A first-in-its-class eye drop to reduce intraocular pressure (IOP) for patients with open-angle glaucoma or ocular hypertension drew high marks at an FDA advisory committee meeting on October 13.
Aerie Pharmaceuticals representatives discussed netarsudil ophthalmic solution 0.02% (Rhopressa), to be taken in a single drop once daily in the evening. The company has run 10 clinical trials, 4 of them phase 3 noninferiority studies against timolol, which is given twice daily.
Netarsudil is more effective than timolol for patients with IOP below 25 mm Hg. About 78% of patients with glaucoma symptoms have IOP below that level, said Richard A. Lewis, MD, chief medical officer at Aerie.
Although all 10 members of the Dermatologic and Ophthalmic Drugs Advisory Committee voted that the clinical trials demonstrate efficacy, 9 voted that efficacy outweighs safety risks, which sparked renewed discussion of the three most common adverse effects. But ultimately committee member Geoffrey Emerson, MD, PhD, from the Retina Center of Minnesota, Maplewood, summed it up: "The fact that the drug is the first in its class makes it valuable, as well as the [daily] dosing and that the side effects are manageable."
Multiple Effects Include a Direct Hit at Mechanism
Existing glaucoma medications reduce aqueous humor production (β-blockers, α-agonists, and carbonic anhydrase inhibitors) or increase its outflow (miotics, prostaglandin analogs, and α-agonists). More than 50% of patients require more than one drug simultaneously, Dr Lewis said, and they all have systemic and ocular side effects. "Given the limitations of current treatment, additional therapeutic options are necessary to manage glaucoma," he added.
Dr Lewis posted a wish list for a new glaucoma drug: "Target trabecular outflow; lower IOP with long-term stability, no systemic side effects, and tolerable and reversible ocular side effects; and convenience for the mostly-older patient population."
Netarsudil targets the trabecular outflow pathway, countering the stiffening and contraction of the meshwork that elevates ocular pressure. These changes are due to alterations in the deposition and organization of elements of the extracellular matrix. And that's where the new drug comes in.
Netarsudil is a rho-associated protein kinase (ROCK) inhibitor, a new class of medications that disassemble actin in the cytoskeleton, affecting cell migration and adhesion. ROCK inhibitors are being investigated to treat cancer, Parkinson's disease, diabetes, pulmonary hypertension, and other conditions.
Preclinical studies on the new drug indicated that in the eye it dismantles actin, thereby thinning the trabecular meshwork; lowers venous pressure around the sclera; reduces aqueous humor production; and increases outflow.
The four phase 3 clinical trials compared once-daily or twice-daily netarsudil to timolol, which is given twice daily. The trials assessed safety and/or efficacy at various time points and for different IOPs, for 1163 eyes in total (510 for timolol, 494 for once-daily netarsudil, and 159 for twice-daily netarsudil).
"Netarsudil led to statistically and clinically significant IOP lowering at all tested baseline levels up to 36 mm Hg. Once-daily administration was shown to be noninferior to timolol given twice daily and is the only nonprostaglandin analog drug to meet noninferiority criteria to timolol. It showed similar efficacy without the systemic side effects of timolol. IOP reductions were stable over 12 months of dosing for a wide range of IOP responses, including reduction up to 12 mm Hg," Janet B. Serle, MD, a professor of ophthalmology at the Icahn School of Medicine at Mt Sinai, New York City, told the committee.
Several speakers mentioned the value of daily dosing for patients in their 80s and 90s, who often have comorbidities and difficulty managing many medications.
Adverse Effects Are Common and Mild and Resolve
"The more than 1000 patients in the 10 clinical trials had minimal treatment-related systemic events and ocular side effects were generally mild and well tolerated," Theresa Heah, MD, MBA, vice president of clinical research and medical affairs for Aerie, told the committee. Although the effects were minor and many were not obvious to patients, they are common.
Treatment-emergent adverse effects occurred in 699 of 839 (83.3%) eyes treated with netarsudil once daily, 261 of 289 (90.3%) with netarsudil twice daily, and 506 of 839 (60.3%) treated with timolol twice daily.
The three top adverse effects were conjunctival hyperemia, conjunctival hemorrhage, and cornea verticillata.
Conjunctival hyperemia occurred in 456 of the 839 (54.4%) eyes given netarsudil once daily, in 202 of the 289 (69.9%) eyes receiving netarsudil twice daily, and in 87 of the 839 (10.4%) of eyes treated with timolol.
Conjunctival hemorrhage occurred in 144 of the 839 (17.2%) eyes receiving netarsudil once daily, in 55 of the 289 (19%) eyes receiving netarsudil twice daily, and in 15 of the 839 (1.8%) eyes receiving timolol.
Corneal verticillata affected 175 of the 839 (20.9%) eyes treated with netarsudil once daily, 78 of the 289 (27%) eyes given netarsudil twice daily, and 2 of the 839 (0.2%) eyes receiving timolol. The condition emerged 6 weeks into the phase 3 trials. These whorls of deposits in the basal corneal epithelium are a known adverse effect of several drugs, most notably amiodarone. The telltale deposits are accumulated phospholipids in lysosomes of the cells.
Because patients are typically unaware of corneal verticillata, the committee discussed whether and how they should be informed. Peter Zloty, MD, ophthalmologist at Southern Eye Network in Mobile, Alabama, and medical moderator of the panel, related a call to a rural emergency department to treat what was thought to be ocular herpes but that was actually corneal verticillata. "The condition isn't well known by optometrists. The package insert should be clear that this is a known but perhaps inconsequential non–visually significant side effect," he said.
Benefits outweighed risks. "Overall, the side effect profile is tolerable, with few if any systemic side effects. Ocular side effects are mostly mild, sporadic, and reversible," said Dr Serle, and others agreed. "This drug may allow these patients to maintain their vision throughout their lifetime and avoid surgery. Netarsudil is an effective, convenient, safe, and important new medication that will help physicians meet the needs of their patients," she added.
Dr Serle receives funding from several companies, including Aerie, for which she is a shareholder. The other quoted speakers have disclosed no relevant financial relationships.
Medscape Medical News © 2017
Cite this: FDA Committee Backs Netarsudil, a Once-Daily Glaucoma Drug - Medscape - Oct 16, 2017.