Effectiveness of Sustained Release TKI Hydrogel Combined with Bevacizumab in a VEGF Induced Retinal Leakage Model Through 12 Months

Abstract

Purpose : The study evaluated the pharmacodynamic effect of a single dose of OTX-TKI as a combination therapy with bevacizumab, compared to bevacizumab monotherapy, delivered via intravitreal injection in Dutch belted rabbits for 12 months.

Methods : Micronized tyrosine kinase inhibitor (TKI) particles were formulated in a hydrogel matrix, OTX-TKI. Animals were randomized to receive an injection of OTX-TKI plus 1.25 mg of bevacizumab (n=15, 30 eyes) or 1.25 mg of bevacizumab alone (n=9, 18 eyes) at Day 0. Eyes were challenged with an injection of vascular endothelial growth factor (VEGF) at predetermined timepoints over 12 months and were evaluated for leakage by fluorescein angiography (FA) and dilated fundus examination. At each VEGF challenge timepoint, treated eyes were compared to untreated control eyes (n=4). Tolerability was assessed via MacDonald Shadduck scores and clinical observations.

Results : OTX-TKI with bevacizumab significantly suppressed leakage at 2 weeks, and sustained efficacy through 12 months when challenged with a VEGF suspension. Bevacizumab monotherapy suppressed leakage at 2 and 4 weeks; leakage returned as expected at the next VEGF challenge timepoint. Untreated control eyes showed high tortuosity and leakage at all time points. Retinal tissue showed high TKI concentration (>2150X IC50) through all time points in the treated animals. MacDonald Shadduck scores showed the treatment was well-tolerated. Other clinical observations raised no safety concerns.

Conclusions : We have demonstrated that a combination of OTX-TKI plus bevacizumab is able to suppress leakage at 2 weeks, with sustained effects seen through 12 months. Bevacizumab monotherapy was efficacious through 4 weeks with leakage returning by week 12, which is consistent with current standard of care. One treatment of OTX-TKI with bevacizumab appears to be superior to bevacizumab monotherapy with regard to duration of therapy 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.

 

Pharmacodynamic Effect of OTX-TKI plus bevacizumab, versus bevacizumab monotherapy through 12 months