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Peter K Jarrett, Rami F Elhayek, Tim Jarrett, Zachary Lattrell, Erica Kahn, Stephen Takach, Jamie Lynne Metzinger, Michael H Goldstein, Amar Sawhney; Efficacy & Tolerability of OTX-TKI, a Sustained Hydrogel Delivery System for a Tyrosine Kinase Inhibitor, in a VEGF Induced Retinal Leakage Model Through 12 Months. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3465.
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© ARVO (1962-2015); The Authors (2016-present)
We evaluated the safety, pharmacokinetics, and pharmacodynamic effect over 12 months of sustained delivery of a tyrosine kinase inhibitor (TKI) from a preformed bioabsorbable hydrogel fiber implant delivered via a single intravitreal injection in Dutch belted rabbits.
Micronized TKI particles were formulated in a hydrogel matrix, OTX-TKI. Thirty eyes of naïve Dutch belted rabbits (n=15) were bilaterally dosed with OTX-TKI at Day 0. Eyes were challenged with an injection of vascular endothelial growth factor (VEGF) at predetermined timepoints over the course of 12 months and were evaluated for leakage by fluorescein angiography (FA) and dilated fundus examination. At each VEGF challenge timepoint, eyes treated with OTX-TKI were compared to untreated control eyes (n=4). Ocular tissue was collected for pharmacokinetic (PK) analysis by liquid chromatography/mass spectrometry (LC/MS) immediately after FA evaluations up to 6 months. Tolerability was assessed via MacDonald Shadduck scores and clinical observations.
OTX-TKI treated eyes significantly suppressed leakage at 3, 6, 9 and 12 months when challenged with a VEGF suspension. The leakage scores in eyes treated with OTX-TKI show minimal to no vascular leakage through 12 months. Untreated control eyes showed high tortuosity and leakage at all timepoints. Retinal tissue showed high drug concentrations (>2800X IC50) through 6 months in the treated animals. MacDonald Shadduck scores showed the treatment was well-tolerated. Other clinical observations raised no safety concerns.
We have demonstrated the ability to deliver a therapeutic dose of TKI to the posterior segment of the eye using an intravitreal bioabsorbable hydrogel implant for up to 12 months. FA leakage scores showed minimal to no change from normal in all OTX-TKI treated eyes at all time points. PK sampling suggests that drug concentrations in retinal target tissues far exceed the IC50 for the study drug. The hydrogel delivery platform could provide patients with a sustained delivery of TKI therapy up to12 months for the treatment of wet AMD.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
PK and PD effect of OTX-TKI in a VEGF-induced leakage model in Dutch Belted Rabbits
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