Dramatic changes in glaucoma drug delivery are moving closer to the clinic. Seven companies reviewed the latest data on variety of solids, gels, particles, and combination platforms designed to deliver sustained, calibrated drug doses for up to six months.
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“Drug delivery is a huge unmet need for all of us,” said Eliot Lazar, MD, president of elCON Medical and co-moderator of New Horizons in Glaucoma Drug Delivery session at the 2016 Glaucoma 360. “Some of the companies here today have gone from preclinical to clinical in the past five years. We hope to hear about approved products in the relatively near future. All of these companies are simply the best in class.”
Envisia has adapted printing technologies used in microelectronics to create drug depots that can be used for glaucoma and other ocular conditions. The particles can be engineered in almost any size or physical configuration from 5 nm to a few millimeters.
“If you can take the right drug and put it at the right spot in the right dose, you can get remarkable performance,” said Benjamin Yerxa, PhD, president. “We are about leveraging perfect drug placement and release. The platform is ready for application in ophthalmology in a wide variety of ways, but glaucoma is the first program to enter clinical trials.”
The goal is 24/7 IOP control with prostaglandin efficacy by injecting drug particles into the anterior chamber, Dr. Yerxa said. That means a 25% to 30% IOP reduction with at least 6 months of action from a single administration and less hyperemia than topical drops because injection bypasses the conjunctival vasculature. The drug carrier is biodegradable and disappears at the end of the dosing period.
Early 4-week trials showed IOP reduction similar to travoprost ophthalmic solution (Travatan Z, Alcon Laboratories) with a high-dose version. A low-dose version showed IOP lowering similar to timolol maleate. Six-month trials have begun and data should be available later in 2016.
Envisia is also developing back-of-the-eye applications for sustained-release formulations of large biomolecules. Early preclinical data are promising and more results should be available in 2017.
ForSight is developing an ocular insert shaped like an O-ring that rests under the eyelid as it elutes drug. The latest phase II trial used a 6-month bimatoprost formulation. The insert is designed for removed and replaced for continuous dosing.
“Highly effective topical medications exist, but up to 60% of glaucoma patients cannot use their drops properly,” said James D. Brandt, MD, professor of ophthalmology and vision science and director of the Glaucoma Service, University of California, Davis. “We need a sustained-release, patient-independent method of delivery of medications. And we demonstrated that this novel, sustained-release delivery of bimatoprost can sustain clinically relevant doses for 6 months after a single application.”
The phase II trial compared the bimatoprost-eluting insert with twice-daily timolol drops. A total of 130 patients were randomized to either a drug-loaded insert and placebo drops or placebo insert and timolol drops. While both groups showed a similar 4- to 6- mm Hg drop in IOP after 6 months, the trial was not powered to demonstrate non-inferiority. A 6-month, phase III non-inferiority trial is planned for later in 2016.
About 90% of the inserts were retained and patients were aware of inserts that became dislodged. The inserts were extremely comfortable, Dr. Brandt reported.
“We would expect this insert to be used in patients who cannot or choose not to use topical medications,” he said. “This level of IOP lowering in highly relevant in this clinical realm.”
GrayBug is developing a microparticle technology created at the Wilmer Eye Institute/Johns Hopkins University School of Medicine.
“We have combined IOP lowering and neuroprotection in a single pro-drug compound that would be very effective dosed twice a year in treating glaucoma,” said Jeffrey L. Cleland, PhD, interim CEO. “You can’t have tradeoffs in drug delivery, you have to have safety. We have no inflammation and no histology out to 6 months after administration.”
The company is developing three glaucoma agents––a single IOP-lowering compound; a dual-action, IOP-lowering compound; and IOP-lowering plus neuroprotection. Administration is by injection, either intravitreal or subconjunctival for glaucoma. The particles are injected outside the visual axis, where they aggregate into a visible implant. The implant is resorbed completely over the 6-month course of dosing.
Dr. Cleland said the company has had useful discussions with the FDA and is moving toward its first IND. Clinical trials of an agent to treat wet age-related maculae degeneration (AMD) are expected to begin later in 2016.
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“Glaucoma has major challenges of compliance,” he said. “Converting people from drops to twice a year subconjunctival dosing would be quite attractive. We are working with a pro-drug approach using metabolites that are already used in the eye, which we believe will make a safe platform.”
Massachusetts Eye and Ear Infirmary
Researchers at Harvard Medical School and the Massachusetts Eye and Ear Infirmary are developing a drug-eluting contact lens. The group has extensive preclinical results and is moving toward commercialization.
“Contact lenses are familiar and can be inserted by patients or by friends and family,” said Joseph B. Ciolino, MD, assistant professor of ophthalmology, Harvard Medical School.
Clinical applications for contact lenses are nothing new, Dr. Ciolino noted. Glaucoma surgeons and other ophthalmologists use contact lenses for post-op bandaging. While contact lenses have been tried as drug delivery devices, they have a significant drawback. Lens material readily absorbs drugs, but they release absorbed materials just as quickly.
