Purchase this article with an account.
Jose Boyer, M. Ross Johnson, John Ansede, Karl Donn, Richard Boucher, William Thelin; P-321, a Novel Long-Acting Epithelial Sodium Channel (ENaC) Blocker for the Treatment of Dry Eye Disease. Invest. Ophthalmol. Vis. Sci. 2013;54(15):957.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Dry eye disease (DED) is a multi-factorial disease, resulting from insufficient tear volume that causes damage to the ocular surface and symptoms of ocular discomfort. Persistent DED results in vision impairment and reduced quality of life. One FDA approved drug is available for the treatment of DED, however, there remains a large unmet medical need for novel, safe and efficacious therapies. Parion is developing P-321, a long acting ocular hydrating agent with a rapid onset of action. This work describes the preclinical properties of this drug candidate.
P-321 was studied in a battery of in-vitro and in vivo pharmacology, toxicology, and tolerability studies in mice, rats, dogs, and rabbits.
P-321 was designed to be retained on the ocular surface while producing limited systemic exposure. P-321 is a small molecule inhibitor of ENaC with an IC50 of 1.9±0.75 nM in human epithelial cells. P-321 is metabolically stable in plasma, blood, and hepatocytes. In normal mice, a single ocular administration of P-321 produced four-fold increase in tear volume. In a dry eye animal model of rats (lacrimal glands excised) exhibiting 60% reduction of tear volume, a single administration of P-321 restored the tear volume to levels observed in control animals. The maximal effect of P-321 was observed within 30 minutes following administration and was maintained for at least 6 hours. The effect of P-321 on tear volume was dose-dependent in both normal and dry eye animals, and the maximal effect was achieved with as low as 0.01%. P-321 is not bioavailable by the oral route of administration and is rapidly cleared from the plasma. P-321 is formulated as a non-preserved, aqueous formulation; preliminary stability studies support storage at room temperature. The formulation is well tolerated in rabbits and dogs in ocular repeat dose toxicology studies, indicating an outstanding safety profile with only minor ocular irritation in one species at concentrations which are 100-fold greater than maximal pharmacologically active doses.
P-321 is a novel ocular hydrating agent capable of restoring normal tear volume with excellent ocular tolerability and limited systemic exposure. P-321 should prove to be an attractive candidate for the treatment of DED.
This PDF is available to Subscribers Only