January 2019

GLAUCOMA

Pharmaceutical focus
Rho kinase inhibitor makes new inroads in glaucoma


by Maxine Lipner EyeWorld Senior Contributing Writer




Morphology of the trabecular meshwork in human donor eyes. The image on the right is tissue treated with a netarsudil solution.
Source: Ren R, et al. Invest Ophthalmol Vis Sci. 2016;57:6197–6209. Used with permission.

 

Physicians discuss what Rhopressa has to offer

Practitioners today have a new type of molecule they can rely on to help lower IOP in glaucoma patients in the form of Rhopressa (netarsudil, Aerie Pharmaceuticals, Irvine, California), a rho kinase inhibitor. With the approval of Rhopressa in December 2017, for the first time in decades practitioners have had the possibility of accessing an agent with a new mechanism for combating issues with IOP. EyeWorld asked leading practitioners what they think this new class has to offer in glaucoma.
Douglas Rhee, MD, department chair, University Hospitals, Case Western Reserve, Cleveland, pointed out that rho kinase controls the cell cytoskeleton. “When you inhibit rho kinase, it allows the cells to become less stiff,” he said. You then increase the para cellular outflow in the trabecular meshwork in Schlemm’s canal, which means you are increasing the flow around or between cells, he explained. “Think of cells like soft bricks. If you make them even softer so that you can squish them more, the fluid can get past the bricks,” Dr. Rhee said.
Arthur Sit, MD, professor of ophthalmology, Mayo Clinic, Rochester, Minnesota, explained that when Rhopressa acts on the trabecular meshwork, it causes a relaxation there and improves outflow facility.
There is an additional mechanism involving the norepinephrine transport inhibitor, another part of the Rhopressa molecule. While in animal models this seems to decrease aqueous humor production, affecting inflow, in a human study on normal subjects in which Dr. Sit took part, there was only a trend to show this decrease, but it didn’t reach statistical significance, he said.1 However, the study did show a significant 9% drop in episcleral venous pressure compared to baseline. Likewise, this is bolstered by animal research that indicates there can be a large decrease in episcleral venous pressure, he noted.2
Because Rhopressa has these differing mechanisms of action, it suggests that it acts on the entire conventional outflow pathway, Dr. Sit noted. “It’s not just the trabecular meshwork, it acts downstream of that as well,” he said, adding that this is where the fluid eventually ends up and may make the drug a useful adjunct to MIGS procedures.
Dr. Rhee pointed out that netarsudil has not been shown to be more powerful than the prostaglandins, but is also not inferior to timolol. “It’s an additive, not a first-line agent,” he said. “However, it has been remarkably effective.” Although this is often added late in the game, he finds that it has worked where others have failed in his patients. In the one case where he used the drug as a second-line agent, he found that it was quite effective. “I think if pricing and other issues could be worked out, it could easily become a great second-line agent,” Dr. Rhee said.
He finds that patients are accepting of the once-in-the-evening dosing, which is akin to how the prostaglandins are dosed. “I was pleasantly surprised because I had been dosing timolol in the morning and prostaglandin in the evening and was wondering how patients would accept two drugs at night,” he said, adding they seem to view this as just like the prostaglandin they are already taking.
Jason Bacharach, MD, founding partner and medical director, North Bay Eye Associates, Sonoma, California, reported that in the Phase 3 clinical trials netarsudil lowered pressure by up to 5 mm Hg. “In the study,3 it was found to be non-inferior to timolol at least in those patients with baseline IOPs up to 25 mm Hg,” Dr. Bacharach said, adding that this accounts for about 80% of individuals. He views netarsudil as having clinical applicability through the spectrum of the disease as an adjunctive therapy, most often to a prostaglandin, or in unusual cases as a first-line agent. “Where it might be used as a first-line agent is in people with low-pressure glaucoma,” Dr. Bacharach said.
In Dr. Sit’s view, netarsudil may also have the ability to reduce IOP over 24 hours. “We don’t have any data yet but I can speculate based on the mechanism of action, which improves outflow facility, that it does have a 24-hour effect,” Dr. Sit said. “In contrast, the aqueous suppressants, like timolol, tend to have minimal effect at night.”
The drug has an excellent systemic safety profile with no labeled contraindications, Dr. Bacharach pointed out. “It had minimal effect on heart rate and blood pressure as compared to the beta blocker in the trial, which was the control wing,” Dr. Bacharach said. “The control wing doses with timolol had a two to three beat per minute reduction in heart rate.”
From a topical perspective, one of the main side effects is conjunctival hyperemia. While on label this is known to affect 53% of individuals, Dr. Bacharach pointed out that about 20% had this condition at baseline, making this number more like 33%. Also, the erythema was mild in 80% of cases. What’s more, it was not a “crescendo of red eye,” Dr. Bacharach said. “In many people, it dissipated by the end of the study.”
Dr. Rhee finds that his patients generally tolerate the redness that occurs. With netarsudil, patients may also get pigmented deposits in the corneal epithelium. However, he distinguishes this from the verticillata side effect associated with the oral heart mediation medication amiodarone. The verticillata deposits with amiodarone occur in Bowman’s membrane and may take years to come out, Dr. Rhee noted. The corneal deposits with netarsudil are within the epithelium, can pop up within a few weeks to a few months, and if you stop the medication, are gone within 1 week. There is also no visual impact in either case, he stressed, adding that while this does happen in a decent number of patients, it is not something that has affected his prescribing patterns.
Such corneal deposits were also visually insignificant in the clinical trial, Dr. Bacharach noted.
One other side effect that can occur with the drug is micro-hemorrhages in the conjunctiva. “Most of the time they are only seen under the microscope and are related to the effect of the drug because rho kinase inhibition can relax the cells that line blood vessels as well, and these fine capillaries might be related enough to cause very small micro-hemorrhages,” Dr. Bacharach said, adding that in most cases, these were visually insignificant, with less than 1% of the people in the trial discontinuing the medication due to this issue.
In addition to the single agent netarsudil, a fixed combination of netarsudil and latanoprost, known as Roclatan (Aerie Pharmaceuticals), is currently under FDA review, Dr. Bacharach noted. “That drug would be the first fixed combination in the U.S. with a prostaglandin in it,” he said, adding that this has been the only clinical trial with a fixed combination containing a prostaglandin that has been able to reach superiority over each individual component. The side effect profile of the fixed combination looked similar to what would be expected with each of the individual components. “It did not appear that there was significant additivity or different side effect profiles,” Dr. Bacharach said.

