Michael N. Cohen, MD; Chirag P. Shah, MD, MPH; and Jeffrey S. Heier, MD

Few therapeutic interventions have been as revolutionary or impactful as the advent of intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy.^1–4 Currently, the standard ophthalmologic route of administration is by direct injection into the vitreous cavity, providing a high, initial drug concentration that decreases over time. The rate of diffusion of the drug through the vitreous is determined by several factors including molecular weight, hydrophilicity, lipophilicity, and ionic charge.⁵ Subsequent elimination is likely controlled anteriorly by aqueous flow dynamics and posteriorly by both retrochoroidal flow and transcellular transport, mediated by proteins in the retinal pigment epithelial cells.⁶ Along with the half-life of the drug, these diffusion and elimination pharmacokinetics ultimately limit its durability, with studies demonstrating that VEGF suppression ranges from 26 to 69 days after intravitreal injection.⁷ To combat this, patients require frequent injections, and vitreoretinal specialists attempt to individualize each treatment schedule to minimize the patient’s total injection burden but still maximize their visual recovery.^8–10 Despite an overall favorable safety profile, intravitreal injections carry a risk of endophthalmitis, cataract, retinal tear or detachment, intraocular hemorrhage, and increased intraocular pressure. Patients face these risks with each injection, and, because of the frequency, can experience an economic and/or even emotional burden over time.¹¹ Perhaps the bigger problem is varying degrees of postinjection discomfort, either the result of the injection itself, or the use of topical betadine for infection prophylaxis. By developing a method, or device, capable of sustained medication delivery into the vitreous cavity and leading to a reduction, or even elimination of intravitreal injections, the landscape of intravitreal drug administration would change dramatically.

As the scope of intravitreal medications continues to intensify and expand, research efforts dedicated toward sustained delivery models continue to emerge. The most promising technologies for sustained anti-VEGF delivery will be discussed herein.

Surgically implantable devices hold promise as vehicles to release the drug directly into the vitreous cavity; they can be equipped with a refillable reservoir capable of minimally invasive refills. Similar to a glaucoma drainage implant, these devices are surgically implanted, rest on bare sclera, and would remain in place as long as therapy is required, or until the device is no longer able to deliver the drug. Two different systems are being developed simultaneously: the Posterior MicroPump Drug Delivery System (Replenish Inc), which delivers nanoliter doses through a wireless, programmable dosing schedule, and the Port Delivery System (Genentech/Roche), which is designed to provide a continuous release of ranibizumab into the vitreous cavity.12,13

The MicroPump system relies on microelectrochemical system technology, consists of titanium, parylene, and silicone, and is implanted underneath conjunctiva and Tenon’s capsule. It is composed of carefully sealed electronics responsible for powering the device and controlling the drug delivery mechanism, a drug reservoir chamber, a one-way, pressure-dependent valve, a refill port that can be accessed with a 31-gauge needle using a transconjunctival approach, and a cannula implanted directly into the pars plana.¹⁴ Drug delivery is based on the low-power process of electrolysis, which electrochemically induces water to change phase to oxygen and hydrogen gas, generating pressure in the drug reservoir and forcing the drug out through the cannula. The length of time required to deliver a specific drug dose is determined by the speed and magnitude of the applied current. Interestingly, the device should be compatible with any available medication intended for intravitreal injection.

After demonstrating the device was biocompatible and safe in animal models, it was subsequently implanted in human participants.^12,14 Researchers conducted a single-center, single-arm, open-label study involving 11 patients with diabetic macular edema, and implanted the Posterior MicroPump Drug Delivery System for the purpose of delivering ranibizumab therapy over a course of 90 days. All 11 surgical implantations were completed without complication, and no serious adverse events occurred during the follow-up period. Four of 11 patients did not receive the full dose of ranibizumab, highlighting several different causes of suboptimal dosing, which will likely be addressed in future models. As the primary goal of this study was to demonstrate safety and tolerability of the device, no comparisons were made between bolus injections of ranibizumab and the microdose infusions via the MicroPump. Of note, there was no statistical difference in the visual acuity and central foveal thickness between baseline and the final visit. Clinical trials for United States Food and Drug Administration (FDA) approval are under design.

The Ranibizumab Port Delivery System is surgically placed in the pars plana with a 3.2 mm sutureless incision and is covered by conjunctiva. After completion of surgical fixation, the proximal end of the device is subconjunctival but external to the sclera, while the body of the implant extends into the vitreous cavity. Designed to work exclusively with ranibizumab, the device’s 500 μg reservoir comes preloaded with the drug. The implant controls the rate and duration of ranibizumab delivery, providing a continuous release of drug into the vitreous cavity between each refill procedure. Reservoir refills are carried out in the office with a custom refill needle.¹⁵

Results of the phase I, proof-of-concept study were released in 2012 and discussed during the 2012 American Academy of Ophthalmology Retina Subspecialty Day.¹³ Twenty treatment-naïve patients, newly diagnosed with neovascular age-related macular degeneration (AMD), were selected for implantation of the Port Delivery System. Surgical implantation of the device was complicated by 4 potentially sight-threatening adverse events (20%): 1 case of endophthalmitis, 2 cases of persistent vitreous hemorrhage, and 1 traumatic cataract. At the end of the study, only 1 patient with persistent vitreous hemorrhage had a poor visual outcome, and the other 3 had improved visual acuity from baseline. At the 1 year primary endpoint of the study, most patients attained significant visual acuity improvement from baseline, gaining an average of 12 letters, and demonstrated a corresponding anatomical improvement in central retinal thickness. Interestingly, patients required a mean of 4.2 refills during the 1 year period. After 1 year, the study protocol called for the explantation of the device in 6 patients and the continued observation of all others for an additional 24 months. There were no other adverse events reported, and patients tolerated the refilling and explantation procedures well.

