September 2017

GLAUCOMA

Pharmaceutical focus
Glaucoma medications update


by Maxine Lipner EyeWorld Senior Contributing Writer


Various mechanisms of action for common ocular hypotensive agents used in the treatment of glaucoma and the classes of medication associated with those actions
Source: Constance Okeke, MD

Experts discuss new drops

Over the next few years, many developments will occur in the glaucoma pharmaceutical space, with several new drugs set to emerge, according to Nathan Radcliffe, MD, New York University Langone Medical Center, New York. “They all involve medications that aid in the outflow of the aqueous humor through the trabecular pathway,” Dr. Radcliffe said. The idea likely resonates with those doing MIGS procedures because practitioners are trying to do many of the same things, namely reestablish natural outflow of aqueous humor through the trabecular pathway.
Constance Okeke, MD, Eastern Virginia Medical School, Norfolk, Virginia, pointed out that there hasn’t been a new glaucoma medication in years. “Even though we have this explosion of new minimally invasive glaucoma surgeries, there’s still a huge window of opportunity for a new drop,” Dr. Okeke said. This may be especially true for the patient who is apprehensive about surgery, has allergies, or has developed tolerances to drops.

Vyzulta on deck

Of three new agents being explored, the first to emerge will likely be Vyzulta (latanoprostene bunod, Bausch + Lomb, Bridgewater, New Jersey), Dr. Radcliffe noted. “It’s a nitric oxide donating prostaglandin analogue,” he said, adding that as far as the FDA is concerned, it’s going to be classified as a prostaglandin analogue, which may have implications for insurance. “It may be tough to get for our patients because Bausch + Lomb will have to compete with the other prostaglandin analogues,” Dr. Radcliffe said. “But it has potency that looks to be better than latanoprost, and that could make it a very appealing first-line treatment for glaucoma.”
Dr. Okeke agreed that Vyzulta is an intriguing new agent. “It has a dual mechanism of action; one is similar to prostaglandins, which is increasing the uveal scleral outflow pathways,” Dr. Okeke said. “The other exciting thing about it is its
effect on nitric oxide.” In addition to relaxing tissue within the trabecular meshwork, the nitric oxide mechanism has an effect on Schlemm’s canal that enables it to regulate the volume within the canal. “Those two mechanisms can help to increase the outflow of the aqueous humor,” she said. “By increasing nitric oxide, it has an effect that can increase how much aqueous humor goes out of the outflow channels.”
Pressure lowering with Vyzulta is about 7 to 9 mm Hg from baseline, Dr. Okeke noted. This may give practitioners even more reason to consider it as a first-line medication, she thinks.
Dr. Radcliffe said that the new agent could be particularly appealing for a younger glaucoma patient in whom practitioners would like to keep fluid going through the pathway with the nitric oxide mechanism; this could help from the standpoint of trying to maintain the normal level of physiologic outflow.
Dr. Radcliffe thinks that some practitioners may want to use this for the next several years until the patient has a stent placed or undergoes some other trabecular outflow procedure.

