The future of glaucoma treatment

Many new developments on the research front suggest the battle against glaucoma is turning. New drugs are now entering the clinic, along with new ways to deliver them. There is growing consensus that the future of glaucoma management will be based more on the optic nerve pathway from the retina to the visual cortex, and not strictly limited to improving outflow. EuroTimes takes a look at what glaucoma treatment may look like in the not-too-distant future.

Near-term – ROCK

With intraocular pressure (IOP) being the only known modifiable factor in glaucoma, current therapy continues to emphasise drugs and surgical methods of keeping pressures under control. The mainstays are prostaglandin analogues, which increase uveoscleral outflow, and beta blockers, which reduce aqueous production.

Considerable activity suggesting that a new class of agents known as Rho Kinase (ROCK) inhibitors, which act mainly on trabecular meshwork outflow, will play a key role in future glaucoma management either alone or in combination with current treatments. ROCK inhibitors are also considered to offer potential in the treatment of heart disease, erectile dysfunction and cancer.

ROCK inhibitors are thought to enhance aqueous drainage by acting on the actin cytoskeleton and cellular motility in the trabecular meshwork, Schlemm’s canal and in ciliary muscle. These drugs appear to lower IOP by decreasing resistance to aqueous outflow by cellular relaxation in the trabecular meshwork.

There is now considerable clinical trial data confirming that ROCK inhibitors do indeed lower IOP. One drug in this class, ripasudil (Glanatec, Kowa), recently received regulatory approval in Japan for the treatment of glaucoma and ocular hypertension.

Hidenobu Tanihara MD, Professor of Ophthalmology, Kumamoto University, Kumamoto, Japan, has been involved from the beginning in trials leading to the approval of the drug. He has reported clinical trial results indicating that the drug produced significant, dose-dependent reductions in IOP in eyes with glaucoma and ocular hypertension. The effects were additive when combined with a prostaglandin agent and beta blocker (timolol). The new drug was well tolerated but did produce transient hyperaemia in a majority of patients.

“Ripasudil is now prescribed as the second-line drug for glaucoma treatment in Japan. I think ripasudil can add IOP-lowering effects to the first-line drugs such as beta blockers and prostaglandins. Patients seem to be accepting the hyperaemia because of its transient nature,” he told EuroTimes.

Another drug in this class, Rhopressa (Aerie Pharmaceuticals), is now in phase III studies. In phase II studies the drug produced sustained reductions in IOP with once daily dosing. However, in phase III studies the drug did not meet its primary efficacy endpoint of non-inferiority to twice daily timolol above 26mmHg IOP.

The company is also developing Roclatan, a single-drop fixed-dose combination of Rhopressa and latanoprost. A third candidate, AR-13533, is in preclinical testing. The Belgian company Amakem also has a ROCK inhibitor in phase II testing for glaucoma treatment.

The mechanism of action of ROCK inhibitors suggests there may be benefits beyond IOP lowering. Studies indicate that drugs in this class increase retinal blood flow by relaxing vascular smooth muscle cells. This could provide a neuroprotective effect. A better understanding of how these drugs work will also provide new insights into the pathology of glaucoma, says Dr Tanihara.

Long-term – follow the optic pathway

There is a consensus among glaucoma researchers that controlling IOP with drops and surgery will simply never be adequate to deal with the underlying causes of the disease.

Rather, the new direction is to look at the relationship between the various types of retinal ganglion cells (RGCs), the optic nerve and the visual cortex. More than a decade ago, Neeru Gupta MD, PhD, MBA, Professor and Dorothy Pitts Chair of Ophthalmology & Vision Science, St Michael’s Hospital, and Chief of Glaucoma, University of Toronto, Canada, proposed that glaucoma should be seen as a neurodegenerative disease. She reported research indicating that a rise in IOP affected not only the RGCs and nerve fibres, but also extended to major vision centres in the brain, experimentally, and in patients with glaucoma.

“There is no question that high pressure causes injury to RGCs. What are the exact pathways of insult that cause this? We don’t know. The big push now is to do something beyond pressure. We are trying to attack the fundamental problem. The optic nerve is really just the cable composed of axons of multiple different RGC types within the eye. We are still learning the specific role of RGCs and other cell players including glial cells. The optic nerve is a highway to the brain and we are only just beginning to understand how everything is segregated and integrated in visual processing,” she told EuroTimes.

She emphasised the importance of thinking of glaucoma as a disorder of the entire visual system. The role of RGCs needs to be considered in relation to the rest of the brain. This will be the basis of therapies that boost the ability of RGCs to connect, to understanding which cells are most susceptible to damage, and under which circumstances.