References

1. Kazemi A, et al. The effects of netarsudil ophthalmic solution on aqueous humor dynamics in a randomized study in humans.
J Ocul Pharmacol Ther. 2018;34:380–386.
2. Kiel JW, Kopczynski CC. Effect of AR-13324 on episcleral venous pressure in Dutch belted rabbits. J Ocul Pharmacol Ther. 2015;31:146–51.
3. Serle JB, et al. Two phase 3 clinical trials comparing the safety and efficacy of netarsudil to timolol in patients with elevated intraocular pressure: rho kinase elevated IOP treatment trial 1 and 2 (ROCKET-1 and ROCKET-2). Am J Ophthalmol. 2018;186:116–127.

Editors’ note: Dr. Bacharach has financial interests with Aerie Pharmaceuticals. Dr. Rhee has financial interests with Aerie Pharmaceuticals, Alcon (Fort Worth, Texas), Allergan (Dublin, Ireland), Bausch + Lomb (Bridgewater, New Jersey), Glaukos (San Clemente, California), and Ivantis (Irvine, California). Dr. Sit has financial interests with Aerie Pharmaceuticals.

Contact information

Bacharach
: jbacharach@northbayeye.com
Rhee: Douglas.Rhee@UHhospitals.org
Sit: Arthur@mayo.edu

Rho kinase inhibitor makes new inroads in glaucoma Rho kinase inhibitor makes new inroads in glaucoma
Ophthalmology News - EyeWorld Magazine
283 110
220 148
,
2018-12-31T11:10:58Z
True, 1