Toward Better Delivery of Glaucoma Meds

Will anything replace the eye drop?

BY JERRY HELZNER, SENIOR EDITOR

In an era in which advanced technology is permeating almost every area of ophthalmology, from diagnostic imaging to gene-based treatments, more than two million Americans with glaucoma are still using a horse-and-buggy era method to administer their medications.

These patients, many of them elderly, visually impaired and afflicted with multiple illnesses, are now held personally responsible for instilling old-fashioned eye drops — sometimes from multiple bottles — according to a strict schedule, and for getting the drops into the eye in a way that maximizes the drug's effectiveness. In study after study, researchers have found non-compliance rates of up to 35%, with higher non-compliance rates correlated to more frequent dosing schedules.

Moreover, glaucoma specialists point out that many patients are relatively symptom-free in the early stages of the disease. Therefore, given the cost of these drugs, there is little sense of urgency to follow the medication schedule. This is in contrast to retinal disease, where patients experiencing vision loss are almost always reported to be highly compliant.

Given all these factors, the multi-billion dollar US glaucoma market has long been fertile ground for innovators who can devise a better and more cost-effective way to deliver glaucoma medications. This article will explore a number of these efforts and where they stand today.

The State of Innovation

Recognizing the magnitude of the non-compliance problem in the treatment of glaucoma, manufacturers of these medications have come up with a variety of devices, reminders, easy-opening bottles and educational materials to encourage compliance. But even when these methods work, many patients lack the physical coordination to get the medication to where it will do the most good. The result is that, with a large percentage of glaucoma patients, only a fraction of the prescribed dosage reaches its intended target in the eye.

“We are still in the dark ages when it comes to the delivery of glaucoma medications,” says Andrew Rabinowitz, MD, a glaucoma specialist based in Phoenix. “We must find better ways to successfully deliver these drugs.”

The good news is that innovation in the delivery of glaucoma medications has progressed to the point where realistic solutions are now on the horizon.

Punctal Plugs With Latanoprost Core

One of the most promising ideas in clinical trials is a concept being developed by QLT, Inc. using punctal plugs with a core of latanoprost as a method of sustained-release drug delivery.

Last summer, QLT announced encouraging preliminary data from its ongoing phase 2 study of its proprietary drug-eluting punctal plug technology. Results from the 44-g Latanoprost Punctal Plug Delivery System show that the mean change in IOP from baseline was −3.5 mm Hg at the week four visit, with 36% of patients having an IOP decrease from baseline greater than or equal to 5 mm Hg. These data resulted from an early, proprietary punctal plug prototype that was well tolerated.

The device is roughly equivalent to 29 latanoprost drops, or about one-third the amount of drug in eye drops given over three months.

Concurrent with the phase 2 clinical trial, newer punctal plug prototype designs for the sustained-delivery system are being tested in an ongoing multicenter study in more than 500 healthy volunteers. Safety, tolerability, comfort, ease of handling, insertion/removal and retention are being assessed. The overall goal for development is to achieve 90% retention for 90 days. The summer 2009 preliminary results for some designs showed an overall retention rate of 75% after eight weeks of follow-up.

Sacramento's Richard A. Lewis, MD, the lead investigator of this study, says that additional progress has been made. “The two big issues are retention and effectiveness,” notes Dr. Lewis. “We have tried some new designs for the punctal plugs that will keep them in the eye longer, as we did have an issue with some of the plugs falling out.”

Dr. Lewis says that as the plug design has evolved, retention rates have improved, with the goal of 90% to 95% retention becoming a realistic one. (In mid-March, QLT announced that the latest clinical data shows an 81% plug retention rate at 90 days).

“We are also looking at the appropriate concentration of the drug needed to deliver the medication for 90 days,” says Dr. Lewis. “That is something we are working out.” (In mid-March, QLT said new clinical data showed no additional lowering of IOP at higher doses of latanoprost).

A pivotal phase 3 study will be necessary before the concept could be approved for routine use in treating glaucoma.

Drug-eluting Contact Lenses

A team primarily made up of Harvard Medical School researchers won a recent MIT innovators competition in the Life Sciences category for their concept of a drug-eluting contact lens that could be used to deliver glaucoma medications, antibiotics or other ocular therapeutics. Their concept was also featured in an article in July 1, 2009 issue of Investigative Ophthalmology and Visual Science (IOVS).

