A novel potent epithelial sodium channel blocker seems to be a safe and well-tolerated therapy in patients with symptoms of mild-to-moderate dry eye disease compared with placebo.
Reviewed by José L. Boyer, PhD, and Gary N. Foulks, MD
Durham, NC-A novel potent epithelial sodium channel (ENaC) blocker seems to be a safe and well-tolerated therapy in patients with symptoms of mild-to-moderate dry eye disease compared with placebo.
The rationale behind the development of this product, as explained by José L. Boyer, PhD, is that the ocular surface epithelia are important players in fluid regulation by the cornea and conjunctiva.
This type of regulation also occurs elsewhere in the body in the epithelia of the lung, gastrointestinal tract, and kidneys. The ocular surface epithelia regulate mucosal hydration through a coupled process involving Na+ absorption and Cl- secretion, he explained.
“The inhibition of ENaC on the ocular surface is predicted to block pathways for tear absorption and at the same time provide a driving force for water secretion, resulting in increased hydration of the ocular surface,” Dr. Boyer pointed out. He is vice president of Research and Ophthalmology Development, head of development of the P-321 dry eye program, Parion Sciences Inc., Durham, NC, and a lead author of the P-321-101 study.
The ENaC blocker under discussion, P-321 ophthalmic solution (Parion Sciences), was evaluated in a single-center, dose-escalation, randomized, double-masked, placebo-controlled, phase I/IIa trial to determine its safety and tolerability in patients with mild-to-moderate dry eye compared with placebo, said co-author Gary Foulks, MD, emeritus professor of ophthalmology, University of Louisville, Louisville, KY.
The study included four consecutive cohorts. Cohorts 1-3 evaluated the drug for up to 15 days and cohort 4 extended the evaluation out to 28 days. Four concentrations of P-321 were tested: 0.0005%, 0.0015%, 0.005%, and 0.01%, in the patients in cohorts 1-4, respectively. The participants instilled one drop of the drug or placebo in each eye twice daily.
The inclusion criteria included men and women aged 18 to 80 years of age with a documented history of dry eye symptoms for at least 4 months who needed to use a topical lubricant or who desired to use topical lubricants at least daily in the past 4 months.
The patients had a Symptom Assessment iN Dry Eye (SANDE) score exceeding 20 and less than 90 for severity and exceeding 10 and less than 90 for frequency, phenol red thread test below 10 millimeters per 15 seconds or a Schirmer’s test score of less than 10 millimeters per 5 minutes, a corneal fluorescein staining score of 2 (out of 15) or higher, or conjunctival staining score of 2 (out of 18) or higher. The use of artificial tears was prohibited during the study.
Subjects with mild-to-moderate dry eye disease who met the inclusion criteria were randomly assigned to either P-321 or placebo in a 3:1 ratio. Cohorts 1, 2, and 3 had five clinical visits with up to eight subjects enrolled in each cohort, and cohort 4 had eight visits and included 28 subjects.
The P-321 ophthalmic solution showed excellent safety and tolerability, with no discomfort or irritation seen upon instillation of the drug, Dr. Boyer noted. There were no significant changes in corneal and conjunctival staining, visual acuity, biomicroscopy, funduscopy, intraocular pressure, plasma/serum potassium, aldosterone, electrocardiography, or laboratory measurements.
The adverse events seen in the patients assigned to P-321 were generally similar to or fewer than those that occurred in the patients assigned to placebo, and none of the adverse events was considered serious.
No subjects left the study as a result of an adverse event. Specifically, nine ocular drug-related events developed in seven patients, all of which were considered to be mild. Two cases of mild conjunctival hyperemia developed, one in a patient assigned to P-321 and one in a patient assigned to placebo.
The drug was not detected in the patient plasma or urine samples, suggesting that P-321 is not systemically available, Dr. Boyer noted.
Analysis of the tear P-321 pharmacokinetic profile indicated that after 28 days of treatment, average tear concentrations above the half maximal inhibitory concentration (IC50) were observed up to 8 hours after the last administration of the drug. The tear meniscus height measurement after treatment with P-321 showed that compared with placebo the average changes from baseline were significant on days 22 and 28.
Dr. Boyer also showed that the changes in the symptom frequency scores and in the severity scores improved significantly with the 0.01% drug concentration.
Based on these results, study investigators concluded: “P-321 has a favorable safety profile and is well-tolerated at all of the dose levels tested. There was no evidence of systemic exposure of P-321. Levels above pharmacologically effective concentrations in tears were observed several hours after administration of P-321. A treatment effect in favor of P-321 versus placebo was observed in the tear meniscus height. Dry eye symptoms improved with treatment with P-321 for 14 to 28 days.”
This first-in-human clinical trial to evaluate the safety of an ENac blocking agent for the treatment of dry eye disease “is very encouraging, as it identifies an agent that is well tolerated and associated with signs of improvement in tear function,” Dr. Foulks said. “The use of a topical ENaC blocking agent provides a novel approach to improving the tear film in dry eye disease.”
Future clinical trials will determine the efficacy of this agent and more comprehensive evaluation of tear function, as well as the health of the ocular surface.
José L. Boyer, PhD
Dr. Boyer is an employee of Parion Sciences Inc.
Gary N. Foulks, MD
Dr. Foulks is a paid consultant to Parion Sciences Inc.