New pharmacotherapies and delivery systems broaden glaucoma landscape

After many years at a standstill, the entire landscape of glaucoma is changing rapidly on both the surgical side and the medical side. MIGS is now a well-established concept, new topical medications have entered the scene, and new modes of delivery are in the pipeline, some near to completion of phase 3 trials.

“It is an exciting time because we are better able to take care of our patients,” OSN Glaucoma Board Member Savak “Sev” Teymoorian, MD, MBA, said. “Patients are so unique with their disease and the way they are in their life that we really have to fine-tune therapy based on what their needs are. We have more options now in our drug armamentarium, and this makes it easier for us to provide that kind of care.”

There have been two recent major newcomers in the field of medical therapy. Vyzulta (latanoprostene bunod, Bausch + Lomb) was approved by the FDA in November 2017, followed 1 month later by Rhopressa (netarsudil, Aerie Pharmaceuticals).

“I had a chance to use both of them for quite some time with very good results. The greatest interest of these drugs is that they both reduce intraocular pressure through a novel mechanism of action that involves the trabecular meshwork, the primary source of normal regulation and dysregulation of intraocular pressure,” Teymoorian said.

Source: Savak “Sev” Teymoorian, MD, MBA

Novel prostaglandin compound

Latanoprostene bunod is a novel prostaglandin compound with a dual mechanism of action. In situ, it is metabolized to latanoprost acid and butanediol mononitrate, a nitric oxide-donating moiety.

“The addition of a nitric oxide group provides an additive IOP-lowering effect compared with other prostaglandin analogues, including latanoprost,” OSN Glaucoma Board Member Robert N. Weinreb, MD, said. “PGAs reduce intraocular pressure by increasing the aqueous humor outflow through the uveoscleral outflow pathway. The addition of nitric oxide is thought to have an effect on the trabecular meshwork and to increase the outflow through that tissue, as well.”

In a direct comparison study, the phase 2 VOYAGER study, latanoprostene bunod showed better efficacy than latanoprost alone in lowering IOP, while side effects were similar. The APOLLO and LUNAR phase 3 studies demonstrated significantly greater IOP-lowering effect as compared with timolol. The JUPITER study showed a statistically significant reduced mean IOP of 14.4 mm Hg at 12 months. This study evaluated the new compound mainly in patients with IOP below 21 mm Hg, classifiable as low-tension glaucoma.

“In clinical practice, there is an additional 1 mm Hg to 2 mm Hg pressure lowering compared with latanoprost and other PGAs in some patients. It is used once daily, typically at night like any other PGA,” Weinreb said.

New method of activation

Rhopressa has unique mechanisms of action and, perhaps, more than two targets. It inhibits the activity of both Rho-associated kinase (ROCK) and the norepinephrine transporter system, actively involved in the regulation of smooth muscle contraction and stress fiber formation. It is an innovative medical product because, unlike other drugs, it targets the primary drainage system of the eye through the trabecular meshwork.

“It relaxes the cells in the trabecular meshwork and the inner wall of the Schlemm’s canal, enhancing outflow, and at the same time inhibits aqueous humor production and inflow. It is also thought to lower episcleral venous pressure,” Weinreb said.

In three phase 3 pivotal trials, Rocket 1, Rocket 2 and Rocket 4, netarsudil was compared with timolol in more than 1,000 patients and was shown to be effective and well tolerated. A once-per-day drop was noninferior to two daily drops of timolol. The best effect was seen in patients with IOP lower than 24 mm Hg, which represents the majority of glaucoma patients.

“It is a very good addition to medications that we already have available. In most of our patients, we use it in combination with a prostaglandin, typically as a once-daily substitute for other drugs they are already taking as an adjunct,” Weinreb said.

It is mostly used as an adjunct, or as a second-line therapy, because prostaglandin analogues are so effective. However, it sometimes can be used as primary therapy in patients who are intolerant to or do not want to administer prostaglandin analogues due to side effects, Weinreb said.

Prostaglandin analogues typically cause elongation and darkening of eyelashes, iris darkening, periocular skin pigmentation and periorbitopathy in some cases. On the other hand, netarsudil is frequently associated with conjunctival hyperemia and cornea verticillata, sometimes leading to blurred vision.

“Tolerance to one or the other of these side effects is very individual. Some patients see eyelash growth as a positive effect,” Weinreb said.

Minimizing patient burden

“What is making these new therapies exciting is not just that they bring the eye pressure down but they are really helping us improve our patients’ quality of life. We know patients don’t like putting eye drops in. There is a big issue with noncompliance in glaucoma, so anything we can do to decrease the burden is going to be an improvement,” Teymoorian said.

