“Dry eye disease (DED) is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.” [1] In a recent review of the large volume of literature, “…the prevalence of DED in the general population ranged from 5 to 50%. The prevalence of signs was higher and more variable than symptoms … Women have a higher prevalence of DED than men … Risk factors were categorized as modifiable/nonmodifiable, and as consistent, probable or inconclusive … The economic burden and impact of DED on vision, quality of life, work productivity, psychological and physical impact of pain, are considerable, particularly costs due to reduced work productivity” [2]. There are overlapping etiologies of aqueous deficient and evaporative dry eye. While evaporative dry eye may be more prevalent than aqueous deficient DED, as the disease progresses, these and other sources become apparent [3]. Desiccating stress ultimately results in ocular surface inflammation [4].

Given that inflammation is a key aspect of the pathophysiology of DED at least in some patients, many approaches have been tried in the pharmacological treatment of DED. Approved pharmacotherapies in the U.S.A. include the immunomodulator cyclosporine, a corticosteroid (loteprednol etabonate), a lymphocyte function-associated antigen-1 (LFA-1) antagonist, lifitegrast, and an intranasal nicotinic agonist (varenicline). As well, medical devices marketed in the U.S.A. for treatment of DED and other ocular surface disorders include a nasal neurostimulatory device and warming of the eyelids.

While safe and effective, not all patients with DED are fully served by these current therapies. The incidence of adverse reactions (including tolerability) in the package insert for lifitegrast ranges from 5-25%. In a controlled safety study, the incidence of instillation site irritation was 15%, and instillation site reaction was 13% [5]. In a real-world, retrospective study, White et al. reported a relatively high discontinuation rate within 12 months for both cyclosporine (70.8%) and lifitegrast (64.4%) – although the reason for discontinuation rate was not explicitly provided [6]. In the package insert for one cyclosporine product, the most common adverse reaction was ocular burning (17%); and for another cyclosporine product, the most common adverse reactions were instillation site pain (22%) and conjunctival hyperemia (6%) [7,8]. It is well known that DED is associated with increased osmolarity [9]. High osmolarity usually results from higher salt content. Thus, there is a need for novel therapies to serve the needs of patients more broadly with this challenging disease.

VivaVision is developing VVN001, a small-molecule antagonist of LFA-1 for the treatment of dry eye disease. VVN001 was designed to have higher solubility then lifitegrast at the pH of natural tears, 7.0–7.4. We hypothesized that higher aqueous solubility may avoid the precipitation of drug when instilled into a high molarity environment, thus it may result in a more favorable ocular adverse events profile. In addition, the VVN001 structure is substantially different from lifitegrast, and the altered structure may lead to fewer users with altered sensation of taste – although it is not known what structural features caused dysgeusia. In an in vitro study, VVN001 demonstrated concentration-dependent inhibition of Jurkat cell intercellular adhesion molecule-1 (ICAM-1) mediated adhesion, VVN001 had an IC50 of 3.2 nM, which was comparable to the reference compound, lifitegrast (4.8 nM). Further, VVN001 was found to inhibit cytokine release but not to inhibit integrins A2B1 and A4B1. Topical ocular VVN001 was evaluated in C57BL/6 mice placed in a low humidity environment and treated with subcutaneous scopolamine. In this in vivo model of DED, VVN001 was similar in efficacy and potency to the reference compound, lifitegrast (Data on File, VivaVision). This is the first-in-human study of VVN001 Ophthalmic Solution.