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ROCK inhibitor represents ‘breakthrough’ treatment with disease-modifying potential
Rhopressa is designed to restore and maintain functionality of the trabecular meshwork, the primary fluid drainage system of the eye.
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A new once-a-day eye drop that works differently from other glaucoma drugs is opening a new horizon in treatment of the disease.
“For the first time, we have a drug which directly addresses specific anatomical and physiological changes that cause pressure rise and works at the level of the pathology rather than just on IOP alone,” Inder Paul Singh, MD, told Ocular Surgery News.
The Rho kinase inhibitor Rhopressa (netarsudil ophthalmic solution 0.02%, Aerie Pharmaceuticals) was approved in the United States following three pivotal phase 3 registration trials, Rocket 1, Rocket 2 and Rocket 4. Netarsudil was compared with timolol in 1,167 patients and found to be effective and well tolerated. With a once-per-day administration, it was noninferior to twice-per-day timolol.
“While pressures above 24 mm Hg demonstrated slightly better control with timolol, Rhopressa consistently had a better response in patients with pressure below 24 mm Hg. This was an interesting finding because most of our glaucoma patients actually have pressures under 23 mm Hg to 24 mm Hg and in the upper teens,” Singh said.
Mechanism of action
Netarsudil acts by suppressing the activity of Rho-associated kinase (ROCK), an enzyme that leads to activation of stress fiber creation within the trabecular meshwork, which causes outflow resistance and consequently IOP rise.
“Actomyosin chains are brought together and held together by the ROCK and form almost like an extra layer, progressively decreasing the size of the openings in the spongy tissue of the trabecular meshwork,” Singh said. “Rhopressa prevents these fibrotic processes, relaxes the trabecular meshwork and increases the outflow.”
In addition, two other mechanisms of action are involved. First is the inhibition of the norepinephrine transporter system, which leads to decreased production of fluid and aqueous humor inflow. Second is the lowering of episcleral venous pressure, an important component of IOP not addressed by other medications, which might be key in treating low-tension glaucoma.
“Those three different components allow for multiple mechanisms to decrease the IOP. What is really important about the ROCK inhibitor is the fact that it works on the conventional outflow system and has disease-modifying properties, which is a breakthrough in the way we treat glaucoma,” Singh said.
Specific target
Beta blockers, carbonic anhydrase inhibitors and alpha agonists work primarily by decreasing aqueous production. But less flow into the trabecular meshwork might potentially increase and/or accelerate the contraction of the trabecular meshwork, causing further damage in the long term, and could lead to tachyphylaxis with other medications. Prostaglandin analogs are effective drugs but work primarily on the uveoscleral outflow drainage system (alpha agonists to some extent), which is an unconventional outflow pathway and represents around 10% of the outflow in healthy eyes.
“None of the currently available drugs enhances the trabecular meshwork outflow route, the primary fluid drainage system of the eye and also the primary source of resistance in [primary open-angle glaucoma]. ROCK inhibitors are the first class of drugs that specifically target the trabecular meshwork, and there is a chance that by opening up those channels, possibly preventing further collapse, we are enhancing flow through the meshwork and protecting it from further long-term damage. This, in turn, might help to halt or even prevent the actual etiology of the resistance,” Singh said.
Minimally invasive glaucoma surgery has given new and fresh impulse to the research on mechanisms of action and has raised specific interest in identification of the points of flow resistance. A drug such as netarsudil that works on a particular area of the outflow pathway may provide new insights to this research.
“It might provide us with powerful diagnostic insights. It could be a way of understanding where the outflow resistance is. If it is efficacious in a patient, we might conclude the resistance is primarily localized in the trabecular meshwork. If it doesn’t have a significant effect, maybe the resistance is distal to the [trabecular meshwork], in the Schlemm’s canal or in the distal channels,” Singh said. “When MIGS devices are considered for a given patient and the surgeon has to figure out which device to use, a good response to Rhopressa may indicate that a trabecular bypass would be a good strategy. On the other hand, a poor response to Rhopressa might prompt opting for a canal-dilating or a conjunctival bypass procedure. Studies are needed to evaluate this theory.”
‘Exciting’ new option
Singh has routinely adopted Rhopressa in his practice, mainly as an adjunct to prostaglandin analogs and especially when IOP is in the mid to upper teens.
“Because it’s working on multiple mechanisms, for me it has become a very common adjunct to prostaglandins because I am convinced that it does something beyond lowering IOP. We are acting on the area of pathology, so we might be preventing further collapse of the trabecular meshwork and halting the progression of resistance,” he said.
In patients with pressure in the low teens in the 13 mm Hg to 14 mm Hg range, Singh reported surprising effects, down to 10 mm Hg, 9 mm Hg and even 8 mm Hg.
“This is very rare with use of other topical medications because it is difficult with any of the other medications to decrease IOP below the range of episcleral venous pressure, which is often 8 mm Hg to 12 mm Hg. This highlights the fact that there is more than one mechanism involved,” he said.
Netarsudil was used a stand-alone treatment in the Rocket studies, and Singh believes that it is a good option as monotherapy in patients with pressure in the mid-teens, such as those with normal-pressure glaucoma. It is also an interesting choice for patients with unilateral glaucoma.
“Prostaglandin analogs have adverse effects such as enophthalmos, periocular changes, pigmentation and eyelash growth, which are particularly unappealing when treatment is unilateral. None of those effects occurs with Rhopressa, and patients can be spared those cosmetically bothersome problems,” Singh said.
Rhopressa is a once-a-day drop, easy to instill and tolerate. Hyperemia, the most common adverse event, might occur, but based on the clinical trials, it is mostly mild and often improves over time.
“The drop can be taken just before going to bed, after the prostaglandin analog or on its own. A once-a-day drug is always an advantage in terms of patient comfort and compliance,” Singh said.
“It is a very exciting new option,” he said. “I see levels of pressures that I could never achieve before with topical medications, and I know I am working in the area of resistance where the pathology is located and possibly preventing further damage.” – by Michela Cimberle
- For more information:
- Inder Paul Singh, MD, can be reached at The Eye Centers of Racine and Kenosha, 3805B Spring St., Suite 140, Racine, WI 53405; email: inderspeak@gmail.com.
Disclosure: Singh reports he is a consultant for Aerie Pharmaceuticals, Bausch + Lomb, Alcon, Allergan, Ivantis, Glaukos and Ellex.