New class of agents

Dr. Radcliffe thinks Rhopressa (netarsudil, Aerie Pharmaceuticals, Irvine, California) may potentially offer a paradigm shift. This rho kinase inhibitor will be the first new class of pressure-lowering agents to hit the market since 1996. “That makes it unique and exciting,” he said.
Rhopressa will likely be marketed as an adjunctive agent. “It has a little less efficacy than latanoprost like most adjuncts that we have,” Dr. Radcliffe said. “But it has once-a-day dosing and a good systemic safety profile.” The main side effect to be on the lookout for is hyperemia. It also has appeal as an option for potentially restoring flow through the natural pathway, something practitioners are very interested in maintaining and enhancing.
“That makes netarsudil by itself exciting,” he said. “Within 1 or 2 years of that becoming available, we’re hoping to see a fixed combination of latanoprost and netarsudil, dosed once daily.” Since practitioners have never had a prostaglandin analogue in fixed combination, this also will be very novel. “They both work on outflow, the prostaglandin antagonist through the uveal scleral pathway and the netarsudil through the trabecular meshwork,” he said, adding that this should be the most powerful agent in a single bottle available.
Dr. Okeke likewise views the emergence of this new class of agents, the rho kinase inhibitors, as an important step in glaucoma treatment. This has a couple of different mechanisms of action. “It can help with increasing outflow through the trabecular meshwork, and it can also help with lowering episcleral venous pressure,” Dr. Okeke said.
She pointed out that while netarsudil alone will have an impact, a new fixed combination will likely reduce pressure even more. This new fixed-combination agent, called Roclatan, includes Rhopressa plus latanoprost.
On its own, the Rhopressa agent can offer glaucoma patients relief. “It has been shown in a number of studies that netarsudil can significantly lower eye pressure from baseline,” Dr. Okeke said. Pressure-lowering tends to be most effective for those who have pressures less than 25 mm Hg, with a reduction in the five- to six-point range. With Roclatan the pressure-lowering ability is even greater, she said. “One study looking at Roclatan versus Rhopressa alone versus latanoprost alone showed the reduction in pressure for Roclatan was 35–40%, whereas with latanoprost it was 28–30%,” Dr. Okeke said, adding that some of the studies for Rhopressa alone have indicated that this may not be as strong as latanoprost by itself.
Still, even if it is not as robust as a single agent, there will likely be a place for it, Dr. Okeke thinks. “Because of its slightly different mechanism of action and how it could work adjunctively with different agents, it’s something that one could consider,” she said.
In Dr. Radcliffe’s view, Roclatan could be a new primary option for some. “In patients who are younger, have more severe glaucoma, or any patient where we don’t want progression, this could be the first therapy,” he said.
Dr. Okeke pointed out that the once-a-day dosing of Roclatan will make it unique. “Right now all of the fixed combinations that we have are typically multi-dosed,” she said. With this fixed combination dosed just once a day and compliance being a constant issue, anything that can simplify the regimen and be more robust is desirable for both the patient and the doctor.

Considering Trabodenoson

Another agent under consideration is Trabodenoson (Inotek Pharmaceuticals, Lexington, Massachusetts), an adenosine cyclase agonist. “It’s going to increase outflow again through the trabecular meshwork,” Dr. Radcliffe said.
Dr. Okeke pointed out that Trabodenoson uses a different mechanism of action from the rho kinase inhibitors. “In the trials so far, its pressure reduction has not been quite as robust as what has been seen with the rho kinase inhibitors,” she said. “Pressure reduction with Trabodenoson is more in the range of 3 to 5 mm Hg.” That may be seen as more of an adjunctive medication than a first-line agent, Dr. Okeke noted, adding that this agent is not as far down the pipeline as the others.
The fact that outflow is enhanced with this (different from some of the other available drops) should not be overlooked, Dr. Okeke thinks. Keeping the trabecular meshwork working is something that has been talked about in other circles. “One of the things that has been discussed recently is the concept of doing laser treatment first because of the effect of the laser treatment on the trabecular meshwork, allowing it to be utilized and enhanced,” she said, adding that some aqueous-inhibiting medications simply reduce the amount of aqueous humor going through the trabecular meshwork over time, which can lead to some level of debilitation. Drops that enhance outflow and keep the trabecular meshwork and Schlemm’s canal moving, rather than taking an inhibitory path, may be more advantageous.
Dr. Radcliffe views the new options as exciting. “It doesn’t take too much for a patient to not be able to use one or two of the medicines that we consider our staples,” Dr. Radcliffe said. “Even though we may have five agents available right now, an asthmatic who develops an allergy to brimonidine, which would be 20% of asthmatics, would be down to three.” It’s not hard to see how a patient could end up needing these emerging new medications. Armed with good quality data from the manufacturers, Dr. Radcliffe thinks practitioners will be able to advocate for the use of these medications. Then it will be a question of doing comparative studies to determine which is best in what situation, he concluded.

Editors’ note: Dr. Okeke has no financial interests related to her comments.

Contact information

Okeke: iglaucoma@gmail.com
Radcliffe: drradcliffe@gmail.com

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