Reshaping medical treatment of glaucoma management

Medical treatment of glaucoma is evolving to include internal and external drug delivery systems that will ensure patient compliance for long periods. 

This article was reviewed by Christophe Baudouin, MD, PhD, FARVO 

The best treatment for glaucoma would be efficient, well tolerated over the long and short term, easily used with minimal constrains, affordable, and having increased duration of effect to increase patient compliance. This is a tall order.

One of the biggest problems that physicians face who treat patients with glaucoma is adherence to the treatment regimen. Poor adherence, according to Christophe Baudouin, MD, PhD, FARVO, has an estimated annual cost of $100 to $300 billion in the US, which translates to from 3% to 10% of health care spending.

Previously by Lynda Charters: Researchers find long-term statin use linked to lower POAG risk 

So, while uncontrolled IOP and visual field deterioration may be considered disease progression, in reality the patient simply may not be treated properly.

“This is an important issue; but patient education is not always the answer because from 25% to 40% of motivated patients have difficulties or fail to properly instill their drops, said Dr. Baudouin, professor of ophthalmology, head, Department of Ophthalmology III, Quinze-Vingts National Ophthalmology Hospital and director, Team S12, Chemokines and Glaucoma, Vision Institute, University Paris 6, Paris.

Recent developments in glaucoma have seen the introduction of preservative-free formulations designed to decrease side effects and drugs with increasing durations of effectiveness have decreased the number of instillations prescribed as have fixed combinations of drugs, gels, and polymers.
However, new routes and delivery systems may represent the future of glaucoma therapy.

“We may have the choice of administering drugs over or under the conjunctiva or subconjunctivally or intraocularly with drugs implanted in the anterior chamber, intravitreally, or in Schlemm’s canal,” Dr. Baudouin commented.

Related: Delivery challenges 
One such challenge is making sure the correct dose of a drug reliably reaches the targeted tissue.

“Only 10% of eye drops reaches the receptor,” he said. Dr. Baudouin likened the eye a fortress in that all of the ocular structures are barriers to effective drug penetration. “We must overcome this barrier to properly deliver a high or sustained medication dose,” he said.

Nanotechnology one approach 
Nanoparticles have been used for more than 10 years, examples of which are cyclosporine and the development of a latanoprost nanoemulsion, both to increase the drug penetration and reduce the amount of the drug in the drop to reduce side effects. The use of gold nanoparticles is also in the development stage to achieve the same goal.

Latanoprost, timolol, and brinzolamide have been tested in nanocarriers with the goals of reducing the concentration and side effects, Dr. Baudouin explained.

Drug penetration has been enhanced using iontophoresis or electroporation with low-voltage current, a technology that has not yet been used in glaucoma. The disadvantage of these approaches is that they do not increase the duration of the treatment for a substantial period of time, he pointed out.
Internal delivery systems 
In light of this, Dr. Baudouin and his team are involved in developing periocular or intraocular longterm delivery systems. While this is not a revolutionary new approach, the development of ganciclovir (Vitrasert, Auritec Pharmaceuticals), an implant to treat cytomegalovirus retinitis, and then the introduction of the dexamethasone intravitreal implant (Ozurdex, Allergan) and fluocinolone acetonide intravitreal implant (Iluvien, Alimera Sciences) were major steps within this technology because of the slow release and duration of biodegradable drug delivery, respectively, that they provided.

More recently, Allergan developed an intracameral implant loaded with brimatoprost.

Related: Intraoperative techniques in glaucoma focus on avoiding issues 

In an ongoing phase I/II study, the six-month results showed, according to Dr. Baudouin, that the loading dose worked quite well; the IOP reduction was slightly less than that achieved with a topical anti-glaucoma medication, but the patients were fully compliant, which is not the case in real life. He emphasized that at six months, 71% of patients implanted with the device did not require rescue medication.

Regarding safety, no more side effects occurred with the implants compared with the topical medication if excluding the few transient side effects related to the procedure itself; 78% of patients indicated that they would undergo the procedure again.

Other intracameral implants include one containing latanoprost (PolyActiva) and one with travoprost XR (Envisia Therapeutics), both provided similar results to those of brimatoprost.