As this was a proof-of-concept study only, it was not powered to sufficiently demonstrate efficacy as a primary outcome measure. A phase II trial (LADDER) is currently underway and estimated to be completed in October 2017. This is a multicenter, randomized, double-blinded, active-treatment controlled study to evaluate the safety and efficacy of different doses of ranibizumab delivered via the Port Delivery System to help find the optimum drug concentration for sustained delivery.16 Low, medium, and high doses of ranibizumab delivered through the Port Delivery System will be compared to monthly intravitreal ranibizumab injections. In an effort to address safety concerns from device implantation during the phase I study, a surgical training program will aim to help minimize risks of the procedure. There is hope that completion of the phase II study will allow clinicians and researchers to achieve a better understanding of true sustained delivery anti-VEGF performance.

Injectable Particulate Systems

Advances in nanotechnology allow for the potential use of nanoparticles for enhanced drug penetration and/or targeting and sustained release. Specific classes of nanoparticles that have potential in the future of anti-VEGF delivery are liposomes and microspheres/nanospheres. Verisomes and hydrogels are 2 additional injectable particulate technologies of particular interest.

Liposomes are small, closed-lipid vesicles that are made of a modifiable phospholipid bilayer. Their size, exact lipid composition, and electric charge can be customized, allowing them to be excellent drug carriers.¹⁷ Additionally, they have almost no toxicity, an extremely low antigenicity, and can be biodegradable. Early research in animal models suggests that intravitreal injection of liposomes containing a drug may allow for controlled and sustained release, an increase in half-life of the drug, and a decrease in potential toxicity.^18–20 In one animal study, aqueous and vitreous concentrations of bevacizumab were compared after either liposomal bevacizumab injection or standard bevacizumab injection. Those that received liposomal bevacizumab showed concentrations that were five-fold higher on day 42 when compared to eyes that received free bevacizumab injections.²¹ Still in the preclinical stage, there are several limitations including the potential for blurred vision after injection, low drug load, poor stability when a water-soluble drug is encapsulated, and limited storage conditions.¹⁶

Although similar to liposomes in both shape and size, microspheres have greater stability and drug-carrying capacity.²² Microspheres are spherical preparations whose particles have diameters ranging from 1 μm to 1000 μm; preparations whose particles have smaller diameters (nanomicrons) are called nanospheres. The drugs are encapsulated in natural and/or synthetic polymers, allowing them to target certain tissues and achieve a state of sustained, continuous release. Frequently used polymers include polylactic acid, polyglycolic acid, and poly (lactic-co-glycolic acid) (PLGA). Research has demonstrated that polylactic acid and PLGA can be inserted without any evidence of histologic or functional toxicity to the retina.23 For comparison, the sustained-release dexamethasone intravitreal implant, Ozurdex (Allergan Inc), is a biodegradable PLGA device. Polylactic acid, polyglycolic acid, and PLGA are also all used as suture material, vascular grafts, and bone screws and all are FDA-approved for drug delivery.²⁴

More than a decade ago, a microsphere system was used in an animal model to provide a continuous release of pegaptanib over several weeks.²⁵ These particles demonstrated promising in vitro results of sustained anti-VEGF release; however, there are no active clinical trials at this time.^11,26

Verisome (Icon Bioscience Inc) is a proprietary technology designed for sustained and controlled delivery of small molecules, proteins, or antibodies for up to one year.²⁷ The Verisome-based drug is injected into the vitreous cavity with a 30-gauge needle and forms a single spherule that settles inferiorly. The system is biodegradable, and its subsequent reduction in size reflects the degradation of both the delivery system and release of active drug.¹¹ Positive results have been demonstrated in a phase I trial using a single intravitreal injection of IBI-20089 (a proprietary drug formulated with the steroid triamcinolone acetonide) to treat patients with macular edema due to retinal vein occlusion.²⁶ Combination therapy with IBI-20089 and ranibizumab for patients with neovascular AMD is currently in phase II clinical trials.¹¹ A Verisome system formulated with an anti-VEGF drug is still in preclinical stages.

Similar to Verisome technology, hydrogels can also be injected in a liquid form, via a small-gauge needle, into the vitreous. Hydrogels are polymeric networks that permit the alteration of diffusion and permeation characteristics, allowing for the creation of an optimal drug delivery system.²⁸ These hydrogels lack hydrophobic interactions that normally denature biomolecules, and are therefore excellent for encapsulating biomacromolecules. Although these natural polymers provide increased biodegradability, increased biocompatibility, and biologically recognizable moieties, they still might provoke inflammatory responses within the body.²⁹

Ocular Therapeutix is in the preclinical stages of developing a polyethylene glycol hydrogel that contains anti-VEGF drug particles. The bioresorbable hydrogel creates a tight meshwork that permits complete embedding of the drug molecules, allowing for controlled release of drug and stability over time. As the hydrogel degrades with hydrolysis, the anti-VEGF molecules dissolve from the surrounding particles and diffuse through the hydrogel and into the surrounding tissue. They have pioneered a coiling process that, because of its “coiled” configuration, allows a larger amount of drug to be deposited than would have been possible without the conformational change (Figure 6-1). Animal studies have been promising thus far, demonstrating a favorable safety profile over a 2-month period, and a very favorable pharmacokinetic profile of its sustained release formulation over a 28-day period.^30,31 The technology remains in the preclinical stages of development, with the goal of drug efficacy set at 4 to 6 months for each injection.

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