For 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. 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. Yet only two of these—diquafosol and lifitegrast—have yielded clinical trials successful enough to warrant submission of a New Drug Application (NDA). 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. Merck acquired Inspire and its holdings in 2011, but has made no additional attempts to gain FDA approval of diquafosol. 

Currently, diquafosol 3% ophthalmic solution is approved for the treatment of dry eye disease in Japan and is marketed as Diquas by Santen Pharmaceuticals.

Combating inflammation in dry eye is the focus of a new investigational therapy.

Shire, the company developing lifitegrast for the treatment of dry eye disease, submitted its NDA for the drug in early 2015. Last October, the FDA requested an additional clinical study, and Shire responded in January 2016. 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. 

Should the FDA rule favorably, a new therapy for dry eye disease may be available shortly thereafter.

The Role of Inflammation

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. To understand the role of this therapeutic agent, we need to first examine the etiology of dry eye disease. While many contributory factors have been proposed and identified, most experts consider one that is universally present in dry eye disease: inflammation.^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.^6-9 

Inflammation of the ocular surface in dry eye disease is mediated, at least in part, by CD4+ lymphocytes, also known as T-cells.^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.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).^7,11 

ICAM-1 is normally expressed on epithelial cells, endothelial cells and immune function cells, but may be significantly upregulated when tissues are stressed.^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.^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. 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.^10,12 Inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1 serve to stimulate additional expression of ICAM-1.¹⁰ This in turn leads to further proliferation and recruitment of T-cells, and perpetuates the cycle of inflammatory dry eye disease.

Pharmacology 

Lifitegrast was engineered specifically to interfere with the binding of LFA-1 to ICAM-1.^10,12-14 Researchers believe that this small molecule exerts its effects by outcompeting ICAM-1 binding to LFA-1 in a dose-dependent fashion.¹⁰ When key sites on the LFA-1 integrin are blocked by lifitegrast, the affinity for ICAM-1 is disrupted, and the T-cell is unable to adhere to the tissue surface. Thus, the subsequent cascade of events is prevented. To use the previous analogy, lifitegrast functions in inflammatory dry eye disease much in the same way that a histamine-antagonist functions in allergic conjunctivitis; by initiating a blockage of the receptor sites, the drug effectively derails the pathological process.

Clinical evaluation of lifitegrast in dry eye patients has been extensive. With more than 2,200 subjects completing four multicenter, randomized, prospective clinical trials, it represents the most thoroughly investigated drug in this category to date.^12,14,15,17 Its two Phase III studies, which employed 5% lifitegrast dosed twice daily for 12 weeks, demonstrated mixed results. In the first of these, subjects treated with the investigational drug demonstrated statistically significant improvement with regard to corneal staining (inferior corneal staining score, mean change from baseline). This was one of the study’s two co-primary endpoints. There was also statistically significant improvement in ocular discomfort and dryness in the treatment group. 

However, the second of the co-primary endpoints, specified as the visual-related function subscale of the Ocular Surface Disease Index (VR-OSDI) was not met.¹⁴ 

OPUS-2 employed a similar clinical protocol; however, in this trial the subjective primary outcome measure was changed from the VR-OSDI to a less complex Eye Dryness Score (EDS). Subjects treated with lifitegrast 5% in the OPUS-2 demonstrated statistically significant improvement in the EDS, but unfortunately did not achieve the same results when compared to placebo in its co-primary endpoint of corneal fluorescein staining.¹⁵ And, since the FDA stipulates that both an objective (sign) and subjective (symptom) endpoint must be met in at least two separate clinical trials, it was no surprise that lifitegrast did not receive approval upon its initial NDA. 

