Will Time-Release Therapy Revolutionize Glaucoma Care?

New devices that automate routine medication dosing could make patient noncompliance a thing of the past.

By Robert Murphy, Contributing Editor

Recent years have witnessed accelerated efforts by large pharmaceutical companies and small biotech firms alike, along with clinical researchers, to develop sustained-release glaucoma drug-delivery devices and methods to address the long-standing, seemingly intractable dilemma of poor patient compliance.

Sources closely involved in these efforts predict it will take at least several years — perhaps up to five or more — before a viable sustained-release glaucoma drug/drug-delivery product becomes commercially available. While many approaches show promise and some have progressed to phase 1/2 clinical studies, troublesome scientific and clinical hurdles stand in the way of developing a safe and effective glaucoma treatment modality that is acceptable to both practitioners and patients. Questionable prospects for reimbursement by Medicare and other payers likewise loom as potential impediments to commercial viability.

Inadequate patient adherence — today's preferred term for what we used to call compliance — owing to numerous factors stands as the primary impetus for these development efforts. Mostly still in the early development stages, these endeavors have attracted attention largely due to corporate and other investors supplying the necessary capital to support them. Meantime, successful intravitreal injections of Lucentis and Avastin for neovascular AMD have shown that clinicians and patients alike will accept moderately invasive therapies when they offer a clear and compelling benefit.

There stands a large and widely acknowledged unmet need for clinically viable sustained-release glaucoma drug delivery. “My sense is that patients would probably put up with almost anything to avoid taking drops, because they hate putting drops in their eyes,” says glaucoma drug-delivery pioneer Alan Robin, MD, an associate professor at Johns Hopkins University School of Medicine and full professor at the University of Maryland School of Medicine.

Today, many scientists and clinicians backed by financial capital are working diligently to meet this need. While commercial availability remains some years off, call this a midterm report card on the multiple hurdles of sustained-release drug delivery, and what's happening in the labs and clinics to overcome them.

Poor Patient Adherence

No one doubts that inadequate adherence to topical glaucoma medication treatment regimens hastens disease progression and leads to unfavorable outcomes. Numerous factors help explain this unfortunate phenomenon.

The first one centers on the patient. Poor IOP control may be due to insufficient adherence to daily topical treatment or confusingly complex dosing regimens involving multiple medications.¹ The latter is especially troublesome in that upwards of 40 percent of open-angle glaucoma patients require combination therapy to reduce IOP, with nearly 75 percent receiving additional treatment within five years.²

Pharmacy data show that most glaucoma patients do not adhere strictly to their topical therapy regimens — often due simply to forgetting — even as many fail to refill their prescriptions when needed; up to two months may go by between refills for once-daily prostaglandin analogs.³ Failure to obtain refills may be due to multiple factors. One is improper drop instillation in which a multitude of drops comes pouring forth, with subsequent waste and the need for an early refill. “The mean number of drops to get a single drop into the eye is seven,” Dr. Robin says.

Another reason why patients fail to refill their prescriptions is the high cost of medications. Corporate patient-assistance programs for low-income patients and increased use of generic drugs may mitigate this factor. In many cases, pharmacists refuse to refill a topical glaucoma prescription earlier than a designated date. “Pharmacies do not give Medicare-age people an extra bottle,” Dr. Robin says. “I hear that every day from patients.”

Even the most careful and dextrous patients may have trouble getting a full drop into their eye. Add to the clinical picture patients with physical handicaps stemming from arthritis or neurodegenerative diseases that produce tremors, and the task becomes all the more insuperable. Videos and questionnaires confirm that many patients fail to administer drops accurately.⁴ A study involving 204 glaucoma patients found that only 71 percent could get a drop in their eye, while only 39 percent did so without touching the bottle tip to the ocular surface.⁵

“We don't know if eye drop administration can be trained,” Dr. Robin says. In any event, “doctors can ask the patient if they can put drops in their eye. But it's difficult to know.” Troublesome side effects from topical agents may further reduce patient adherence.

QLT's investigational punctal plug provides a 90-day supply of IOP lowering medication. COURTESY OF QLT.

Finally, in glaucoma care we have a clinical scenario in which patients with an initially asymptomatic chronic disease may question the need for diligent adherence. Why take drops when they're functioning just fine? When visual field loss begins, why take a drug that provides no demonstrable improvement? Compelling patient education is necessary to dispel complacent and misguided opinions.

