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New therapies may prompt proactive approach to glaucoma care
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New medications set for release and changes in treatment philosophy offer exciting potential for patients with glaucoma.
With new technologies to diagnose glaucoma and improving treatment options, ophthalmologists can be proactive in treating the disease, instead of historically being reactive, OSN Glaucoma Board Member Savak “Sev” Teymoorian, MD, MBA, said.
The biggest instrument of change, more so than any one therapeutic, is in the philosophy of how to think about glaucoma, Teymoorian said.
“It used to be that we did not have a lot of good options for treatment, and it took a while for diagnosis. It was a very reactive kind of disease. We would react when there was a loss of the nerve. Now, with newer technologies to diagnose and better treatment options, it is more of a proactive kind of disease. Instead of waiting for the damage to be done, reacting and hoping for the best, we are now looking at ways to prevent damage,” he said.
The past 18 months have seen an “explosion” of new developments for the treatment of glaucoma, according to OSN Glaucoma Board Member Douglas J. Rhee, MD.
Source: Savak “Sev” Teymoorian, MD, MBA
Newly FDA approved therapeutics include Vyzulta (latanoprostene bunod ophthalmic solution 0.024%, Bausch + Lomb) and Rhopressa (netarsudil ophthalmic solution 0.02%, Aerie Pharmaceuticals).
Latanoprostene bunod
The FDA approved Vyzulta, a once-daily glaucoma drop, in November 2017, and it is expected to be available later this year, according to Rhee.
The efficacy and safety of Vyzulta, the first prostaglandin analogue with a nitric oxide metabolite, were evaluated in two randomized phase 3 studies, APOLLO and LUNAR. The studies compared Vyzulta with timolol maleate ophthalmic solution 0.5% in 831 patients with open-angle glaucoma or ocular hypertension. In both studies, Vyzulta met the primary efficacy endpoint of mean IOP reduction over 3 months of treatment.
“My initial clinical experience with it, which is at this time extremely limited, is that it works, but it is not necessarily a home run,” Rhee said. “I have been doing replacements at this point, switching people from a prostaglandin to Vyzulta, and the clinical benefit has been modest.”
Although the potential for latanoprostene bunod is exciting, the exact mechanism of action needs to be known in order to evaluate its utility, according to Rhee.
In March, Bausch + Lomb signed an agreement with Express Scripts to expand insurance coverage of Vyzulta, thus expanding access in the U.S.
Rho kinase inhibitors
The exact mechanism of action is known for Rho kinase inhibitors, however, and ophthalmologists know exactly how they work at the molecular level, Rhee said.
Rhopressa, approved in December 2017, is a once-daily eye drop designed to lower IOP in patients with open-angle glaucoma or ocular hypertension.
With Rho kinase inhibitors, patients do not have to balance treatment and side effects, according to Teymoorian.
“An adjunctive therapy Rho kinase inhibitor, like Rhopressa, does not have systemic side effects, is used once a day, and you can combine it at night with your prostaglandin analogue,” Teymoorian said.
In phase 3 study results, Rhopressa dosed once or twice daily in patients with glaucoma demonstrated a consistent level of IOP lowering across all baseline IOPs throughout the 90-day efficacy period.
“Instead of wondering, ‘Is this disease bad enough now that it is worth putting the patient on this medicine with these bad side effects?’, we have other options. Because the side effects and compliance will be so much better, we can be more aggressive,” Teymoorian said.
MIGS and meds
Both Rhopressa and Vyzulta do something new for glaucoma patients; they target the trabecular meshwork and increase outflow, Nathan M. Radcliffe, MD, of New York Eye Surgery Center, said.
“The reason that is important is because if you think about what probably happens in glaucoma over time, it is a lack of fluid going through the trabecular meshwork that ends up in this cycle of atrophy in the outflow pathway. Less fluid comes into the trabecular meshwork, the canal of Schlemm may undergo some changes, the collector channels bringing fluid out of the canal to the episcleral veins may atrophy, and ultimately 10 to 20 years later when you try to do something to open up the trabecular meshwork, there is nothing there to catch the fluid,” he said.
Therapies to open the trabecular pathway and maintain it, or potentially restore it through pharmacological mechanisms, are the closest ophthalmology has come to a rejuvenating therapy, he said.
These medications may change the way ophthalmologists think about treating glaucoma in the future, he noted.
“In early disease, we may ask ourselves whether we want to use a drop that shuts down aqueous production and drives fluid away from the trabecular meshwork, or do we want to use an agent that encourages the flow of fluid through the trabecular meshwork and potentially keeps what is left of this patient’s outflow system healthy for as long as possible,” Radcliffe said.
By keeping the system healthy and restoring natural outflow, when it comes time for cataract surgery, a MIGS device can be used to bypass the trabecular meshwork.