“The trick is to control release of the drug from the lens,” Dr. Ciolino said. “We have created a thin polymer film around the periphery of a contact lens, much like the film on a cosmetic-colored contact lens. We modulate the film to control the drug release rate.”
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In animal tests, ciprofloxacin has been released at a controlled rate for up to 30 days. An antifungal lens showed a burst effect followed by sustained release that killed all fungi for 3 weeks. A dexamethasone lens showed 100 to 1,000 times the drug concentration in cornea, iris and ciliary body compared to hourly drops and several thousand times greater concentration in the retina.
Testing with glaucomatous monkeys showed better IOP reduction using latanoprost contact lenses compared to latanoprost drops.
“We have a technology that addresses the problem of compliance,” Dr. Ciolino said. “We have increased efficacy and efficiency and we can deliver drugs that can’t be delivered by drops.”
Ocular Therapeutix is best known for ReSure, an ocular wound sealant, but the company is developing a drug-eluting punctal plug. An NDA has been filed for Dextenza, a 30-day, sustained-release formulation of dexamethasone for post-surgical pain. The company is also working with the FDA to create a viable phase III study design for OTX-TP, a travoprost-eluting plug for glaucoma.
“Once inserted, the plug hydrates and lodges in the canaliculus,” said Jonathan H. Talamo, MD, chief medical officer. “A single placement is designed to last 2 to 3 months delivery of preservative travoprost.”
The device looks like a standard punctal plug, Dr. Talamo said, and is inserted like a punctal plug. Phase II trials in South Africa and the United States showed slightly less IOP lowering compared to timolol drops, but within the expected range. Both trials used a double-dummy design––an active plug with placebo drops in one arm and placebo plug with active drops in the other arm.
The trial design raises questions about the results, he continued. It is possible that the dummy eye drops may dilute the effect of the latanoprost in the device. And it is equally possible that the inserted device enhances the effect of the Timolol drops.
“We were encouraged by the phase II results and the clinically relevant IOP lowering out to 90 days,” Dr. Talamo said. “We also saw a consistent 90% retention rate and the device was easy to replace if needed.
Ohr is developing a platform to produce micro and macro particles of any shape or size that can be loaded with drugs. Work to date shows that the platform can be used with a variety of agents, small molecules, large molecules, biologics, and layers of different agents for multi-drug dosing.
“These particles can be used to treat any indication in the eye,” said Barbara Wirostko, MD, vice president of clinical development. “These particles can be placed as needed in, on, or around any portion of the eye for glaucoma, steroid-induced glaucoma, allergies, retinal disease, and more.”
One version of the platform is being developed for a variety of VEGF-induced retinopathies. A wet AMD product is moving into phase III trials while products for retinal vein occlusion, proliferative diabetic retinopathy, and diabetic macular edema are in phase II trials. Particles designed to treat steroid-induced glaucoma have demonstrated zero order release profiles for as long as 6 months. The same technology is also feasible for large molecule biologic agents.
“We see a large unmet need for steroid-induced glaucoma,” Dr. Wirostko said. “Due to the increasing delivery of steroids to the eye, there is an emerging need to treat this type of glaucoma. Disease is directly related to the potency of the steroid, the delivery mode of the steroid, as well as the frequency of the steroid. And we don’t have a good solution.”
About 30% of the general population appears to be susceptible to steroid-induced glaucoma, she continued, although patients with primary open-angle glaucoma (POAG) have a higher likelihood of developing the disease.
“With an emerging and increasing burden of diabetes and higher use of intravitreal steroids, there is going to be a higher incidence and prevalence of steroid-induced glaucoma,” Dr. Wirostko said. “We are positioned to move this technology forward with a glaucoma-sustained delivery product.”
Glaucoma treatments come in two broad options: patient-administered topical systems and invasive clinician-administered systems. Topical systems have the potential to treat glaucoma effectively, but adherence is a problem. Clinician-administered systems can be effective, but tend to be invasive, expensive, and used only after topical systems fail.
“We developed a system that combines the advantages of both topicals and clinician-administered treatments,” said Morgan Fedorchak, PhD, co-founder, Selkie Therapeutics and assistant professor of ophthalmology, University of Pittsburgh School of Medicine. “Our SoliDrop is administered as an eye drop. Once the drop hits the lower fornix, it forms a gel that provides 30 days of continuous release.”
SoliDrop is a thermo-responsive hydrogel carrier with drug-loaded polymer microspheres. At room temperature, the gel is slightly viscous than water. At body temperature, it quickly coalesces into a gel that lodges beneath the lower eyelid.
Preclinical data with brimonidine in rabbits are promising, she added. The gel showed similar IOP-lowering effects as twice-daily brimonidine drops and 100% retention during a 28-day trial.
There was also no change in IOP in the contralateral eye in the SoliDrop group. The eye drop group showed a significant drop in the contralateral eye, a common occurrence.
“This shows a significant decrease in systemic absorption compared to eye drops,” Dr. Fedorchak said. “One reason for that could be that we are administering about 100 times less drug in total using SoliDrop compared to twice daily eye drops.”