Reaching the Target Tissue

A further challenge in developing a viable sustained-release glaucoma drug delivery device concerns bioavailability. Topical drops must penetrate multiple protective transport barriers in the eye — most notably the cornea — in order to reach the target tissue.⁶ The cornea possesses a lipophilic surface and hydrophilic stroma; molecules that easily cross the epithelium penetrate the stroma poorly, and vice-versa.⁶

Besides, most of the instilled topical drug escapes through the nasolacrimal duct anyway.⁷ The conjunctiva and episclera, meanwhile, possess vascular and lymphatic systems that hasten the clearance of topical drops.⁸ Unable readily to transmit through the cornea, less than one percent of topical glaucoma drugs ultimately reaches the aqueous humor.⁹

“We know from experience that current glaucoma medications are generally effective,” says Malik Kahook, MD, director of the glaucoma service at the University of Colorado School of Medicine. “Problems with efficacy of medications often relate to poor adherence or poor access to targeted tissues. These problems may be overcome with alternative drug delivery techniques. Our ophthalmic drug delivery team is innovating more efficient methods for delivery of medications to target tissues. We are also interested in studying therapeutic agents that might have been deemed ineffective in the past due to poor performance as a standard topical formulation.”

Regulatory Hurdles

On one hand, the topical agents used most commonly in glaucoma treatment — prostaglandins, beta-blockers, alpha agonists — long ago met the FDA's approval for safety, efficacy and tolerability. The challenge now is to obtain approval for novel sustained delivery devices that must demonstrate efficacy equal to that of topical beta-blockers or prostaglandins — a concern exacerbated by uncertain bioavailability — as well as new safety issues associated with intraocular or periocular avenues of drug delivery.

“The FDA is still going to be concerned with safety and efficacy, as with any glaucoma drug, this will still need to be adequately and robustly demonstrated,” says Barbara Wirostko, MD, a clinical adjunct associate professor at the University of Utah's Moran Eye Center and chief medical officer of Altheos, Inc. “You don't need to show superiority [compared with topical beta-blockers or prostaglandins], you can just show equal efficacy and or non-inferiority.”

Thornier regulatory matters have to do with a sustained-release drug-delivery system's safety and tolerability, and perhaps the chance that a device such as a punctal plug or contact lens may fall out. “If you want to make a six-month sustained-release device, you are going to have to run those clinical trials for six months, maybe even for a year,” Dr. Wirostko says. “Because the FDA is going to want to see what happens when you replace it. For a longer-acting sustained- release product, unfortunately the whole development process is now lengthened.”

Complicating long-term sustained-release efficacy is the fact that many polymers currently being tested for such devices become degraded by enzymes or undergo changes in pH as they disintegrate. “That could have implications on the drug's inherent properties when they are in that polymer,” Dr. Wirostko says.

Reimbursement

A major commercial concern centers on the question: Will third-party payers be willing to reimburse perhaps up to $200 or more for a sustained-release drug-delivery device, especially when the drug under consideration, when used topically and daily, costs a small fraction of that? The cost comparison is particularly vexing when it comes to inexpensive generic topical agents such as timolol and latanoprost.

Clinicians must be ready to make a compelling case for the multiple benefits — both economic and health-related — associated with sustained-release glaucoma delivery devices. That case hinges on several points: A more expensive drug-delivery device would yield better long-term efficacy and less disease progression compared with topical comparators, especially when you factor patient adherence into the picture.¹⁰ Numerous glaucoma patients currently using topical drops could benefit. Better patient care and potential long-term cost savings arguably justify a sustained-release drug-delivery device's greater initial cost. Unfortunately, payers tend to focus narrowly on the short term.

Adding to the challenges described here are scientific and clinical challenges. Many of these have to do with the interaction among the compound, its resident polymer and the target tissue. They include, among others, such matters as loading efficacy, initial burst effect, drug-release kinetics, biocompatibility with target tissues, device degradation and the timing of replacing or refilling a delivery device's repository. (A full description of these factors transcends the scope of this discussion.)

What's Happening: An Overview

Multiple sustained-release glaucoma drug-delivery avenues are currently under exploration and investigation, some still in the lab or being tested with animal models, others under clinical study. A brief rundown of some of the more promising developments and their pros and cons:

• Punctal plugs. Perhaps the drug-delivery device that's furthest along in clinical development and testing is QLT's hydrogel punctal plug that serves as a reservoir for medication release over a 90-day time span; a trial is underway using latanoprost.¹⁰

Minimally invasive punctal plugs already have a successful track record as sustained treatment for patients with dry eye syndrome, a familiarity that promotes acceptance and tolerability. Potential advantages over topical drops include dose reduction, better efficacy and improved patient compliance. Yet, excessive tearing and loss of the plug have hampered its development. The recent use of a thermosensitive hydrophilic acrylic polymer that changes from a rigid solid to a soft cohesive gel that expands with body temperature is said to promote retention.

