Neuroprotection, sustained drug delivery at forefront of glaucoma research

Glaucoma is an enigmatic disease that presents with a variety of subtle, slowly progressing anatomic changes and symptoms such as visual field loss. Diagnostic parameters such as IOP vary widely, even in a single patient, depending on diurnal changes, medication use and other factors.

Subtle changes in the anatomical angle and the effects on the optic nerve are difficult to identify and track.

Common challenges to effective treatment include low patient compliance and adherence to daily medication dosing instructions, variable efficacy of therapies and chronicity of treatment. To address these challenges, novel drugs and technologies are being developed that offer sustained and targeted drug delivery.

Reducing IOP alone may not address damage to these vulnerable structures. Some research is focused on non-IOP factors such as neuroprotection of optic nerve and retinal ganglion cell preservation as well as improving ocular perfusion.

New drugs and delivery systems are at various stages of the development and regulatory approval pipeline.

At the American Glaucoma Society 2012 meeting, speakers discussed strategies to identify unmet needs in glaucoma, such as sustained drug delivery, 24-hour IOP monitoring and IOP-independent glaucoma therapy.

At the meeting, James C. Tsai, MD, MBA, explained the need for neuroprotection in glaucoma treatment.

“Over the past decade, physicians have come to realize that glaucoma should be treated as a [central nervous system] disease,” Dr. Tsai said. “I believe there’s a lot of exciting research occurring in the field, but this effort will require clinicians in the glaucoma community to partner with basic scientists to translate advances in neuroprotection research into clinical practice.”

Clinicians have been searching for neuroprotective agents for decades, Malik Y. Kahook, MD, who also presented at the AGS meeting, said in an interview with Ocular Surgery News.

“The difficulty with finding a promising neuroprotective agent for treatment of glaucoma is in being able to track disease progression and show that a given medication might be effective independent of IOP-lowering efficacy. We have a hard time quantifying the potential effects of non-IOP-lowering medications,” Dr. Kahook said.

A definition of meaningful therapy needs to be established before sustained drug release finds a suitable niche in clinical practice, Barbara M. Wirostko, MD, said at the AGS meeting.

“‘Meaningful’ is whether we develop a mechanism of action and can treat glaucoma through several approaches: IOP lowering and/or non-IOP lowering,” Dr. Wirostko said, adding that patient acceptance of the products would be a driving factor.

Development also rests on the successful combination of compounding agents with polymers, as well as the reimbursement for generic agents, Dr. Wirostko said.

“Think about your patients,” she said. “Would they tolerate it? Would they accept it? Would you trust it? … Is the product going to do what you want it to do? What’s the safety risk profile? You’re now taking a topically administered drop and putting it into the eye in a more invasive procedure. What’s the trade-off? What’s the additional benefit? And who will pay?”

Sustained drug release may also play a significant role in the delivery of neuroprotective treatments, Dr. Tsai said.

“I think it’s fitting that we’re attempting to marry sustained release with neuro-protection,” he said.

Sustained drug delivery

Traditionally, ocular medications have been delivered through eye drops, intravitreal injections and systemic channels. Current research is trending toward implants that deliver drugs through extraocular and intraocular means.

“A lot of people are interested in this,” Dr. Wirostko said at the meeting. “There’s a lot of innovation going on here, a lot of development, a lot of hard work but with a lot of challenges.”

New sustained drug delivery technologies center on injections in or around the eye. Sustained delivery approaches can take advantage of properties of the vitreous that slow the elution of medication, and novel polymers can be used to further control drug release, Dr. Kahook told OSN.

“Using novel polymer systems to control release of active molecules in the eye is the mainstay of current research in this area,” he said.

More than 200 companies are currently developing noninvasive drug delivery devices such as punctal plugs, contact lenses, conjunctival inserts and cul-de-sac implants, Dr. Wirostko said at the meeting.

Minimally invasive IOP-lowering devices in clinical development include subconjunctival biodegradable, erodible and non-erodible inserts. pSivida is developing an erodible insert, and Aerie Pharmaceuticals is developing a non-erodible insert.

The pSivida erodible insert, a biodegradable polymer that dissolves in the subconjunctival space, is undergoing U.S. Food and Drug Administration clinical trials. Aerie’s non-erodible device is expected to enter clinical trials soon.

Currently, there are various basic punctal plug eluting devices in development, Dr. Wirostko said.

A targeted-tissue approach would enhance safety.

“One thing that’s really unique here … is that if you’re giving a drug under the conjunctiva in a sustained-release manner, you don’t need preservatives. Clearly, this provides a better safety profile from a surface tolerability perspective,” Dr. Wirostko said.

Another category of drug delivery mechanisms encompasses micro-electromechanical systems that would pump medication into specific areas of the eye, Dr. Kahook told OSN, noting that new polymers that differ from biodegradable poly lactic-co-glycolic acid (PLGA) polymers are also being developed.

Potential obstacles and risks

Although promising, many emerging drug-release technologies raise concerns about patient intolerance and discomfort, safety, efficacy and duration of therapy, Young H. Kwon, MD, PhD, said in a presentation at the AGS meeting.

