Cataract patients may benefit from new drug-delivery methods

Ninety-three percent of patients do not correctly apply eye drops they were prescribed after cataract surgery, which means introducing new drug routes.

New systems for delivering antibiotic and anti-inflammatory drugs hold promise for cataract surgery, said Francis S. Mah, MD. Patients will benefit from not having to administer eye drops, explained Dr. Mah, director of cornea and external disease, Scripps Clinic, La Jolla, CA.

“One of the drivers for this is to improve compliance to improve efficacy and reduce problems with the medication,” he said.

Applying eye drops requires more knowledge and manual dexterity than most patients can muster. One recent study (J Cataract Refract Surg. 2014;40:1857–1861) showed that 93% of patients do not correctly apply eye drops they were prescribed after cataract surgery, even when carefully educated, Dr. Mah said.

“And that’s when they were in a study and educated in the proper methods,” he said. “Our patients are probably getting much less education.”

New devices might improve efficacy and reduce toxicity as well, he said. “If we’re talking about drops in general something like less than 1% of the drop gets to the site of the target,” he said.

Some of the eye drop drains through the lacrimal system, he said, and the cornea and epithelium also keep the drops from penetrating into the eye. Pharmaceutical companies are also interested in developing drug-delivery systems that are unique so they can patent them, fending off competition from generic versions of their drugs, Dr. Mah said.

The devices may become even more important for glaucoma and retina diseases because the targets are inside the eye, he said. For prevention of miosis and pain in cataract surgery, the FDA has approved some new drug delivery devices and others are in the pipeline.

One approved drug is phenylephrine/ketorolac injection 1%/0.3% (Omidria, Omeros Corp.) One 4-ml single-use vial is added to a 500-ml container of irrigation solution. Preservative and bi-sulfite-free, the drug product is considered safe and well tolerated.

Adverse reactions were similar to those of placebo in clinical trials. It increased pupil diameter by at least 2.5 mm in 27% in one phase III trial and 28% in another while reducing pain. Patients taking phenylephrine/ketorolac used fewer analgesics.

In a retrospective study of real-world outcomes by Drs. Donnenfeld and Rosenberg, phenylephrine/ketorolac caused fewer complications, less papillary dilating device dependence, improved best-corrected visual acuity on day one in select age groups, and decreased procedure times compared with intracameral epinephrine alone. Some physicians are also administering compounded antibiotics, steroids, and non-steroidal anti-inflammatory drugs (NSAIDs) in the anterior chamber or through intravitreal or transzonular injection.

Examples include:

• Tri-Moxi-Vanc, Imprimis’ proprietary injectable formulation of triamcinolone acetonide, moxifloxacin hydrochloride, and vancomycin.

• Tri-Moxi, Imprimis’s proprietary injectable formulation of triamcinolone acetonide and moxifloxacin hydrochloride.

• Dex-Mox, Ocular Science’s clear formulation of dexamethasone and moxifloxacin hydrochloride.

• Pred-Moxi, a combinations of prednisolone aceteate or prednisolone sodium phosphate with moxifloxacine hydrochloride.

• Pred-Ketor, a combination of prednisolone acetate or sodium phosphate with ketorolac tromethamine.

• Pred-Moxi-Ketor, a combination of prednisolone acetate or sodium phosphate with moxifloxacin hydrochloride and and ketorolac tromethamine.

• Pred-Levo, a combination of prednisolone sodium phosphate and levofloxacin.

A compounded combination of topical drops may reduce the number of prescriptions and cuts the number of surgical drops up to 75% Dr. Mah said.

Fewer bottles are needed; compliance is better; costs are lower; fulfillment of the medication is guaranteed, and there are fewer calls back. The overall healthcare system may save, as long as the compounded medications are safe and efficacious, he noted.

In his own practice, Dr. Mah uses compounded intracameral moxifloxacin-dexamethasone for routine cataract procedures, along with topical difluprednate 0.05% QD (off-label) and nepafenac 0.3% or bromfenac 0.075% QD for 4 weeks (off-label). In a study published by Dr. Mah, he showed that antibiotic and/or anti-inflammatory drugs can also be combined with hydrogel sealants used to prevent leakage from corneal incisions.

Alternatively, Sun Pharmaceutical’s BromSite, which recently received FDA approval, delivers 0.075% bromfenac in a synthetic polymer of crosslinked polyacrylic acid developed as DuraSite by InSite Vision.

DuraSite is also the vehicle for Bausch + Lomb’s besifloxacin ophthalmic suspension (Besivance) and Akorn’s azithromycin ophthalmic solution (AzaSite). The formulation improves solubility, absorption, bioavailability and residence time compared to other topical therapies, Dr. Mah said.

In phase III trials, 38% to 57% of patients were free of inflammation at day 15 compared with 19% to 22% who received the vehicle alone. And at day one, 76.8% to 82.1% were painfree compared with 48.2% to 62.4% of those on the vehicle alone.

Another route of administration is Ocular Therapeutix’s dexamethasone depot, which is placed in the canaliculus of the eyelid. According to the company, 36.2% of patients implanted with the depot had no anterior chamber cells at day 14, compared with 22.7% of patients implanted with a placebo depot.

Icon Biosience iconducted a phase III clinical trial of a bioabsorbable vehicle for 342 μg or 517 μg dexamethasone, which maintains therapeutic levels of the drug for 21 days. In a study the company presented at ASCRS 2015, 63.1% of patients on the low dose and 66% of patients on the high dose were clear of anterior chamber cells at day 8.

This device has recently been FDA approved and acquired by EyePoint Pharmaceuticals. More is in the pipeline, Dr. Mah said, including:

• Kala Pharmaceuticals phase III trial of KPI-121 loteprednol delivered through mucus-penetrating particle (MPP) technology.

• Envista Therapeutics (which recently licensed its propietary drug-delivery device to Aerie Pharmaceuticals) phase I trial of ENV905 difluprednate delivered through particle replication in non-wetting templates (PRINT), a technology platform used to create a pipeline of small- and large- molecule, particle-based ocular therapeutics.

• Mati Therapeutics phase I trial of EVOLUTE steroids and NSAIDs through a punctual plug.

Even when these drugs earn approval, reimbursement can prove challenging, Dr. Mah said. “In cataract surgery, if I were to use a medication in the operating room, I cannot have the patient nor the insurance buy it separately,” he explained.

“However, if I write a prescription, the patient picks it up before or after surgery and the insurance company, or the patient, covers the cost.” Advocates for these drugs are working on legislation to improve reimbursement.

“It’s not unusual for cataract patients to put in 12 drops a day-4 drops of 3 medications-in addition to having to go to the pharmacy and buy the medications, which might be hundreds of dollars, even for generics,” said Dr. Mah, adding that patients would welcome not needing to take eye drops.

Disclosures:

Francis S. Mah, MDE: margolisT@vision.wustl.edu
This article was adapted from Dr. Mahs’ presentation at the 2017 meeting of the American Academy of Ophthalmology. Dr. Mah disclosed fi nancial relationships to Abbott Medical Optics, Alcon Laboratories, Allergan, Bausch + Lomb,CoDa Therapeutics, ForSight Labs,Novabay Pharmaceuticals,Ocular Therapeutix, Ocular Science, Omeros, PolyActiva, Shire, and TearLab.