Anti-angiogenic agent, platform planned for human trial


Findings from preclinical studies show that a novel intravitreal depot of an anti-angiogenic drug releases the medication over a period of at least 6 months, is well-tolerated, and prevents VEGF-induced retinal vascular leakage.

Take-home: Findings from preclinical studies show that a novel intravitreal depot of an anti-angiogenic drug releases the medication over a period of at least 6 months, is well-tolerated, and prevents VEGF-induced retinal vascular leakage.

An intravitreal sustained hydrogel delivery system, releasing a tyrosine kinase inhibitor (TKI) with known anti-angiogenic properties, demonstrated positive results in preclinical studies investigating tolerability, efficacy, and pharmacokinetics.

Planning for the first human trial to investigate the TKI depot as a treatment for retinal vascular disease is underway. Ocular Therapeutix is developing the product, OTX-TKI, and is collaborating with Regeneron to develop a 6-month depot delivery system for its aflibercept (Eylea).

“Studies performed in Dutch Belted rabbits showed that the hydrogel platform delivered a low molecular weight TKI at zero order kinetics for a period of longer than 6 months,” said Peter Jarrett, PhD, chief scientific officer, Ocular Therapeutix. “The system had excellent tolerability, and we also obtained evidence of biological activity.”

Dr. Jarrett pointed out that the findings of these studies indicate that the TKI delivery platform could provide patients with an alternative treatment for retinal vascular diseases. The platform would reduce the injection burden compared with used anti-VEGF agents that are administered every 4 or 8 weeks.

The investigational product formulates micronized particles of the TKI into a bioabsorbable depot made of a synthetic hydrogel. The anti-angiogenic activity of TKIs is mediated by preventing activation of VEGFR-2 receptors, and the synthetic hydrogel has a record of excellent biocompatibility.

“TKIs are insoluble molecules that would precipitate to create floaters in the vitreous,” said Dr. Jarrett. “(The molecules) would then be cleared quickly as they slowly dissolve. Our goal was to develop a platform that could deliver the TKI to target tissues over a period of six months,”

The hydrogel matrix is a shape-changing device. It is formed into a long fiber that can be placed inside the lumen of a 27-gauge (or smaller) needle. Once the needle penetrates into the vitreous, a wire is used to push the depot into the eye. As the fiber gets wet, it becomes shorter and thicker, acquiring a configuration that will not obstruct the visual axis.

Preclinical testing


Preclinical testing

Dutch Belted rabbits were chosen as the model for the preclinical studies because the eyes of these animals are highly sensitive to implanted foreign materials. In the tolerability study, 9 animals were bilaterally injected with OTX-TKI and followed for up to 6 months with comprehensive evaluations.

The evaluations included clinical examination, electroretinography, optical coherence tomography, fluorescein angiography, and fundus photography. In addition, 6 eyes each were enucleated at months 1, 3, and 6 for detailed histopathologic analysis. The clinical and imaging evaluations showed no abnormalities, and the histopathology revealed no to minimal inflammatory response.

A pharmacokinetics study measuring concentrations of the TKI in ocular tissues and fluids demonstrated zero order release from the sustained release platform over the 6-month study period. Levels in the vitreous, retina, and choroid exceeded the minimal inhibitory concentration (IC50) by more than 3,800-fold.

“In the aqueous humor, the TKI was below the level of quantification (< 0.015 ng/mL), indicating that the drug is cleared through the back of the eye,” Dr. Jarrett said. “Its concentration was also below the level of quantification in plasma at all time points evaluated.”

The bioabsorbable hydrogel matrix disappeared about 7 to 8 months post-injection. 

A study evaluating biological activity of OTX-TKI included 9 animals that were bilaterally injected with OTX-TKI and a group of 4 control eyes that were challenged with VEGF injections after 2, 3, and 6 months.

The follow-up examinations showed the VEGF injections induced significant vascular leakage in the control eyes, but fluorescein angiography leakage scores in the eyes injected with OTX-TKI were at most minimally changed from baseline.

“This is a very rigorous test for evaluating the anti-angiogenic activity of OTX-TKI,” Dr. Jarrett added. “The finding that there was essentially no vascular leakage is very encouraging.”

Potential indications being targeted for OTX-TKI include neovascular age-related macular degeneration, retinal vascular occlusion, and diabetic macular edema.


Peter Jarrett, PhD


Peter Jarrett, PhD, is an employee of Ocular Therapeutix, Bedford, MA. This article is based on studies presented at the 2017 annual meeting of the Association for Research in Vision and Ophthalmology on this technology.

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