RVO induced disorganization of the inner retinal layers (DIRL); eyes treated with OT-717 had less DIRL than eyes treated with anti-VEGF (p<0.01). OCT imaging revealed retinal atrophy following resolution of edema; OT-717 reduced atrophy of the inner nuclear layer and outer nuclear layer (p<0.001), while anti-VEGF injections had no effect on retinal atrophy. ERG assessment of retinal function measured deficits in amplitude and timing of A wave, B wave, and oscillatory potentials (p<0.001). OT-717 eye-drops conferred superior protection of retinal function compared to anti-VEGF injections. Co-treatment with OT-717 and anti-VEGF had comparable efficacy to OT-717 monotherapy. Assessment of OT-717 eye-drops in rabbits showed retinal uptake following 5 days of BID topical administration, and no adverse ocular effects.

Conclusions : OT-717 eye-drops reduce retinal edema, preserve retinal layer integrity and protect retinal function in a mouse RVO model, with greater efficacy compared to intravitreal anti-VEGF injections. Topical ophthalmic OT-717 has a favorable ocular safety profile and shows robust retinal uptake in rabbit eyes.

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