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Pharmacologic products and devices in development continue to gain momentum in the glaucoma treatment armamentarium.
Take-home message: Pharmacologic products and devices in development continue to gain momentum in the glaucoma treatment armamentarium.
By Laird Harrison; Reviewed by Andrew Iwach, MD; Joel Schuman, MD, and Robert Stamper, MD
New glaucoma drugs and new delivery systems for them both inched forward into 2016, bolstering hopes for more effective and less burdensome treatments.
Researchers reported promising phase III results for latanoprostene bunod (Bausch + Lomb) and netarsudil ophthalmic solution (Rhopressa, Aerie Pharmaceuticals).
Both companies ran into manufacturing problems, however, that set back their new drug applications to the FDA.
Meanwhile, ForSight Vision5 reported hopeful phase II data for its topical ring that slowly releases bimatoprost (Helios).
Latanoprostene bunod not only matched but also beat the IOP-lowering effects of timolol in two phase III trials published in 2016. In the most recent one, published July 6 in the American Journal of Ophthalmology (2016;168:250-259), IOP fell at least 25% in 31.0% of patients who received latanoprostene compared with 18.5% of patients who received timolol.
The patients required only once-daily administration of latanoprostene bunod, an advantage for adherence since several other classes of anti-glaucoma drugs require multiple dosing during the day.
Ocular treatment-emergent adverse events, while uncommon, appeared more frequently in the latanoprostene group, but all were mild-moderate except one case of severe hyperemia.
Latanoprostene bunod is metabolized in the eye to latanoprost acid and butanediol mononitrate. An F2α prostaglandin analog, latanoprost acid increases outflow of aqueous fluid primarily through the uveoscleral pathway. Butanediol mononitrate releases nitric oxide, which is reported to induce relaxation of cells in the trabecular meshwork and Schlemm’s canal, increasing outflow through them.
Despite the hopeful findings, Bausch + Lomb’s new drug application for the drug met with rejection from the FDA for manufacturing reasons. The company planned to meet with the regulators to resolve the problem.
Meanwhile, netarsudil ophthalmic solution passed a couple of milestones. First, on Sept. 6, Aerie announced that it had filed a new drug application to the FDA.
Then on Oct. 27, Aerie announced that it had hopeful data from a phase III clinical trial. At the same time, it withdrew its FDA application, also because of manufacturing problems, but planned to resubmit it in January.
According to Aerie, the drug inhibits both Rho-kinase (ROCK) and noreprinephrine transporters (NET). Inhibiting ROCK relaxes the trabecular meshwork cells, while inhibiting NET reduces production of aqueous fluid. Preclinical results have demonstrated that netarsudil also lowers episcleral venous pressure, which contributes about half of IOP in healthy subjects, and may have an anti-fibrotic effect on the trabecular meshwork.
But netarsudil does not seem more potent than the most widely used glaucoma drugs currently on the market, so Aerie is positioning it as an adjunct to prostaglandin analogues. On Sept. 14, it announced that netarsudil in combination with latanoprost-a product the company is calling Roclatan-lowered IOP 1 to 3 mm Hg more than either of these drugs by themselves in a phase III trial. The subjects took Roclatan once per day, which may prove to be its key advantage over other glaucoma medications, since they require multiple daily doses.
Netarsudil does not appear to have systemic effects. It can cause conjunctival hyperemia, corneal deposits, conjunctival hemorrhages, blurry visions and reduced visual acuity, but these tend to resolve with time, according to Aerie.
Netarsudil by itself got mixed phase III results in 2015, first failing to match the beta blocker timolol maleate in lowering IOP in patients with baseline IOP below 27 mm Hg, then proving non-inferiority compared with timolol in subjects with baseline IOPs between 20 and 25 mm Hg. In the new trial, Rocket 4, netarsudil this time proved non-inferiority to timolol at pressures up to 28 mm Hg, as well as confirming the results in pressures between 20 and 25 mm Hg, the company said.
“This may be an agent that has special utility in certain types of glaucoma that affect people at slightly higher than normal, or normal pressures,” said Joel Schuman, MD, chairman of ophthalmology, New York University, New York.