Having Rhopressa as a possible adjunct to prostaglandins is a step in this direction, he said. Before Rhopressa, adding a second agent was almost like picking the lesser evil because all other options need multiple daily dosing and have systemic side effects. Rhopressa is a once-a-day medication, is not known to have systemic side effects and can be instilled at nighttime with the prostaglandin.

“So, patients only have to put one more drop at nighttime. Before Rhopressa, we had to use one drop in the morning, maybe one drop in the afternoon and two drops in the evening. That was a lot of drops. The addition of this product makes compliance significantly better,” Teymoorian said.

In May, Aerie submitted to the FDA the application for another new drug, a fixed-dose combination of netarsudil and latanoprost. With the brand name of Roclatan, this option has a Prescription Drug User Fee Act date of March 14.

“We are very excited to have this combination in one drop. This will be a further improvement, truly minimizing a patient’s burden with just one drop per day at nighttime,” Teymoorian said.

A good alternative

According to Teymoorian, Rhopressa can be used as first-line therapy in some cases.

“If you have a patient who is concerned about pigmentation of the iris, like many of the patients with blue eyes, Rhopressa would be a good alternative to propose instead of a PGA. It might also be a safer option in patients with diabetic retinopathy and macular edema because prostaglandins are known to cause macular edema-related issues,” he said.

He switched some of his patients from prostaglandin to Rhopressa because they were intolerant of side effects or had problems with macular edema. In his experience, the main issue related to the drug — hyperemia — is bothersome for no more than one out of 10 patients.

“I switched many patients who were already on adjunctive therapy, dosed multiple times a day, to give them an easier regimen. Most patients are really excited to hear they can go down on their drops. I tell them about the irritation, but most patients want to try. They know they can stop the medicine and the redness goes away. For my own family members, I would definitely do the same,” he said.

Combinations

In October, the European Medicines Agency accepted for review the marketing authorization application for Rhokiinsa, the prospective brand name for Rhopressa in Europe.

Meanwhile, the Mercury 3 trial assessing the safety and efficacy of Roclatan compared with Ganfort (bimatoprost/timolol, Allergan) is ongoing in nearly 60 centers in 11 European countries.

“We are looking forward to having these new options available in Europe,” Frances Meier-Gibbons, MD, said. “Aerie has been very prominent in the research on ROCK inhibitors, while no European company has taken steps in the same direction, probably because we have many combinations already, much more than in the U.S.”

Neither Ganfort, DuoTrav (travoprost/timolol, Novartis), nor any of the prostaglandin-beta blocker combinations available in Europe have been approved in the United States, as they failed to prove superior to the individual components. One exception is Simbrinza (Alcon), a combination of brinzolamide and brimonidine tartrate.

“I use combinations very often because they have a big advantage concerning adherence and have fewer preservative agents. However, in some patients the clinical effect is better if the compounds of combined drugs are given separately,” Meier-Gibbons said.

She believes that the combination of latanoprost and netarsudil will be particularly welcome because it is another option without beta blockers.

“Many patients have trouble with beta blockers, and we’ll be happy to have a combination that is equally effective without their systemic side effects,” she said.

Adherence is key

Meier-Gibbons is a firm believer that adherence is what largely determines the success or failure of glaucoma therapies.

“Medicines work if you take them, and what we should primarily improve is the adherence of the patients. Today, when I asked a patient how she was doing with her drops, she said, ‘Well, you know, I forget them’, and that is the main problem,” she said.

Lack of compliance does not surprise Meier-Gibbons, given the older age, multiple health issues and visual limitations of many glaucoma patients.

“Some patients are on 10 systemic medications for whatever reasons, and then you give them eye drops. How would they remember that? Often they don’t know when to take them, how many and in which order. Even if you tell them and write everything on the bottle, they cannot remember and cannot read what you write on the bottle. They are confused. They forget,” she said.

For these reasons, Meier-Gibbons is an advocate of sustained-release medications and believes that once these technologies become available, the benefits will be huge.

“Sustained for at least a couple of months, though. That’s what we need if we want to see an improvement,” she said.

Sustained release

The current low compliance rates and the need to improve compliance are the rationale for sustained release, Devesh Varma, MD, said.

“If you have a medication that you can put in and lasts for weeks or months, then you take the compliance issue out of the picture. That’s the main rationale, and that’s where I think these technologies will have a role,” he said.

There are some promising options for sustained release in the pipeline, and different approaches will allow tailored choices, putting in balance the amount of invasiveness with the amount of longevity and significance of action.