“There are many obstacles remaining to provide sustained drug release in glaucoma,” Dr. Kwon said. Ideally, drugs of all sizes, including macromolecules, would be delivered noninvasively or minimally invasively, would eliminate patient adherence and cooperation issues, and would be well accepted by patients, he said.

Furthermore, the desired characteristics of optimal sustained ocular drug delivery would include effective reduction of IOP, neuroprotection of the retinal ganglion cell, and minimal or tolerable side effects, Dr. Kwon said. Duration of action would last months to years with a single application, zero-order release characteristics would be achieved, and therapy could be terminated at will, if necessary.

There are advantages and disadvantages to the various sustained-release technologies in development, Dr. Kwon said, focusing on the range of methods from less invasive to more invasive drug delivery systems.

The less invasive systems deliver medication extraocularly, for example, via contact lens, conjunctival insert, biodegradable subconjunctival injection and non-degradable episcleral implants, whereas the more invasive systems deliver medication intraocularly, for example, by pars plana injection and surgical implants with drug reservoir, Dr. Kwon said. The less invasive extraocular delivery methods are limited to small lipophilic molecules, whereas intraocular delivery methods can accommodate larger molecules. Furthermore, the more invasive systems, which incorporate a drug reservoir, can provide prolonged drug release, up to years, whereas extraocular methods of injection typically yield an initial burst release of medication followed by steady release.

Extraocular systems

The least invasive of the extraocular systems of drug delivery is via hydrogel contact lenses, according to Dr. Kwon. One such lens in development incorporates a biodegradable nanosphere encapsulating ciprofloxacin that is released in vitro over 3 to 4 days. The drawbacks include short duration of drug release; uneven drug release, giving an initial burst of medication before steady release; poor penetration by large hydrophilic molecules when delivered extraocularly; and the need for patient adherence to and tolerance of soft contact lens wear.

An extraocular conjunctival insert is a nondegradable solid insert with a drug reservoir placed in the conjunctival cul-de-sac. The drug reservoir is enclosed by a release-controlling membrane. The insert could cause patient discomfort or fall out spontaneously, and the patient must be able to apply the insert, Dr. Kwon said. As with other extraocular systems, duration of drug delivery is limited, and only small molecules can be eluted.

One example of an extraocular subconjunctival injectable system is an as-yet unavailable timolol microsphere based on biodegradable PLGA polymers, which can sustain drug delivery for up to 3 months in vitro. The polymer dissolved in solution can be injected subconjunctivally through a 25-gauge needle. Potential barriers to the device’s use include difficulty removing the injected polymer drug in case side effects occur; the limitation to small-molecule drugs; its more invasive design; potential complications such as infection, hemorrhage and inadvertent ocular perforation; and possibly poor patient acceptance, Dr. Kwon said.

Lumitect (Lux Biosciences) is an example of an extraocular episcleral implant, which in this case is made of a nondegradable silicone matrix with a drug reservoir that holds cyclosporine. It is surgically placed under the conjunctiva, similar to a tube shunt, making it one of the more invasive of the extraocular technologies. It releases cyclosporine for up to 3 years and may be modified to handle multiple drugs, Dr. Kwon said. However, drug molecules must be small, and the implant is difficult to reverse if side effects or complications become unbearable. Implantation and explantation are surgical procedures accompanied by potential risks and complications of surgery.

Intraocular systems

“Moving on to intraocular systems, or biodegradable injectable systems, a great example is Ozurdex [dexamethasone, Allergan],” Dr. Kwon said.

This system, made of a solid, rod-shaped polymer matrix based on PLGA coupled with dexamethasone, is injected through the pars plana with a 22-gauge injector, providing sustained release for 6 months in vivo. It may be modified to handle other drugs.

Drawbacks include uneven delivery of drug and difficulty in removing the drug if necessary.

“There’s a peak release in the first 2 months, with a lower dose in the subsequent 4 months,” Dr. Kwon said. “If there are intolerable side effects, it can be very difficult to remove the drug without vitrectomy.”

There are risks and complications associated with this more invasive technology, including endophthalmitis, vitreous hemorrhage and retinal detachment, and potentially poor patient acceptance, Dr. Kwon said.

A nondegradable surgical implant is exemplified by Retisert (fluocinolone acetonide intravitreal implant, Bausch + Lomb), a disc-shaped polyvinyl and silicone implant that releases drug for up to 2.5 years. It may also dispense multiple drugs. This system is the most invasive delivery system, Dr. Kwon said, with implantation and explantation done surgically. Serious surgical risks and complications include endophthalmitis, retinal detachment, vitreous hemorrhage and proliferative vitreoretinopathy. In addition, it may not be well-tolerated by patients, Dr. Kwon said.

Need for neuroprotection

Glaucoma is a central nervous system disease that requires the incorporation of neuroprotection strategies in clinical practice, Dr. Tsai said at the AGS meeting. He believes that future research should center on non-IOP treatment modalities, the role of sustained drug delivery and the development of novel therapies aimed at neuroregeneration.

“It is going to require a collaborative integration of our clinical and research efforts. Of the potential revolutionary therapies, neuroregeneration and/or neuroenhancement may come out as a result of these coordinated activities,” Dr. Tsai said.