Since that time, however, Shire has submitted additional data from its one-year, multicenter safety study as well as results from another Phase III clinical trial, which has yet to be published.^16,17 Interestingly, it appears that trial had only a single primary endpoint of EDS, which was met in the treatment group (p=0.0007).^17,18 Perhaps more impressive, patients using lifitegrast demonstrated symptom improvement as early as two weeks after initiating therapy.¹⁷ 

1. Javadi M, Feizi S. Dry eye syndrome. J Ophthalmic Vis Res. 2011 Jul;6(3):192-8. 2. Stevenson W, Chauhan SK, Dana R. Dry eye disease: an immune-mediated ocular surface disorder. Arch Ophthalmol. 2012 Jan;130(1):90-100.  3. Stern M, Schaumburg C, Pflugfelder S. Dry eye as a mucosal autoimmune disease. Int Rev Immunol. 2013 Feb;32(1):19-41.  4. Hessen M, Akpek E. Dry eye: an inflammatory ocular disease. J Ophthalmic Vis Res. 2014 Apr;9(2):240-50. 5. Wei Y, Asbell P. The core mechanism of dry eye disease is inflammation. Eye Contact Lens. 2014 Jul;40(4):248-56.  6. Stern M, Gao J, Schwalb T, et al. Conjunctival T-cell subpopulations in Sjögren’s and non-Sjögren’s patients with dry eye. Invest Ophthalmol Vis Sci. 2002;43:2609–2614. 7. Gao J, Morgan G, Tieu D, et al. ICAM-1 expression predisposes ocular tissues to immune-based inflammation in dry eye patients and Sjögrens syndrome-like MRL/lpr mice. Exp Eye Res. 2004 Apr;78(4):823-35. 8. Chotikavanich S, de Paiva CS, Li de Q, et al. Production and activity of matrix metalloproteinase-9 on the ocular surface increase in dysfunctional tear syndrome. Invest Ophthalmol Vis Sci. 2009 Jul;50(7):3203-9. 9. Yoon K, Park C, You I, et al. Expression of CXCL9, -10, -11, and CXCR3 in the tear film and ocular surface of patients with dry eye syndrome. Invest Ophthalmol Vis Sci. 2010 Feb;51(2):643-50.  10. Perez V, Pflugfelder S, Zhang S, et al. Lifitegrast, a Novel Integrin Antagonist for Treatment of Dry Eye Disease. Ocul Surf. 2016 Jan 22. [Epub ahead of print] 11. Tsubota K, Fujihara T, Saito K, Takeuchi T. Conjunctival epithelium expression of HLA-DR in dry eye patients. Ophthalmologica. 1999;213(1):16-9. 12. Semba C, Torkildsen G, Lonsdale J, et al. A Phase II randomized, double-masked, placebo-controlled study of a novel integrin antagonist (SAR 1118) for the treatment of dry eye. Am J Ophthalmol. 2012;153:1050-1060. 13. Sun Y, Zhang R, Gadek T, et al. Corneal inflammation is inhibited by the LFA-1 antagonist, lifitegrast (SAR 1118). J Ocul Pharmacol Ther. 2013 May;29(4):395-402. 14. Sheppard J, Torkildsen G, Lonsdale J, et al. Lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease. Results of the OPUS-1 Phase III study. Ophthalmology. 2014;121:475-483. 15. Tauber J, Karpecki P, Latkany R, et al; OPUS-2 Investigators. Lifitegrast Ophthalmic Solution 5.0% versus Placebo for Treatment of Dry Eye Disease: Results of the Randomized Phase III OPUS-2 Study. Ophthalmology. 2015 Dec;122(12):2423-31. 16. Donnenfeld E, Karpecki P, Majmudar P, et al. Safety of Lifitegrast Ophthalmic Solution 5.0% in Patients With Dry Eye Disease: A 1-Year, Multicenter, Randomized, Placebo-Controlled Study. Cornea. 2016 Apr 6. [Epub ahead of print] 17. Shire’s OPUS-3 Phase 3 trial with lifitegrast meets primary and key secondary endpoints, significantly reducing patient-reported symptoms for dry eye disease. Available at: www.shire.com/newsroom/2015/october/shires-opus-3-phase-3-trial-with-lifitegrast-meets-primary-and-key-secondary-endpoints. Accessed April 9, 2016. 18. ClinicalTrials.gov. A study to evaluate efficacy and safety of lifitegrast in subjects with dry eye (OPUS-3). Available at: https://clinicaltrials.gov/show/NCT02284516. Accessed April 9, 2016.