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A Nano Approach to Posterior Segment Drug Delivery in DME Patients

Diabetic macular edema (DME) is a leading cause of vision loss. Intravitreal corticosteroids remain important options for patients who fail to respond to anti-VEGF agents. These are two known facts in the ophthalmic world. 

However, their use [intravitreal costicosteroids] in DME patients has been limited by increased risks of infectious and non-infectious endophthalmitis. Since most patients are treated with a series of intravitreal injections, the cumulative per-patient risk of endophthalmitis is higher than the per-injection risk.

Reducing this lifelong cumulative risk by decreasing the number of injections represents one of the major benefits of extended-release drug preparations. Therefore, an extended release biodegradable intravitreal implant, which delivers a decreased dose of dexamethasone in a linear manner over approximately six months while still achieving efficacy, could reduce cataract and intraocular pressure (IOP) elevation rates associated with current therapies.

At the American Society of Cataract and Refractive Surgery (ASCRS) 2017 meeting in Los Angeles, USA, Dr. Benjamin Yerxa and colleagues from Envisia Therapeutics (in Durham, North Carolina, USA) presented a poster entitled Nonclinical Development of An Intravitreal Extended Release Implant for the Treatment of Diabetic Macular Edema. 

In that poster, Dr. Yerxa reported that ENV1105 was designed for intravitreal delivery using a novel nano and microparticle precision implant manufacturing (PRINT) technology to release dexamethasone over a long period (approximately six months). In ENV1105, according to Dr. Yerxa, implants were fabricated using dexamethasone and polymers designed to produce a linear release rate, and content and release were measured by reversed-phase high performance liquid chromatography (RP-HPLC). 

“These extended release dexamethasone implants were fabricated with a focus on two key features: a high degree of mass and drug content uniformity, and a low degree of implant to implant variability in drug release. In vitro data demonstrated a near zero-order release rate over six months,” explained Dr. Yerxa and colleagues. 

following a single, bilateral, intravitreal administration of ENV1105 in an albino rabbit, with analyses performed at week 1, month 1 and month 3 timepoints. At these timepoints, dexamethasone concentrations were measured in ocular matrices, remaining implants, and plasma by LC-MS/MS (liquid chromatography-mass spectrometry). The rabbits were examined via slit lamp biomicroscopy and indirect ophthalmoscopy.

In this study, Dr. Yerxa and colleagues demonstrated that following the administration of ENV1105, therapeutically relevant dexamethasone concentrations were present in target tissues of retina, choroid, and vitreous up to the third month after administration. More importantly, anterior and systemic exposure was not quantifiable. This has important implications for patients, as the side effects of intravitreal corticosteroids could be eliminated by minimizing anterior segment and systemic exposure.

However, with ENV1105 administration, posterior segment tissue concentrations following administration were generally not quantifiable at month 3, and dexamethasone was quantifiable in aqueous humor and plasma through month 1. 

According to Dr. Yerxa and colleagues, “Intravitreal administration of a dose sparing, uniformly releasing dexamethasone implant produced extended delivery to the posterior target tissues with no anterior or systemic exposure and excellent ocular tolerability, and may thus decrease the risk of adverse effects.”

Reference:

ASCRS 2017 Eposter #32392-0234: Nonclinical Development of An Intravitreal Extended Release Implant for the Treatment of Diabetic Macular Edema by Dr. Benjamin Yerxa, et.al.

Editor’s Note: The 2017 annual meeting of the American Society of Cataract and Refractive Surgeons (ASCRS 2017) was held in Los Angeles, California, USA, on May 5-9, 2017. Reporting for this story also took place at ASCRS 2017.

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