Glaukos developed the iDose Travoprost, a non-degradable device implanted into the trabecular meshwork that should deliver the drug for a minimum of 1 year; the results are good compared to timolol with no side effects but the technique requires replacing the device after one year, according to Dr. Baudouin.

Related: Device renews hope for artificial vision External delivery systems 
Conjunctival rings containing brimatoprost, the Helios (ForSight Vision5) BIM ring, delivers the drug for six months after insertion in the fornix; a phase II study demonstrated that the device did not achieve noninferiority to timolol.

Because of the nature of such study where one eye received the ring, patient compliance was naturally much higher for instilling timolol in the fellow eye.

However, the safety profile was wanting: 28 dislodgements occurred in 15 patients and nine patients withdrew from the study because of the side effects compared with only one receiving timolol.

The long-term results after readministration were stable, although the IOP was slightly higher compared with timolol.

Travoprost is contained in two new delivery systems, TODDD (Amorphex Therapeutics) is a polymer implanted subtarsally in the superior lid intended to deliver drug for 180 days, and OTX-TP (Ocular Therapeutix) is a punctal plug that delivers drug for 90 days. A phase IIb study of the latter device showed a greater IOP decrease at 90 days with timolol that likely resulted from punctal occlusion.

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Challenges with new delivery systems
Problems are present with internal and external approaches. The first concerns device performance. With the iDose, for example, the device must be removed or replaced at 1 year, but how many times is unknown.

Possible concerns exist for narrow angles. The intracameral implants can migrate. Extrusion can occur with rings and plugs. Patient tolerance of plugs or subtarsal polymers may be problematic.

Finally, are these implantations in-office or operating room procedures? Another question revolves around detecting loss of efficacy.
 

Related: Glaucoma, retinal diseases present collaborative opportunities 
 

For example, when the dexamethasone implants are no longer efficacious, macular edema may occur again with decreased visual acuity, but what is the clinical course in patients with an asymptomatic disease?

Dr. Baudouin reminded that 28% of patients with a BIM implant did not need rescue therapy after two years of a single implantation; however, there is no way to know if that is good or bad result as a careful follow-up will remain necessary to detect loss of efficacy and propose a new implantation.

And the question arises about whether a repeat injection will modify ocular tissues and increase the effects over time; however, all of this remains unclear. In addition, can clinicians determine who are high and good responders?

Are there lower pressure and higher responses to prostaglandins?

Again, these questions remain unanswered. With all of this in mind, Dr. Baudouin suggested that development of a follow-up algorithm and possibly self-monitoring of IOP may be good options.

Related: Look beyond IOP when managing glaucoma patientsAnother approach: neuroprotection
“There still is no treatment that targets the optic nerve,” he said. Different protective mechanisms can be addressed, such as oxidative stress, inflammation, growth factors, and primary and secondary apoptosis, numerous candidates have been studied.

However, Dr. Baudouin recounted, the 10-year memantine study showed no significant results compared with placebo. He suggested that polylactic-co-glycolic acid biodegradable implants containing neuroprotective agents, cells encapsulated in microspheres (ciliary neurotrophic factor, Renexus, Neurotech, now in development), and stem cells locally incorporated into tissues may protect against degeneration, which offers new strategies to protect the optic nerve.

Tissue regeneration
Can tissues negatively impacted by glaucoma be regenerated? Delivery of stem cells to the anterior chamber or the posterior eye may serve that purpose. Stem cells from bone marrow, adipocytes, or embryonic tissue, or induced pluripotent stem cells can be used.

Related: New options address challenges of managing uveitic glaucoma

Dr. Baudouin noted that when mesenchymal stem cells were injected into the trabecular meshwork in rats, the transplantation reduced the IOP for a short time. The stem cells also may be deleterious as shown by cases of blindness resulting from injection into the eye.

“The next steps may be a combination of different factors that may be useful to protect against glaucoma, gene therapy, and transfection of genes coding for trophic factors to make the retina secrete factors to self-protect against degeneration,” Dr. Baudouin explained.

A promising procedure, CRISPR-Cas9 gene editing, gene remodeling, has revolutionized biomedical research. Mice treated with adenovirus-delivered CRISPR-Cas9 targeting the mutated myocilin protein had lower IOP for at least two months after the first injection, he said.

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