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EW GLAUCOMA 32 January 2019 Pharmaceutical focus by Maxine Lipner EyeWorld Senior Contributing Writer on the mechanism of action, which improves outflow facility, that it does have a 24-hour effect," Dr. Sit said. "In contrast, the aqueous sup- pressants, like timolol, tend to have minimal effect at night." The drug has an excellent sys- temic 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 conjunc- tival hyperemia. While on label this is known to affect 53% of individ- uals, 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 verti- cillata side effect associated with the oral heart mediation medica- tion amiodarone. The verticillata deposits with amiodarone occur in Bowman's membrane and may take agent, he found that it was quite ef- fective. "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 ac- cepting 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, found- ing 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 netar- sudil 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 glauco- ma," 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 there and improves outflow facility. There is an additional mecha- nism involving the norepinephrine transport inhibitor, another part of the Rhopressa molecule. While in animal models this seems to de- crease 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 ve- nous 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 trabec- ular 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 pros- taglandins, 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 Physicians discuss what Rhopressa has to offer P ractitioners 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, Roch- ester, Minnesota, explained that when Rhopressa acts on the trabecu- lar meshwork, it causes a relaxation Rho kinase inhibitor makes new inroads in glaucoma 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.

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