Existing glaucoma treatments address IOP lowering and do not offer non-IOP-related neuroprotection, Dr. Tsai said.

Clinical outcomes of many current glaucoma treatments vary because only one risk factor for this disease — IOP — is being controlled, Dr. Tsai said. The challenge is to explore what else can be done.

IOP-lowering drugs are inherently neuroprotective but only indirectly, Dr. Kahook told OSN.

“We know that reducing intraocular pressure in itself is neuroprotective,” he said. “Drugs that decrease eye pressure protect the optic nerve from further damage.”

Studies have shown that there might be a directly neuroprotective quality to Alphagan (brimonidine, Allergan) independent of IOP lowering, although more information is needed to bolster these claims, Dr. Kahook said.

Data from the Low-Pressure Glaucoma Treatment Study, published in the American Journal of Ophthalmology, focused on the role of brimonidine vs. timolol in preserving vision in low-pressure glaucoma.

Ongoing research has been centered on therapies such as Namenda (memantine, Forest Laboratories), an oral medication for Alzheimer’s disease; the cytokine erythropoietin; brain-derived neurotrophic factor; and ciliary neurotrophic factor, Dr. Tsai said at the meeting.

Other research efforts are based in translational research areas such as gene therapy and stem cell therapy, he said.

Yale’s departments of biomedical engineering and ophthalmology have joined forces to develop nanospheres that provide long-term sustained drug elution of neuroprotective agents, Dr. Tsai said.

“We have shown that microspheres with a mean diameter of 2.4 µm offer immediate release of drug with minimal residual release at 175 days,” he said. “In contrast, a nanosphere delivery system (mean diameter of 360 nm) provides sustained release of the neuroprotective agent out to the full 175 days.”

“Agents in the research queue also include endothelin receptor antagonists, which act on receptors in and around the retina, optic nerve and trabecular meshwork,” Dr. Kahook said. – by Matt Hasson

Should IOP-lowering microinvasive surgical procedures such as canal stent insertion be placed in the hands of cataract surgeons?

Cataract surgeons fit into MIGS paradigm

With the recent FDA approval of the Glaukos iStent, the glaucoma treatment paradigm has another viable surgical option for the management of glaucoma. This promising trabecular micro-bypass device has been approved for utilization in mild to moderate open-angle glaucoma patients undergoing cataract surgery. The pivotal FDA clinical trial for this device demonstrated that using a single iStent lowers IOP better than cataract surgery alone and has an excellent safety profile. In the months and years ahead, clinicians will further elucidate the role of the iStent procedure in glaucoma care.

Although thorough understanding and superb clinical examination skills in regard to glaucoma are necessary to perform the iStent procedure safely, quality cataract surgeons will be successful in introducing this new procedure into their practice with proper training. Fortunately, iStent insertion can be easily accomplished through the cataract surgery incision. The procedure is conducive to being performed in conjunction with cataract surgery and is generally performed after cataract extraction is completed.

Direct gonioscopic techniques may require tilting of the microscope and adjustment of patient head position for adequate visualization of the anterior chamber angle structures. With the recent development of newer gonioscopic lens technologies (eg, Transcend Vold goniolens), these maneuvers may be reduced and possibly eliminated, making the procedure even easier to perform and potentially enhancing patient safety profiles as well.

In light of the fact that comprehensive ophthalmologists take care of a significant portion of all glaucoma patients, cataract surgeons will almost certainly play an important role in the surgical management of glaucoma using newer microinvasive glaucoma surgical techniques. Both glaucoma patients and physicians alike will benefit in the inclusion of these less invasive surgical modalities in the glaucoma treatment paradigm.

Steven D. Vold, MD, is a cataract and glaucoma surgery consultant at Vold Vision, PLLC in Fayetteville, Ark. Disclosure: Dr. Vold is a consultant and investigator for Glaukos Corporation, Transcend Medical, AqueSys, Ivantis, iScience Interventional, SOLX and Alcon.

Surgical nuances present technical challenges

 

Douglas J. Rhee

My feelings are slightly more complicated than a simple "yes" or "no." If forced to make a choice, I would tend toward "no" for the following concerns. I would be reluctant for the technology to be widely available to those whose practices do not have a significant majority of glaucoma and whose surgical practice does not already comprise a significant number of glaucoma surgeries. For the typical cataract surgeon, neither of these is typical. As with the current glaucoma surgeries, the technical challenges of the procedure itself are only part of the concern. There must be a sound preoperative understanding of when to proceed to incisional surgery and the ability to offer a full "menu" of options to the patient. Canal stent insertion is not going to be appropriate for all patients. Furthermore, excellent gonioscopy skills pre-, intra- and postoperatively are needed. No procedure is without risk or potential for complication. All surgeons, especially those who do not routinely perform glaucoma surgery, should be certified for the procedure. Finally, the surgeon who implants a stent or performs a micro-invasive procedure should be able to handle the complications.

Douglas J. Rhee, MD, is an OSN Glaucoma Board Member. Disclosure: Dr. Rhee has no relevant financial disclosures.