Though the idea of a drug-eluting contact lens isn't new, team member Daniel Kohane, MD, PhD, an anesthesiology and critical care pediatric specialist from Boston, thinks this particular design has promise. “It's relatively simple,” says Dr. Kohane. “It's kind of like a pita pocket with an outer shell and the drug inside.”

The IOVS article describes the prototype as being created “by coating polylactic-co-glycolic acid (PLGA) films containing test compounds with polyhydroxethyl methacrylate (pHEMA) by ultraviolet light polymerization.” The films contained encapsulated fluorescein or ciprofloxacin.

According to the article, the prototype contact lenses demonstrated controlled release of the drugs, with the rate of release adjusted by “changing either the ratio of drug to PLGA or the molecular weight of the PLGA employed.”

The early studies of this concept have been “more successful than we anticipated,” Dr. Kohane says. “We are continuing to refine the concept and may be ready to begin a human trial within a year.”

The research is being funded by multiple sources, including the National Institute of General Medical Studies, the National Eye Institute and the Boston KPro Foundation, which is part of the Massachusetts Eye and Ear Infirmary.

Dr. Kohane says the duration of sustained release could be as long as 100 days, but the duration could be limited by the amount of time the contact lens could remain in the eye. The contact lens could be designed to be therapeutic and also serve to correct vision, says Dr. Kohane.

One drawback would be that a percentage of patients would resist having to wear contact lenses to obtain medicine and would seek alternative delivery methods.

Intravitreal and Other Implants

Sustained-release technology has been used successfully for years to treat certain retinal diseases with intravitreal implants. It is not much of a stretch to believe that already approved implants such as Bausch + Lomb's Retisert and Allergan's Ozurdex could be adapted to deliver glaucoma medications.

Indeed, Allergan is one of the few pharmaceutical companies to have in-house expertise in sustained-release technology. Scott Whitcup, MD, Allergan's executive vice president of research and development, told Ophthalmology Management that the company considers Ozurdex technology “a platform” to create a range of sustained-release drug systems. This is being borne out by the fact that Allergan has initiated clinical trials for sustained-release delivery of brimonidine for both geographic atrophy and glaucoma.

Mark Humayun, MD, of the Doheny Retina Institute of the University of Southern California, who is mainly known for his work in creating a camera-like device to restore a level of sight in patients with retinitis pigmentosa, is currently involved in an effort to develop a refillable electronic pump to dispense glaucoma medication over a period of three to four months before requiring a refill. The pump — known as the Replenish — is powered by a rechargeable, miniature battery and can be implanted in the eye in a procedure similar to implanting a tube shunt.

Oral Delivery

A successful effort to create a safe oral medication for glaucoma would go a long way to reduce problems with both compliance and incorrect administration. However, efforts in that direction have thus far proved fruitless.

Allergan spent years and million of dollars in an innovative but ultimately failed attempt to adapt the Alzheimer's drug memantine as a glaucoma treatment. The company took a different approach with memantine, which was viewed as a neuroprotective agent for the optic nerve rather than an IOP-lowering drug.

Two oral medications — the diuretic Diamox and the carbonic anhydrase inhibitor Neptazane — are used on a short-term basis to lower extremely high IOP that is accompanied by pain. However, these drugs have intense negative side effects that limit usage to several weeks with most patients.

“Neptazane is a little easier to tolerate than Diamox,” asserts Dr. Rabinowitz, “but almost no one can stay on these drugs for very long. Basically, they buy some time. The drugs can be used as a stopgap in very severe cases until you can determine whether the glaucoma can be treated medically or requires surgery.” Side effects from these drugs can include overall weakness, kidney stones, loss of appetite, tingling in hands/feet and dangerous forms of anemia.

“The side effects can turn a patient into a shell of a person,” says Dr. Rabinowitz.

Potential for Improved Delivery

Many glaucoma specialists believe that some form of sustained-release glaucoma medication will be approved for use within the next decade. They note that the medications currently available are already effective when correctly administered and that improved delivery will maximize their effectiveness.

Once a sustained-release glaucoma medication is approved, it is expected that treatment of the disease will undergo a major and positive change. OM