“The concept is that the trabecular meshwork will probably be opened up at the time of cataract surgery, so if we can keep that option viable, that’s important,” Radcliffe said. “What I think is unfolding in 2018 is a story of MIGS and meds — meds to do what you can to enhance and restore outflow, and then MIGS at the time of cataract surgery to capitalize on that or permanently to maintain or permanently stent open the outflow pathway.”
Treatments pending
Roclatan (Aerie), a combination of Rhopressa and latanoprost, is under review by the FDA. A once-daily eye drop designed to lower IOP, Roclatan demonstrated successful 12-month safety results with no new adverse events after an initial 90-day efficacy period. Aerie is on target to submit a new drug application to the FDA by the middle of the second quarter of this year, according to a company press release.
New therapeutics can also help address medication compliance, which makes glaucoma treatment difficult, Teymoorian said.
A 2017 observational study published in the British Journal of Ophthalmology found nearly 30% of 1,050 patients with glaucoma were nonadherent to their medications. Increased medication adherence is associated with better management of glaucoma, according to the study.
New medication delivery systems
Finding new ways to deliver glaucoma medication instead of topical drops will be important in managing disease in the future, Teymoorian said.
If approved by the FDA, a bimatoprost ocular insert (ForSight Vision5) could reduce IOP in patients with glaucoma and improve adherence to glaucoma medications, he said.
A phase 2 prospective, randomized, double-masked, active-controlled, parallel-arm study published in Ophthalmology included 130 adult patients with open-angle glaucoma or ocular hypertension. Patients were randomized to receive a placebo insert plus twice-daily timolol 0.5% or a bimatoprost ocular insert plus twice-daily artificial tears for 6 months.
At 6 months, patients who received the ocular insert experienced a mean reduction in IOP from baseline of 3.2 mm Hg to 6.4 mm Hg compared with a reduction of 4.2 mm Hg to 6.4 mm Hg in the timolol group. The primary retention rate of the insert was 88.5% at 6 months, according to the study.
“The treatments have potential. The bimatoprost ring goes under the upper lower eyelid, and we can go all the way to the injection medications, where we can implant medicine into the eye. These are better ways of addressing the major issue in glaucoma, which is a compliance problem. Either it’s a side effect profile of medications that are better now, or it’s a better way of delivering it. The other thing it could be besides the ring or injection, it could be punctal plugs, so these are all exciting ways of treating glaucoma and they’re all improving,” Teymoorian said.
Punctal plugs can be inserted into a patient’s eye to deliver glaucoma medication for several months at a time. The Journal of Glaucoma published a study that showed patients were willing to accept punctal plugs as a sustained drug delivery modality as an alternative to IOP-lowering eye drops.
In 150 patients surveyed, 57% said they would accept punctal plugs if they prevented glaucoma surgery.
The results of a phase 2 trial of the Evolute (Mati Therapeutics), a silicone punctal plug, showed statistically significant results in lowering IOP in glaucoma patients, as reported on by Annette Giangiacomo, MD, at Hawaiian Eye 2018.
The results of the trial showed the plug was effective at lowering pressure 5 mm Hg to 5.5 mm Hg at 12 weeks after implantation. The study showed a retention rate of 92% to 96%, and drug delivery was possible for up to 3 months.
Regeneration, restoration
The goals for glaucoma therapies should include regenerative and restorative properties, Jeffrey L. Goldberg, MD, PhD, professor and chair of ophthalmology at the Byers Eye Institute at Stanford University, said.
“We have three unmet needs in glaucoma. One is, we still need more and better ways to control eye pressure. We have the two new drops that are coming out, Rhopressa and Vyzulta. There is surgical innovation as well, providing better ways to lower eye pressure safely and effectively in the area of MIGS. We do already have a lot of tools in that space, so I think an even greater unmet need is for treatments that directly target retinal ganglion cells, the optic nerve and visual function, and these include drugs that can provide neuroprotection, keeping the retinal ganglion cells alive despite the insult of glaucoma, and neuroenhancement, that’s giving a booster shot to the sick neurons or dysfunctional axons in the optic nerve and getting them to function better and perhaps acutely improving vision,” Goldberg said.
Ultimately, therapies for regeneration and vision restoration, such as regrowing axons down the optic nerves or replacing dead ganglion cells, could be possible through cell or stem cell therapies, he said.
Additionally, Goldberg noted that Rho kinase inhibitors have shown potential in promoting retinal ganglion cell survival and regeneration in preclinical glaucoma models and could offer new treatment options after more research.
“I’m bullish on these possibilities for Rhopressa and ROCK inhibitors, in addition to their eye pressure-lowering effects. They’ve been very well studied in preclinical models for being neuroprotective and promoting regeneration, so the idea that they may have that effect in human glaucoma patients is very exciting. I do think that hopefully a message will get across that between new ways to measure the disease and better ways to select patients for clinical trials, we’re now in a phase where we can reasonably test candidate therapies in humans. I’m looking forward to a very exciting next few years as more of these therapies get tested particularly for their neuroprotective or neuroenhancing ability,” he said.
