Tomorrowland: What the future holds in glaucoma therapies

April 17, 2015

The present method of lowering IOP as a means of preventing optic neuropathy is expanding beyond prostaglandin analogues and beta blockers to include novel therapeutics, such as Rho kinase (ROCK) inhibitors, the adenosine class of drugs, and nitric oxide added to prostaglandins, said John R. Samples, MD.

San Diego-The present method of lowering IOP as a means of preventing optic neuropathy is expanding beyond prostaglandin analogues and beta blockers to include novel therapeutics, such as Rho kinase (ROCK) inhibitors, the adenosine class of drugs, and nitric oxide added to prostaglandins, said John R. Samples, MD, Olympia, WA.

“Glaucoma therapy is on the cusp of a revolution,” he said-with three or more drugs in “truly new classes,” new drug delivery devices that will obviate patient compliance, and surgical devices and techniques that will prove “more effective with a lower morbidity” than what is currently available.

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Two ROCK inhibitors are well on their way-Aerie Pharmaceuticals is conducting two phase III studies on the inhibitors with some results anticipated this year. Kowa has a ROCK inhibitor in phase III studies in Japan. Most other new therapies are only in phase II or phase IIa, he said.

“But soon we’re going to be able to measure the actual loss of retinal ganglion cells to define glaucoma,” he said during Glaucoma Day at the 2015 meeting of the American Society of Cataract and Refractive Surgery.

Clinicians will be able to treat the specific underlying molecular abnormality discovered with lab and genetic testing, he said.

“We will be able to confer health on the meshwork and the nerve,” Dr. Samples said, with a combination of protective agents and stem cell therapies.

Bausch + Lomb is developing a nitric oxide-donating latanoprost that is in phase 3, and Santen and Ono are developing prostaglandins that are also likely incompatible with today’s medical therapies, he said.

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“There is so much more to learn about this new ROCK/norepinephrine transporter (NET) class of drugs,” he said.

For instance, while they have shown neuroprotective traits in animal models, there is no guarantee that will translate to equivalent efficacy in humans.

The adenosine mimetics modulate IOP in mice, and trabodenoson (INO-8875) is “optimized as a highly selective agonist to subreceptor A1,” Dr. Samples said.

Its lipid solubility allows for corneal penetration so it can reach the trabecular meshwork and “has high compatibility with tissues in the front of the eye,” he said.

“Adenosine protects the retina against ischemia in animal models, and adenosine A1 receptors are found on retinal ganglion cells,” he said.

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Early studies show trabodenoson 500 mcg lowers IOP by 6 to 7 mm Hg by day 28.

Changing how drugs are delivered is another avenue being explored by several companies, he said. Both QLT and Ocular Therapeutix are investigating punctal plugs, while Aerie and Refocus are investigating novel reservoir insertions to deliver their pharmacologic agents.

“Many other companies are also investigating reservoir insertions, with and without nanoparticles,” he said.

On the disappointing side, memantine failed to prove efficacy as a neuroprotector, but other theoretical neuroprotectors have been investigated outside of ophthalmology, included ROCK inhibitors for stroke, he noted.

Silencing RNA therapy for caspase 2 has been “very promising” in small clinical studies, Dr. Samples said.

Next: Delivery of meshwork stem cells

 

“Another future so-called ‘pharmacologic’ avenue is delivery of meshwork stem cells,” he said.

Work being done in the Oregon Trabecular Meshwork Lab has been surprisingly successful, he added.

“It’s been successful all the way up to human studies,” Dr. Samples said.

And, finally, glaucoma surgery developments “will change everything,” Dr. Samples promised.

Among the techniques in development are new trabecular meshwork treatments (Eyesonix), new pars plana treatment that may increase uveal outflow (Iridex), “many new surgical approaches with decreased morbidity-what I’m calling ‘Beyond MIGS’,” he said.

Suprachoroidal stents “are easy to implant and are very effective,” he said. “I’m a big fan of these” because the scleral spur guides the device into the space.

Finally, he said, glaucoma genetics and gene-targeted or therapy treatments for the disease are other potential avenues.

There are currently eight well-accepted genes associated with glaucoma, and researchers are discovering others rapidly.

“From a geneticist’s perspective, primary open-angle glaucoma is a number of diseases, not just one,” he said.

In short, he said there is “no more exciting a time” to be involved in the field of glaucoma.

“With all these new options, the winners will be the ones that are easiest to put in,” he said.