QLT's punctal plugs are currently in phase 2 clinical studies. Early reports show that 60 percent of subjects at four weeks experienced an IOP reduction of 5 mm or greater with an improved retention rate than that of previous iterations. Still, its IOP-lowering effect remains inferior to that of daily topical Xalatan when used with ideal patient adherence to the prescribed regimen.

• Conjunctival inserts. Thin, multilayered, drug-infused inserts can be placed in the cul-de-sac or conjunctival sac to access the bulbar conjunctiva.¹⁰ Insoluble inserts feature a core drug reservoir tucked between rate-limiting membranes. The devices are designed for controlled sustained release, permitting reduced dosing frequency and good bioavailability. Drawbacks: expulsion and discomfort.
• Subconjunctival inserts. Implants placed in the subconjunctival space can match the advantages of viscoelastic depot-delivery injections. But they carry the risks that may accompany minimally invasive surgery.

Since last summer, a company called pSivida has collaborated with Pfizer to deliver latanoprost using a subconjunctival insert.¹⁰ The companies are now engaged in phase 1/2 clinical trials at the University of Kentucky.¹¹

Another player is Aerie Pharmaceuticals, with a latanoprost-loaded ocular insert in preclinical development.¹² The insert is produced by compressing latanoprost pellets and then coating them with a membrane such as ethylene vinyl acetate.¹³ Such an insert may better control the burst effect thanks to its porosity and membrane thickness, allowing hydrophilic drugs to permeate the sclera.

• Intravitreal inserts. Allergan's topical brimonidine is said to work effectively in glaucoma not only by lowering IOP but also by wielding potential neuroprotective properties. The company currently markets a degradable dexamethasone intravitreal implant called Ozurdex to treat macular edema. Bolstered by that success, Allergan is conducting clinical trials of implants designed similarly to Ozurdex but containing brimonidine to treat geographic atrophy associated with AMD.¹⁴

Many observers foresee considerable clinical potential for brimonidine and other potential neuroprotective agents of varying mechanisms tailored for sustained-release glaucoma drug delivery. “We use the bucket term ‘neuroprotective,'” Dr. Wirostko says. “But, really, neuroprotective effects are a mix of anti-apoptotic, anti-inflammatory, anticaspase, anti-oxidative and vasodilatory mechanisms.” (An extensive review of current neuroprotective-medication preclinical developments lies beyond this discussion's scope.)

Additional glaucoma drug-delivery devices still in the preclinical stage include such avenues as external pumps, contact lenses and subconjunctival injections. Each has its advantages and drawbacks. Further study will reveal the clinical viability of these preclinical innovations.

The Ideal Delivery Device

Multiple criteria define an ideal sustained-release glaucoma drug-delivery device. Dr. Wirostko identified some of the key ones in a 2011 paper:¹⁰

• Comparable efficacy to a topical comparator.
• A safety risk profile acceptable to patients and practitioners.
• A demonstrated advantage over daily topical generic comparators, including long-term benefits such as better IOP control, less IOP fluctuation, and better patient outcomes.
• Easy to administer using a minimally invasive, preferably in-office, procedure every few months.

Many of the devices mentioned here possess some but not all of these optimal qualities. Much work remains to be done. Multiple hurdles stand in the way of clinical development, regulatory approval, commercial viability and acceptance among patients and practitioners. The long-term view is that efforts to surmount these obstacles will yield better patient outcomes and, ultimately, lower overall cost to society.

After many years working in drug and drug-delivery development, Dr. Robin offers a perspective shared by many: “The future of medical therapy for glaucoma is going to be not only novel drugs, but novel delivery systems and formulations. If we can take the bottle out of the patient's hands and put it in the doctor's hands, patients will do much better long-term.” OM

References

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4. Robin AL, et al. Adherence in glaucoma: objective measurements of once-daily and adjunctive medication use. Am J Ophthalmol 2007;144(4):533-40.
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11. University of Kentucky Clinical Trial: Safety study of latanoprost slow release insert (latanoprost SR), 2010, www.clinicaltrials.gov.
12. Aerie Pharmaceuticals Inc. December 2011, www.aeriepharma.com.
13. Kopezynski C, Lin CW, Sutay C. Drug Delivery Devices for Delivery of Therapeutic Agents. 2010: United States.
14. Allergan Clinical Trial: Safety and efficacy of brimonidine intravitreal implant in patients with geographic atrophy due to age-related macular degeneration (AMD). 2008, www.clinicaltrials.gov.