Clinical trial underway
Goldberg is currently conducting a clinical trial sponsored by Stanford University to examine the safety and efficacy of an intravitreal implantation of NT-501 encapsulated cell therapy (ECT). The randomized, sham-controlled, masked clinical trial involves 60 patients with glaucoma. Patients who receive the ECT implant are examined for safety 1 day and 1 week after implantation and periodically for 24 months after implantation. The patients will be compared with a control arm, in which subjects may be offered an NT-501 ECT implant at the 12-month time point.
The study began in June 2016, and the estimated study completion date is January 2020.
Interrupting the disease process
Ophthalmologists may someday be able to interrupt the disease process. Every treatment for glaucoma right now is palliative and addresses the symptoms, Rhee said.
“Maybe in the next 10 to 15 years we’d like to see therapies that actually interrupt the disease process. ROCK inhibitors are close, but I think it’s still a little controversial whether this is actually part of the primary disease pathophysiology. It may be; I think a little bit more work needs to be done to show that, but at least we’re at the right tissue. As opposed to uveoscleral agents, like the prostaglandin, they’re all palliative. There is no pathophysiology that causes glaucoma in the uveoscleral pathway. It happens to be a very effective pressure-lowering pathway, but it’s not part of the disease pathophysiology itself. That’s the next hurdle and, of course, neuroprotection,” Rhee said. – by Robert Linnehan
- References:
- Aerie Pharmaceuticals announces U.S. FDA approval of Rhopressa (netarsudil ophthalmic solution) 0.02% for the lowering of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. investors.aeriepharma.com/news-releases/news-release-details/aerie-pharmaceuticals-announces-us-fda-approval-rhopressar. Published Dec. 18, 2017. Accessed Feb. 14, 2018.
- Aerie Pharmaceuticals reports positive Rhopressa phase 3 efficacy results. investors.aeriepharma.com/news-releases/news-release-details/aerie-pharmaceuticals-reports-positive-rhopressatm-phase-3. Published Sept. 16, 2015. Accessed Feb. 13, 2018.
- Brandt JD, et al. Ophthalmology. 2016;doi:10.1016/j.ophtha.2016.04.026.
- Giangiacomo A. Sustained-release glaucoma treatment. Presented at: Hawaiian Eye; Jan. 13-19, 2018; Wailea, Hawaii. www.healio.com/ophthalmology/glaucoma/news/online/%7b6a75fb25-50b9-4d97-9e02-48fe93706d72%7d/sustained-release-glaucoma-treatments-in-the-pipeline-will-increase-adherence. Published Jan. 17, 2018. Accessed Feb. 15, 2018.
- Glaucoma drug Roclatan shows superior efficacy in late-stage study. www.aao.org/headline/glaucoma-drug-roclatan-superior-efficacy. Published May 24, 2017. Accessed Feb. 12, 2018.
- Kim CY, et al. Br J Ophthalmol. 2017;doi:10.1136/bjophthalmol-2016-308505.
- Varadaraj V, et al. J Glaucoma. 2018;doi:10.1097/IJG.0000000000000913.
- For more information:
- Jeffrey L. Goldberg, MD, PhD, can be reached at Byers Eye Institute at Stanford, 2452 Watson Court, Suite 2700, Palo Alto, CA 94303.
- Nathan M. Radcliffe, MD, can be reached at New York Eye Surgery Center, 1101 Pelham Parkway North, Bronx, NY 10469; email: drradcliffe@gmail.com.
- Douglas J. Rhee, MD, can be reached at Department of Ophthalmology and Visual Sciences, Case Western Reserve University School of Medicine, Euclid Ave., Mail Stop WRN5068, UHI Institute, Cleveland, OH 44106; email: dougrhee@aol.com.
- Savak “Sev” Teymoorian, MD, MBA, can be reached at Harvard Eye Associates, 24401 Calle De La Louisa, Suite 300, Laguna Hills, CA 92653; email: steymoorian@harvardeye.com.
Disclosures: Goldberg reports he is a consultant for Bausch + Lomb, Aerie Pharmaceuticals, Allergan and Alcon/Novartis. Radcliffe reports he is a consultant for Allergan, Alcon, Aerie Pharmaceuticals, Ellex, Iridex, Lumenis, Sight Sciences, New World Medical, Glaukos and Shire. Rhee reports he receives stock options with Aerie Pharmaceuticals and research funding from Glaukos, Ivantis and Merck. Teymoorian reports he is a consultant for Aerie, Allergan, Alcon, Bausch + Lomb, Ellex, Glaukos and Ivantis and does research for Aerie, Bausch + Lomb, Glaukos and Ivantis.
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