![]() 10,12 Inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1 serve to stimulate additional expression of ICAM-1. The interaction of LFA-1 with ICAM-1 on the ocular surface facilitates a complex cascade of events, beginning with T-cell adhesion, followed by migration into the tissue, T-cell activation (upon binding with antigen presenting cells) and ultimately, cytokine release. 7,10-16 LFA-1’s affinity for ICAM-1 can be likened to a histamine receptor’s capacity to attract and bind its ligand, histamine. 7,10,12 T-cells are attracted to and bind with ICAM-1 on the ocular surface by virtue of a specific integrin, a protein attached to the T-cell’s cytoskeleton, designated lymphocyte function-associated antigen (LFA)-1. ICAM-1 is normally expressed on epithelial cells, endothelial cells and immune function cells, but may be significantly upregulated when tissues are stressed. 10 Research shows that T-cells are attracted to, and subsequently bind with, receptors on the ocular surface due to the presence of a signaling transmembrane protein known as intercellular adhesion molecule (ICAM-1). 3,10 Recruitment and activation of these T-cells leads to the release of effector cytokines, which directly contributes to the ocular tissue damage seen in patients with dry eye disease. Inflammation of the ocular surface in dry eye disease is mediated, at least in part, by CD4+ lymphocytes, also known as T-cells. 1-5 Whether the initiating event is due to mechanical, environmental, autoimmune or other insult, the ocular surface in dry eye patients ultimately displays characteristic inflammatory changes. While many contributory factors have been proposed and identified, most experts consider one that is universally present in dry eye disease: inflammation. To understand the role of this therapeutic agent, we need to first examine the etiology of dry eye disease. Trade publications and scientific journal articles have described lifitegrast as an “integrin antagonist,” “ICAM-1 decoy” and “LFA-1 inhibitor,” yet these terms are lost on many of us in the clinical trenches of optometry. Should the FDA rule favorably, a new therapy for dry eye disease may be available shortly thereafter. The FDA acknowledged receipt of the additional data and assigned a six-month review period for the NDA, with a Prescription Drug User Fee Act (PDUFA) goal date of July 22, 2016. ![]() Last October, the FDA requested an additional clinical study, and Shire responded in January 2016. Shire, the company developing lifitegrast for the treatment of dry eye disease, submitted its NDA for the drug in early 2015. Merck acquired Inspire and its holdings in 2011, but has made no additional attempts to gain FDA approval of diquafosol.Ĭurrently, diquafosol 3% ophthalmic solution is approved for the treatment of dry eye disease in Japan and is marketed as Diquas by Santen Pharmaceuticals.Ĭombating inflammation in dry eye is the focus of a new investigational therapy. Inspire Pharmaceuticals filed an NDA for diquafosol in mid-2003, but despite additional studies, subsequent amendments and numerous discussions with the FDA, the drug was never approved in the US. Yet only two of these-diquafosol and lifitegrast-have yielded clinical trials successful enough to warrant submission of a New Drug Application (NDA). ![]() Technically, it is indicated “to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca.” Since the launch of Restasis in 2003, numerous companies have filed Investigational New Drug (IND) applications for similar consideration by the FDA, including anakinra, bromfenac, diquafosol, ecabet sodium, isunakinra (EBI-005), lifitegrast, rebamipide, tavilermide (MIM-D3) and tofacitinib. F or the last 13 years, Restasis (0.05% cyclosporine ophthalmic emulsion, Allergan) has reigned as the only FDA-approved prescription pharmaceutical product for the treatment of dry eye disease.
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