Good drugs need better delivery plan

Developers want to find methods of releasing drugs into the eye that are safer, more effective, longer-lasting.

By Vanessa Caceres, Contributing Editor

Ophthalmologists have long relied on eyedrops and, more recently, injections and stents to treat various eye diseases. But mostly these therapies have been far from perfect, for myriad reasons. Drops can be difficult for patients to insert into the eye, and they often have to be inserted a few times a day. Patients who need direct, short-term injections into their eyes can balk at the thought. And stents have only been on the market for a couple of years; researchers have called for studies to assess long-term outcomes.¹

Researchers recognize these shortcomings. After the successes of Iluvien and Ozurdex, both sustained-release intravitreal therapies, a few companies have dedicated resources, skills and patience to developing patient-friendly, long-term treatments for chronic eye diseases.

No single delivery system works for every drug, says Vicente Anido Jr., PhD, chairman of the board, Aerie Pharmaceuticals. “This is why venture companies have spent so much money to start drug delivery companies. Depending on the chemical structure, certain drugs are more amenable to certain delivery systems than others. You really have to kick the tires before you find the right one.”

Microparticles injected into a rabbit eye.
COURTESY AERIE PHARMACEUTICALS

Ozurdex and Iluvien: The game changers

Among the current methods of drug delivery, retinal specialist Randall V. Wong, MD, of Fairfax, Va., identifies the two that will expand. First is intraocular. It is widely accepted, easy to use and safe, he says. “The variety of drugs available for intraocular delivery will continue to increase the development of multiple platforms or ways in which drugs are introduced directly to the eye,” says Dr. Wong.

The second is the continued development of sustained release and controlled-release formulations of drugs that can deliver longer-term treatment for chronic diseases, Dr. Wong says.

And that’s all because of Ozurdex and Iluvien. Their developers broke out of the box.

Ozurdex (Allergan), which releases in the eye for four to six months to treat branch retinal vein occlusion, and Iluvien (Alimera Sciences), which releases steroids for up to three years to continuously treat DME, have made researchers rethink the rules, Dr. Wong says. “These long-term controlled release medications may prove to be more effective, have the promise of more efficient treatment and avoid the peaks and valleys of monthly treatment, and have financial savings,” Dr. Wong says. The latter includes fewer office visits, saving the patients or their caregivers time and money.

What’s also happened is that researchers look at eyedrops differently, Dr. Anido says. “Over the years the larger companies would take a drug that has been useful in one area and put it in an eyedrop formulation and market it for the eye. Then, about 10 years ago, Eyetech, Inc. launched Macugen [an intravitreal injection], and it opened the imagination. Folks had never thought about drug delivery systems in a large way.”

But ophthalmologists and drug manufacturers looking for the next breakthrough in drug delivery are still focused on effective, safe, disease-site targeted treatments, says Daniel H. White, CEO and president, Clearside Biomedical. What is different is the effort to create them with an extended time between retreatments.

“From a drug delivery perspective, the industry is always looking for alternative solutions that are less irritating, safer and less toxic,” adds Breca Tracy, PhD, vice president and managing director, Caisson Biotech.

The search

Much (although not all) of the new research into ocular drug delivery focuses on treating glaucoma or retinal diseases, such as wet age-related macular degeneration or diabetic macular edema (DME), because the retina is a traditionally hard-to-reach area due to the blood–brain barrier. “This restricts most drugs taken by mouth or given intravenously from treating the brain and the retina,” Dr. Wong says. However, newer approaches that directly inject drugs to the target area have changed the way that retina diseases are treated, he says.

Although injections have become an effective way to reach the eye, ophthalmologists need to consider how realistic or safe it is to provide multiple injections to a patient over the course of decades, says Rafal Farjo, PhD, founder and COO of EyeCRO LLC.

Dr. Anido says that ophthalmology has been late to the party compared with other specialties’ innovations in drug delivery, but the specialty is making progress. Venture companies invested in drug-eluting stents used in microinvasive glaucoma surgery are now following one another to find other ways to treat other ocular diseases.

Heparosan delivery system

With its drug delivery system HEPtune, Caisson Biotech uses heparosan, a polymer that naturally occurs in the body, to improve drug efficacy, half-life extension and safety, Dr. Tracy says. Heparosan can be used as an alternative to polyethylene glycol (PEG), which many drug manufacturers use so a drug can circulate longer in the body. However, PEG is not considered safe for everyone, Dr. Tracy says.

HEPtune schematic of the process of coupling the drug to the heparosan polymer.
COURTESY CAISSON BIOTECH

“Caisson has demonstrated long plasma half-lives and stability in the bloodstream,” according to the company website. “The body produces no extracellular enzymes that degrade heparosan, and there are no known receptors or binding proteins for heparosan.”

Caisson is exploring opportunities in ophthalmology because its technology is potentially synergistic for the treatment of AMD as well as other ocular-related diseases, Dr. Tracy says. It hasn’t settled on any one type of delivery method, but injectables may be the company’s “sweet spot,” she adds.