“Some of the devices are under development and some are currently in phase 3 trial, quite close to conclusion. A few are in phase 2 and look quite promising, and some are in the preclinical phases. They may or may not make it into the market, but each one has a place in terms of the concept they are trying to achieve,” Varma said.

Devices under clinical investigation

The devices that look more promising and are in the later stages of development belong to the subcategory of intracameral implants. They are the most invasive but work with a lower amount of active principle and avoid most of the typical side effects related to topical administration.

“You need a mega-dose of each medication to get through the barrier of the cornea, and a lot is dispersed. In the anterior chamber, only a fraction is needed to achieve the same effect. The disadvantage is that you need to have these devices injected in the office, and this entails a completely different model of practice,” Varma said.

The injection model is familiar to the retina world but is new for glaucoma.

“It requires a big change, which together with the cost for the patient and the clinic, may or may not be a barrier,” he said.

Three of these implants look particularly promising. One of them is Bimatoprost SR (Allergan), which showed efficacy in phase 2 studies. The key question for it is longevity. Travoprost XR (Envisia Therapeutics) has a similar mechanism, and phase 2 studies showed sustained efficacy over 11 months.

“Pretty impressive, pretty ideal. You see a glaucoma specialist once a year for an anterior chamber injection, which is painless, and then you don’t have to worry about drops for the whole year,” Varma said.

The third one, at the crossroads of the two worlds of minimally invasive surgery and medications, is the iDose (Glaukos), which uses a MIGS device platform as a refillable container that elutes travoprost.

The Durasert subconjunctival implant (EyePoint Pharmaceuticals) is now undergoing phase 3 investigation. It has perhaps more side effects because it is subconjunctival rather than intracameral, but it uses the same well-known platform as the Iluvien intravitreal implant (fluocinolone acetonide, Alimera Sciences) for the delivery of latanoprost.

An interesting, less invasive option, the Bimatoprost Ring (Allergan), was close to phase 3 but may not be pursued. The ring, 1 mm thick with a diameter variable between 24 mm and 29 mm, was designed to be placed in the fornix and release bimatoprost over 6 months.

“This, like other surface implants, would be easy to insert even by the patient. Efficacy may not be quite the same as drops because comparison with timolol is the standard for approval in the U.S., and you cannot load enough drug onto a topical device to beat timolol. Maybe the standard is wrong; maybe the benefits of increased compliance would outweigh the IOP bar that is set with timolol. That has been a challenge for the approval process of the Bimatoprost Ring. A drug-eluting ring that patients can learn, maybe with a little practice, to put in by themselves would be really great,” Varma said.

Earlier stages

Several other methods are still at the stage of preclinical investigation. One of them, the SoliDrop (Otero Therapeutics), uses a gel matrix as a carrier for brimonidine. Administered in the eye just like a traditional eye drop, it transforms into a viscous gel that adheres to the fornix and lasts for 1 month.

“The problem with gel-forming drops is that they tend to have a burst effect. Most of the drug is released in the first week. Making it more of a consistent drug delivery is the hurdle,” Varma said.

Clearside Biomedical has developed a short needle to inject drugs through the sclera into the supraciliary space, using various vehicles as sustained-release reservoirs.

“This mechanism of delivery could be used with any of the drugs we currently have and has a potential to provide a longer effect rather than on the surface, with fewer side effects,” Varma said.

“The MIGS landscape has really transformed glaucoma care, but it may not be the last stop for us,” Varma said.

He said that a significant portion of glaucoma is treated by comprehensive ophthalmologists and not all of them are comfortable with surgery. Many patients, therefore, do not have access to MIGS devices.

“So, if this area of work can offer solutions for those people, who are probably the majority of glaucoma patients, it could be very promising,” he said. – by Michela Cimberle

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• For more information:
• Frances Meier-Gibbons, MD, can be reached at Eye Center Rapperswil, Merkurstr. 50, CH-8640 Rapperswil, Switzerland; email: frances.meier@bluewin.ch.
• 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.
• Devesh Varma, MD, can be reached at Prism Eye Institute, 3200 Erin Mills Parkway, Unit 1, Mississauga, ON L5L 1W8, Canada; email: deveshvarma@me.com.
• Robert N. Weinreb, MD, can be reached at Shiley Eye Institute, 9415 Campus Point Drive, La Jolla, CA 92093; email: rweinreb@ucsd.edu.

Disclosures: Meier-Gibbons reports she is a consultant for Alcon, Allergan, Novartis and Santen. Teymoorian reports he is a consultant for Aerie Pharmaceuticals, Bausch + Lomb and Glaukos. Varma reports he is a consultant for Allergan and Glaukos. Weinreb reports he is a consultant for Aerie Pharmaceuticals and Bausch + Lomb.

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