A topical epithelial sodium channel blocker is being investigated in a phase I/IIa clinical trial as a novel treatment for dry eye disease.
TAKE HOME MESSAGE: A topical epithelial sodium channel blocker is being investigated in a phase I/IIa clinical trial as a novel treatment for dry eye disease. It acts as an ocular hydrating agent and is designed to have a long duration of action, which is supported by a preclinical pharmacokinetics study.
By Cheryl Guttman Krader; Reviewed by Richard C. Boucher Jr., MD
Durham, NC-Researchers developing a topical epithelial sodium channel blocker as a novel ocular hydrating agent (P-321 Ophthalmic Solution, Parion Sciences) are hopeful that it will be effective for treating all dry eye disease, irrespective of etiology, and with a low dosing burden.
Development of P-321 is based on the premise that dryness is the primary event in the pathophysiology of dry eye. The dryness, which is due to imbalance of the major components of the tear film, compromises the innate mucosal defense system on the ocular surface, inciting a chronic cycle of inflammation that leads to tissue damage.
As an epithelial sodium channel blocker, P-321 inhibits the absorption of sodium and water from the ocular surface, resulting also in the stimulation of the secretion of chloride and water, thereby restoring normal tear quality and quantity.
Preclinical study results showed that treatment with P-321 restored normal tear volume in animals with experimentally induced dry eye. Findings of an ocular pharmacokinetics study also conducted in an animal model showed prolonged persistence of the agent in the tear film and the conjunctiva with minimal penetration into the cornea or aqueous humor.
A first in man, phase I/IIa dose-ranging, masked study is now underway investigating 4 concentrations of topical P-321 in sequential cohorts of patients with mild to moderate dry eye disease. Treatment of the final cohort has begun, and results of the study are expected to be reported mid-year.
“When it comes to dry eye disease, the question of what comes first, dryness or inflammation, has not yet been fully resolved,” said Richard C. Boucher Jr., MD, Kenan Professor of Medicine, Cystic Fibrosis and Pulmonary Research and Treatment Center Director, University of North Carolina School of Medicine, Chapel Hill.
“Certainly, however, techniques to promote dryness are the basis for creating and exacerbating dry eye in experimental models in animals and humans, and so we believe it is a tenable hypothesis that dryness is producing the inflammatory response,” Dr. Boucher said.
Furthermore, it is well established in the lung that improper hydration of the epithelial surface provokes poor mucus clearance and ultimately inflammation and infection, he noted.
“P-321 addresses dryness as the underlying cause in dry eye and was designed to have a long duration of action at its target site, which should allow more convenient dosing for patients with this chronic condition,” Dr. Boucher said.
Achieving prolonged activity required that the molecule be resistant to both absorption through the cornea and mechanical clearance by blinking of the lids. In the animal pharmacokinetics study, P-321 had a terminal elimination half-life of 24 hours, and its concentration in conjunctival tissue remained stable for up to 48 hours after a single dose.
José L. Boyer, PhD, vice president, ophthalmology development, Parion Sciences, Durham, NC, told Ophthalmology Times that the clinical phase I/IIa study of P-321 is investigating twice-daily dosing. “However, based on the pharmacokinetics data, P-321 could potentially be administered with a once a day regimen,” Dr. Boyer said.
While it is hypothesized that the ocular hydrating agent will be effective in relieving inflammation in dry eye regardless of the trigger for the disease, dual treatment combining P-321 with an anti-inflammatory medication would also be a rationale regimen, he added.
Richard C. Boucher Jr., MD
Dr. Boucher is co-founder and chairman of the board of directors of Parion Sciences.