Ocular pharmacokinetics, pharmacodynamics, and safety analysis of a novel dexamethasone intravitreal implant

Abstract

Purpose : We have developed a non-polymeric intravitreal implant (IBE-814 IVT implant) designed to deliver a low, sustained dose of dexamethasone out to 6 months. The IBE-814 IVT implant is fully degradable and is delivered through a 30 gauge needle (30G x 6 mm implant dimensions). Pharmacokinetics (PK) in different ocular tissues and pharmacodynamics (PD) have been completed and the safety of the IBE-814 IVT implants is ongoing.

Methods : PK of the IBE-814 IVT implants were evaluated in New Zealand white rabbits with terminal timepoints from 1 week through 14 months. Drug was quantified by LC/MS/MS in ocular tissues (vitreous humour, aqueous humour, retina, and choroid) and in plasma. PD of the IBE-814 IVT implants was evaluated in Dutch Belted rabbits using a VEGF-induced model of vascular leakage. Implants were analyzed in this model until drug released from the implants was no longer high enough to inhibit blood-retinal barrier breakdown as observed by fundus and fluorescein angiography. Safety of IBE-814 IVT implants was evaluated in New Zealand white rabbits by microscopy, clinical ophthalmic exams, and histopathology.

Results : The IBE-814 IVT implants released a low and consistent dose of dexamethasone in the vitreous humour, retina, and choroid out to 12 months with no drug detected at 14 months. Aqueous humour dexamethasone concentrations were below the limit of quantification (1 ng/ml) for all time points. The sustained release of dexamethasone from the IBE-814 IVT implants inhibited VEGF-induced vascular leakage (as early as 1 week) through 6 months, with diminishment of efficacy occurring around 9 months. Histopathology of IBE-814 IVT implants showed no remarkable safety findings at a 3 month time point. Later safety time points are ongoing.

Conclusions : The IBE-814 IVT implant is a novel non-polymeric biodegradable surface-eroding implant delivered with a 30G needle that releases a low, consistent, and efficacious dose of dexamethasone out to 6 months. Ongoing safety studies will support a Phase 2 clinical trial for patients with diabetic macular edema and macular edema from retinal vein occlusions.

This is a 2020 ARVO Annual Meeting abstract.

 

Drug concentration (ng/mL) in Vitreous and Aqueous Humour

 

Fluorescein angiography after VEGF stimulation