To serve those patients who find it difficult to use eye drops even once a day, researchers made progress on another solution in 2016. In a phase II study published in Ophthalmology (2016;123:1685-1694) patients with the bimatoprost ocular insert achieved a mean reduction over 6 months from baseline IOP of –3.2 to –6.4 mm Hg compared with –4.2 to –6.4 mm Hg for the timolol group.
While the reduction in pressure fell short of timolol at several time points, the researchers predicted that the device will clear that hurdle in phase III trials when larger patient groups will provide more statistical power.
The ring-shaped insert sits in the eye like a contact lens without the center. An eye-care professional places it circumferentially in the upper and lower fornices.
“It’s quite promising, particularly for those people who have adherence issues, or particularly patients who have difficulty administering drops for themselves, people with arthritis or tremors or just poor hand-eye coordination, which would be a significant percentage of glaucoma patients,” said Robert Stamper, MD, professor of ophthalmology, University of California, San Francisco.
In a vote of confidence, Allergan announced Aug. 11 that it will acquire ForSight Vision5.
Another drug-delivery system working its way through the pipeline is OXT-TP from Ocular Therapeutix. OXT-TP is a punctum plug designed to deliver the prostaglandin analogue, travoprost, to the ocular surface continuously for up to 90 days. Patients and physicians can monitor the drug presence though a fluorescent visualization aid. The company announced Oct. 4 that it is enrolling patients for a phase III clinical trial.
Further down the pike, neuroprotective agents are working their way through earlier stages of research. But developing these treatments presents a problem, said Andrew Iwach, MD, executive director, Glaucoma Center of San Francisco.
Rather than lowering IOP, these agents affect non-IOP parameters that may improve patients’ vision or show some other evidence of slowing the progress of the disease.
“However, at this time, we don’t have the best biomarkers in glaucoma for the required studies,” he said.
The year 2016 brought incremental change in most diagnostic tools, and one complete novelty: the Triggerfish, a one-time use contact lens used to indirectly measure IOP.
The FDA approved the device, developed by Sensimed of Lausanne, Switzerland, on March 4 for sale in the United States.
The device uses four circular strain gauges embedded within the contact lens, which are capable of sensing circumferential changes at the limbus. This gives an approximation of IOP by virtue of the changes in ocular volume, and measures fluctuate over the course of a day.
An antenna taped around the patient’s eye wirelessly receives data from the contact lens and transmits it through a cable to a portable recorder worn in a pouch around the patient’s neck.
“It’s has some interesting research benefits,” said Robert L. Stamper, MD, professor of ophthalmology, University of California, San Francisco. “It has shown, as everyone suspected, that pressure can spike at night, and that can explain why people seemed to have good pressure in the doctor’s office but their glaucoma progresses anyway.”
Another innovation showing good potential is the use of optical coherence tomography (OCT) angiography. In an article for Ophthalmology (2016 Oct 7. pii: S0161-6420(16)31087-9) researchers from the University of San Diego showed a close correlation between vessel density and severity of visual field loss.
“OCT angiography data may complement the structural measurements we get from the retinal nerve fiber layer and allow us to better understand the disease and predict progressions,” said Joel Schuman, MD, chairman of ophthalmology, New York University in New York.
In other respects, diagnostics in 2016 moved forward incrementally, he said, as manufacturers brought out small refinements on existing tools.
-By Laird Harrison; Reviewed by Joel Schuman, MD, and Robert L. Stamper, MD
Andrew Iwach, MD
Dr. Iwach has been a consultant to Acumen Pharmaceuticals, Alcon Laboratories, Allergan, and Bausch + Lomb.
Joel Schuman, MD
Dr. Schuman was on the Scientific Advisory Board of Sight Sciences and is the past Chair of the Data and Safety Monitoring Committee of the Cypass Compass Study for Transcend Medical.
Robert Stamper, MD
Dr. Stamper was consultant to Transcend Medical and Sight Sciences, and participated in one of the trials of Rhopressa. He has received research support from Diopsys.