She predicted that future glaucoma treatment would involve more personalised care, where phenotyping and genotyping will help guide a pharmacogenetic approach. This will allow for the treatment of specific genetic defects with an appropriate individual therapy.

“We will see new agents and therapeutic cocktails that will address the RGC sickness. We are starting to discover that there may be intrinsic fundamental distress in areas of the brain that process vision, so we will need to be looking at therapies that make the system more robust,” she explained.

The road to discovering these new treatments will in turn depend on clinical studies that will help find more clues about glaucoma pathogenesis, such as biomarkers in blood and aqueous humour. In addition, major advances in imaging capability will allow researchers to study actual damage to visual centres in the brain.

“We can look forward to a more personal and proactive approach to choices and timing of treatments, to prevent damage throughout the visual system, and to keep glaucoma patients seeing for a lifetime,” says Dr Gupta.

Researchers are looking at treatment strategies that might approach RGC loss at different stages in the disease process. Early intervention would aim to preserve existing RGCs by using neuroprotective agents. A related approach would involve introducing neurotrophic factors and growth factors that could help the cells regenerate. Some factors under investigation include ciliary neurotrophic factor (CNTF), endothelin-1, TGF-b, connective tissue growth factor (CTGF), and ghrelin.

Jeffrey Goldberg MD, Director of Clinical Research, Shiley Eye Institute, UCSD, San Diego, US, (pictured above)  is another investigator pushing the boundaries of glaucoma research. His team is involved in looking at how and why RGCs die after optic nerve injury.

“Learning about the molecular pathways that, during early development, turn off RGC intrinsic capacity for rapid axon growth has led to new therapeutic approaches to reverse regenerative failure and promote axon growth in the injured or degenerating optic nerve. Such therapeutic approaches are just beginning to enter human clinical testing in early phase trials,” he told EuroTimes.

Dr Goldberg was involved in some of the first trials testing the ability of a growth factor, CNTF, to promote both RGC survival and optic nerve regeneration in glaucoma patients. CNTF is a member of the IL6 cytokine category. It is released by retinal glial cells. Laboratory research has shown that CNTF promotes RGC survival, protects RGCs from degeneration, and promotes optic nerve regeneration.

Two open-label safety studies enrolled 11 patients with primary open-angle glaucoma. Patients received CNTF delivered via a proprietary approach known as encapsulated cell therapy (NT-501, Neurotech). The implant is a small immunologically neutral capsule designed to release a steady stream of CNTF. The 1.0 x 3.0mm implant contains RPE cells primed to produce CNTF. All patients completed the study with no serious adverse events related to treatment.

There are also a number of promising animal studies in which implanted RGCs showed evidence of growing both dendrites into the retina and axons along the retinal nerve fibre layer and across the optic chiasm. This suggests that it may be possible to transplant RGCs even in the very late stages of glaucoma, he said.

Research hits a wall

However, there is a sense that glaucoma research has a hit a wall, with quite a lot of promising animal studies but little movement towards early clinical studies in humans.

Dr Goldberg told EuroTimes that the main obstacle to success is the reticence to move such approaches into early phase trials for human testing. But he said this reticence is beginning to melt away as more confidence is gained in the ability to design clinical trials for neuroprotection and neuroenhancement.

“Examples are coming from growth factors and stem cell trials that are just beginning to enter human testing. From here forward it is an empiric question: will the treatments that work so well in animal models of human diseases, like glaucoma or optic nerve stroke, prove their worth in humans with these diseases? The only way we will answer that question is to do the actual trials,” he said.

Gene therapy is another area of active investigation, and is a good example of this situation where promising in vivo research awaits the next step into human trials. Animal studies have shown the basic feasibility of introducing genes to the back of the eye that can inhibit apoptosis and encourage neurotrophic factors to preserve RGCs. Another approach is the development of therapeutic constructs that target the cytoskeleton of the trabecular meshwork.

Yet another avenue of gene therapy in the pipeline involves using non-viral gene replacement therapy delivered in DNA nanoparticles.

“Gene therapy holds the ultimate promise to eliminate glaucoma-induced visual disability across a spectrum of possibilities: pre-disease onset detection, treatment targeted at basic cellular dysfunction (whether in the outflow pathways or in the retina/optic nerve head), optimal use of individualised pharmacological neuroprotection and/or IOP reduction, and even neural regeneration and/or repopulation,” commented Ivan Goldberg MD, Director of Eye Associates in Sydney, and Head of the Glaucoma Unit at the Sydney Eye Hospital, Australia.

Hidenobu Tanihara: tanihara@pearl.ocn.ne.jp

Neeru Gupta: GuptaN@smh.ca

Ivan Goldberg: eyegoldberg@gmail.com

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