Eyeworld

I REVOLUTION IN GUCOMA MEDICATIONS N FOCUS 56 | EYEWORLD | MAY 2020 by Chiles Samaniego Contributing Writer the secondary mechanism is lowering episcleral venous pressure." She added that a small reduction in aqueous humor flow rates was identified in preclinical nonhuman primate studies as a third mecha- nism. Meanwhile, latanoprostene bunod is "cur- rently the first and the only ocular hypotensive agent that is a nitric oxide donor," Dr. Serle said. "Evidence for reduced levels of nitric oxide in the aqueous and plasma of glaucoma patients has been reported." "When applied topically to the eye, Vyzulta breaks down into two metabolites: latanoprost acid and butanediol mononitrate," Dr. Lee said. Butanediol mononitrate is a nitric oxide-donat- ing moiety. "Nitric oxide is proposed to relax trabecular meshwork cells by working at the intracellular level (suggested mechanisms of action include inhibiting actin-myosin interaction and release of intracellular calcium, among others)," Dr. Khouri said. "For clinicians, the desired effect is lowering IOP with a well-tolerated side effect profile." Given this proposed mechanism, "Vyzulta is thought to lower IOP by increasing aqueous humor outflow through both the trabecular meshwork via nitric oxide, and the uveoscleral route via latanoprost," Dr. Serle said. Efficacy Vyzulta and Rocklatan "have the additional punch of a prostaglandin. Rocklatan in MERCURY trials delivered 40% reduction in about a third of patients," Dr. Khouri said. In particular, he noted how by netarsudil's effect on episcleral venous pressure, "these agents work even when baseline pressures are lower. Such effects were observed in multiple studies with new agents including ROCKET, MERCURY, and JUPITER trials." "Phase 3 pivotal clinical trials, which led to the U.S. FDA approval of these drugs, con- firmed the relative efficacy of these three new agents to topical medications commonly used to treat elevated IOP," Dr. Serle said. " S eemingly, the glaucoma stars have aligned," said Daniel Lee, MD. "Three novel medications received FDA approval in a very short window." "Since November 2017, three new topical, IOP-lowering agents have been approved by the U.S. FDA," said Janet Serle, MD. "Vyzulta [latanoprostene bunod, Bausch + Lomb] in November 2017, Rhopressa [netarsudil, Aerie Pharmaceuticals] in Decem- ber 2017, and Rocklatan, the fixed-dose com- bination of netarsudil and latanoprost [Aerie Pharmaceuticals], in March 2019." "Those new medications represent the first approved novel agents in more than 2 decades when prostaglandins and alpha agonists were approved in 1996," said Albert Khouri, MD. "Since then, we have only had different formu- lations and combinations of existing agents." EyeWorld spoke with Drs. Khouri, Lee, and Serle for a comprehensive overview of these three novel glaucoma medications. Mechanism of action "These new agents are thought to target the tra- becular meshwork, which is the site of patholo- gy leading to ocular hypertension in glaucoma," Dr. Khouri said. "Because the new agents target the site of pathology, they seem to be effective at wide ranges of IOP." Netarsudil is a rho kinase inhibitor—it inhibits rho-associated protein kinase (ROCK) and norepinephrine transporter (NET). "ROCKs induce the formation of stress fibers and focal adhesions, which result in increased contractility," Dr. Lee said. ROCK inhibition "leads to relaxation of the TM and reduction of episcleral venous pressure, improving outflow to the proximal and distal conventional outflow pathway. NET inhibition leads to reduced aque- ous production." Netarsudil thus acts "directly at the cellular level," Dr. Serle said, noting that episcleral venous pressure is the most distal resistance to trabecular outflow. "The primary mechanism is enhancing trabecular outflow and An overview of new glaucoma medications At a glance • The three recently approved agents for the treatment of glaucoma excluding sustained- release drugs are: –Latanoprostene bunod (Vyzulta, Bausch + Lomb) –Netarsudil (Rhopressa, Aerie Pharmaceuticals) –Fixed-combination netarsudil and latanoprost (Rocklatan, Aerie Pharmaceuticals) • Believed to target the site of pathology, these medications appear to be effective at a wide range of IOPs, including lower baseline IOPs. • FDA studies and limited real-world experience show these agents to be comparable to existing glaucoma medica- tions at once-daily dosing with minimal, typically mild and self-limited side effects. • While challenges remain in terms of cost and insurance, clinically these drugs appear suitable for use as first-/ second-line treatments or adjuncts to existing treatment.

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