In 2012, Caisson Biotech disclosed its first partnership with global health-care company Novo Nordisk AS. Last year, Caisson expanded that agreement’s scope to be nonexclusive for drug indication areas, including diabetes care products, human growth hormone therapy, treatments for obesity and for inflammatory diseases, such as Crohn’s disease, lupus, and rheumatoid and psoriatic arthritis.

Sustained treatment using punctal plugs

Punctal plugs, or intracanalicular depots, are usually associated with dry eye treatment, but the company Ocular Therapeutix is using the same anatomical approach for its Dextenza, which offers a sustained four-week release of dexamethasone in the drug depot. The product is now in phase 3 trials for the treatment of postoperative inflammation and pain.

Other ongoing trials for Dextenza include an allergic conjunctivitis trial (phase 3) and inflammatory dry eye disease (phase 2). Both trials have completed enrollment; efficacy results will be reported later this year.

Ocular Therapeutix also is testing, via a phase 2b trial, its sustained-release travoprost. This drug, meant to last for up to 90 days, is administered the same way as Dextenza. Efficacy results will be reported later this year. With both Dextenza and sustained-release travoprost, physicians and their patients will have a way to monitor that the drug is still in the eye during the treatment period. Once treatment is finished, “the hydrogel resorbs and exits the nasolacrimal system without need for removal by the physician,” according to the company website.

Also in development is a sustained release anti-VEGF hydrogel injection for retinal diseases. The injection would combine the treatment with a PEG hydrogel and anti-VEGF molecules.

EyeCRO’s Micro-emulsion ocular penetration system uses stable micro-emulsions as its delivery system.
COURTESY EYECRO

Using the suprachoroidal space

Clearside Biomedical focuses on treating retinal diseases such as uveitis, retinal vein occlusion, wet AMD and DME by administering drugs through the suprachoroidal space with a micro-injector, according to Mr. White. “We believe that targeting drugs to the pathological tissues of the disease can lead to better management of the course of the disease, and we make this a core part of our drug development programs,” he says.

Potential advantages, Mr. White says, for suprachoroidal delivery over other intra- and periocular delivery methods are that it could allow for lower doses or fewer doses than current local treatments, with potentially better efficacy and fewer adverse events.

The company has a lead product for noninfectious uveitis and retinal vein occlusion. It also has multikinase inhibitors for wet AMD under development, as well as other therapies with third-party collaborators such as Santen and Spark Therapeutics, Mr. White says.

Micro-emulsions

EyeCRO’s Micro-emulsion Drug Ocular Penetration System (MiDROP) uses stable micro-emulsions as its delivery system, and is designed to provide better eye-drop drug delivery to all eye tissues, Dr. Farjo says. The company’s rabbit studies² show that micro-emulsions have a laser-like focus.

“Typically, the aqueous and vitreous humor act as a sink for drug deposition, but in our data, we have found the least amount of drug there and find most of it appears to be trafficking through the actual tissues of the eye,” Dr. Farjo says. MiDROPS, if successful in obtaining FDA approval, would let physicians develop personalized treatments for patients using many different agents deemed safe for chronic use.

EyeCRO researchers have developed a patented library of formulations³ that use FDA-approved ophthalmic materials, according to Dr. Farjo. Along with its partnerships, EyeCRO has created a spinout company to further advance the MiDROPS platform.

Large clinical studies in the United States and Australia have demonstrated that systemic delivery of fenofibrate can slow the progression and severity of diabetic eye disease, and EyeCRO’s spinout is developing an eyedrop formulation of fenofibrate. “Our data indicates that the eyedrop application of fenofibrate in MiDROPS will provide improved efficacy through targeted delivery to the posterior segment,” Dr. Farjo says.⁴

Microparticle release

In August, Aerie Pharmaceuticals announced a partnership with GrayBug, a venture pharma company developing an injectable therapy to treat wet AMD and glaucoma. The technology incorporates a microparticle, controlled-release drug delivery system.

Aerie will test whether GrayBug’s biodegradable polymer can deliver its AR-13154, a small molecule for wet AMD, in a successful multi-month release form. “As [AR-13154] erodes in the back of the eye, that’s how the drug gets released,” Dr. Anido says. “We are hoping it will last there for about six months.”

Under the collaboration, Aerie will also evaluate long-term sustained delivery of the active ingredient in its drug Rhopressa for glaucoma and ocular hypertension. Aerie announced recently it will file an NDA next year for Rhopressa.

Aerie executives will know in about a year if the wet AMD small molecule delivery system will work for its intended use, but Dr. Anido is realistic about the possible outcome. “It is very risky at this stage of development,” he says. “This is why we are also finding other ways to deliver our drugs to the back of the eye.”

The investigative drugs are undergoing animal testing right now. If the company’s push for innovative drug delivery works, it could take about six years before it would reach practices, Dr. Anido says. OM

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