Sustained drug delivery moving toward clinical use

By Fred Gebhart

Ophthalmologists have terrific treatments for glaucoma and less-than-terrific treatment results. Eye-drop adherence falls below 50% within a few months. One solution: replace daily drops with sustained-delivery technology.

“We have a spectrum of drug-delivery technologies that are moving quickly toward clinical relevance,” said Eliot Lazar, MD, president of elCON Medical. “These new technologies will help us support and treat glaucoma patients better than we have ever been able to do with topical medications.”

Dr. Lazar co-moderated the “New Horizons in Glaucoma Drug Delivery” session that reviewed nine development programs. Some companies are focusing on micro- and nano-scale particles, others on gels and solid drug depots. Some are designed for topical administration, some for injection, and others are implanted like a contact lens. All aim for controlled, steady state delivery over specific time periods to enhance drug delivery to the target tissue and improve therapeutic outcomes.

Amorphex Therapeutics

The topical ophthalmic drug delivery device (TODD) is a soft elastomer drug depot that floats atop the sclera under the eyelid. It can be inserted or removed as easily as a contact lens with none of the problems associated with soft contact lenses that dry out or collect deposits.

“We are delivering therapeutic doses of drug, but without any of the systemic exposure you get from eye drops,” said Robert Thompson, president and CEO. “You can deliver multiple drugs at multiple rates of release with a single device. In all of the testing we have done on animals and human subjects, we have never seen any detectable amount of drug in the blood.”

Clearside Biomedical

Clearside aims to exploit one of the largest yet most contained channels in the eye, the suprachoroidal space. If current clinical programs support successful animal studies, the company will transform the choroid into a drug target and the suprachoroidal space into a reliable delivery channel.

“You can put a large amount of drug into the suprachoroidal space and it spreads very evenly across the posterior of the eye,” said Daniel White, president and CEO.

Injection into the suprachoroidal space compartmentalizes drug in the choroid and the retina with minimal diffusion into other ocular tissues. Suprachoroidal delivery produces similar therapeutic results as intravitreal injection, while using just 10% of the drug concentration typically injected.

Envisa Therapeutics

Drug makers who want uniform tablets use molds; so do electronics manufacturers. Why not use miniature molds to create micro-size injectable rods that contain nano-sized drug particles?

“Our technology is gentle enough that we can formulate very sensitive substances, such as DNA, monoclonal antibodies, even cyclosporine, to create clinically useful products,” said Chief Scientific Officer Benjamin Yerxa, PhD. “We can very precisely create microgram doses with the precise size, shape, and physical characteristics needed to ensure optimal therapeutic activity.”

Trials of extended release prostaglandin in canines show an almost immediate response and a sustained 30% reduction in IOP over more than 120 days. Clinical trials are planned for later this year.

GrayBug

Sustained delivery is an idea whose time is coming, but not quite yet. Only four sustained release ophthalmic formulations have been approved anywhere and most are not available in the United States. Michael O’Rourke, president and CEO of GrayBug, would like to change that.

“We can tailor microparticle and nanoparticle platforms with delivery times from days to months, depending on the need,” O’Rourke said. “We have seen a 30% to 50% increase in drug in target tissues compared to topical delivery for up to 115 days and very good long-term lowering of IOP in animal models.”

The miniature particles are extremely well tolerated, he added. In rabbit tests, particle injections induced inflammation similar to saline injections and significantly less than convention PLGA particles.

Kala Pharmaceuticals

Kala makes nanoparticles designed to penetrate the mucus barrier protecting the eye and other tissues. The mucus-penetrating platform (MPP) uses nanoparticles smaller than the pores in the mucin mesh that protects the eye.

“Our drug particles have been coated with an engineered polymer layer to penetrate the mucin layer, like they were coated with Teflon, to reach the target tissue,” said Chief Medical Officer Kim Brazzell, PhD.

When applied to the surface of the eye, particles quickly migrate to the cornea, aqueous humor, retina, choroid, and sclera but not into the aqueous humor. That migration, via the suprachoroidal space, could transform glaucoma treatment with the potential for neuroprotection with a sustained release topical agent.

Ocular Therapeutix

Ocular Therapeutix’s hydrogel sealant, ReSeal, launches in the United States this year. The same hydrogel technology is being developed for sustained release drug delivery.

“We have an opportunity in glaucoma to do a better drug delivery,” said Scott Corning, vice president of marketing and sales. “Our punctal plug with a prostaglandin analog shows very good IOP lowering at 1 month and 2 months with no hyperemia.”

The company is launching a phase IIb trial in glaucoma later this year, using a 90-day sustained release plug. Other products in development include a dexamethasone-loaded plug for inflammation and an injectable anti-VEGF depot for 6-month use in wet age-related macular degeneration (AMD) and other retinal conditions.

SKS Ocular

SKS uses micro-molds to build bioerodable polymers using gelatin hydrogels. The gels can be layered with multiple drugs released at different rates, according to Barbara Wirostko, MD, chief medical officer of the glaucoma program.

“Glaucoma is our most advanced product,” Dr. Wirostko said. “We have high drug-loading capabilities that can be injected with small needles for long-term sustained release. Sustained delivery is the delivery system of the future for ophthalmic care.”

Other vehicles are being tested for AMD, retinal vein occlusion, diabetic macular edema, and other conditions.

Zordera

Zordera is an early stage university start-up. The goal is to commercialize novel thin-film polymer fabrication for glaucoma and other ophthalmic conditions.

“In glaucoma, we have great drugs and patients are using them 50% of the time, maybe less,” said Co-Founder Robert Bhisitkul, MD, PhD, professor of clinical ophthalmology at the University of California, San Francisco. “We are creating tiny biodegradable films that I can inject in the office that give linear drug release over an extended period.”

The new polymer uses pores matched to the drug to allow diffusion at a controlled rate. Results in animal trials show no evidence of cataracts, endophthalmitis, glaucoma, retinal degradation, or uveitis.