In April of this year, the FDA granted priority review to the lifitegrast new drug application (NDA) for the treatment of dry eye disease. Priority review is granted to drugs believed to have the potential to improve the treatment, diagnosis or prevention of serious diseases. Priority review accelerates the review process, reducing it from 12 to eight months.¹ 

Lifitegrast’s developer, Shire Pharmaceuticals, obtained it in 2013 when it acquired SARcode Bioscience. FDA approval would make it the first prescription dry eye drug available to treat both signs and symptoms of the disease.³ The first Phase III study demonstrated improvement in signs but not symptoms, while the second met the co-primary endpoint of relieving dry eye symptoms, but missed the second endpoint: improvement in corneal staining.^3,5,6

The FDA was expected to release a decision on October 25, 2015 regarding lifitegrast; however, eight days prior, the agency declined approval of the drug at this time, citing the need for additional clinical tests and further information about product quality.² This column will provide some background. 

Beneath the Surface
Lifitegrast is a first-in-class, small-molecule antagonist of the lymphocyte function-associated antigen-1 (LFA-1) integrin, inhibiting interaction with its cognate ligand, called intercellular adhesion molecule-1 (ICAM-1).^7,8 Whew! That’s a sentence-full. So, what does this mean clinically?

Integrins are heterodimeric (i.e., a protein composed of two different polypeptide chains) cell surface receptors found in nearly all cell types that act as bridges for cell-to-cell and cell-to-extracellular matrix interactions. They are comprised of α and β subunits, which determine the ligand specificity for a particular integrin. The ligand is described as cognate, meaning that a specific ligand normally interacts with a given integrin. The ligand is usually the signal-triggering molecule that, upon binding to the integrin, results in a wide range of integrin-mediated interactions, including pathological processes such as inflammation, wound healing, angiogenesis and tumor metastasis.^8-10 The ligand ICAM-1 is a protein normally present in low levels on the surface of lymphocytes, macrophages and vascular endothelium, but is overexpressed in the presence of inflammation. 

The binding of LFA-1, a cell surface adhesion molecule found on all leukocytes, with ICAM-1, is essential for the migration and proliferation of T-cells at inflammatory sites as well as subsequent cytokine release. This T-cell-mediated inflammation is a mechanism known to be present in dry eye disease.⁶ Blocking the interaction of integrins with their ligands is a major target for new pharmaceutical agents, with recent drugs approved or in trials for conditions such as multiple sclerosis, Crohn’s disease, osteoporosis, cancer, AMD and now dry eye.^9,10 

Lifitegrast acts as an ICAM-1 decoy, preventing LFA-1 from binding to ICAM-1, which presents abundantly on inflamed cells. This inhibition of LFA-1 binding to ICAM-1 is believed to break the inflammatory cycle, thereby reducing a dry eye patient’s signs and symptoms.⁸

Magnum OPUS
The original lifitegrast NDA included one Phase II study, two Phase III efficacy and safety studies (OPUS-1 and OPUS-2) and one long-term Phase III safety study (SONATA). More than 1,800 patients were enrolled in these four randomized clinical trials.⁴

A Phase II study of lifitegrast conducted from 2009 to 2010 recruited 230 dry eye patients at five sites. Typically in Phase II studies, the drug concentration and dosing frequency are established; in this study, lifitegrast was evaluated at 0.1%, 1% and 5% concentrations. Subjects used the drops for 12 weeks and were evaluated at several screening and on-treatment visits. Using the controlled adverse environmental (CAE) procedure to reduce variables, signs and symptoms were assessed before and after ocular surface drying. The CAE is a chamber that regulates environmental factors including humidity (<10%), temperature (76±6º), airflow and lighting. In this study, there was an improvement in signs and symptoms of dry eye in the lifitegrast group as compared to placebo with a dose response for staining.¹¹ A clinically meaningful response, as defined by the FDA, requires statistically significant improvement in one sign and one symptom that must be replicated in Phase III studies.^7,12 

Entering Phase III studies, lifitegrast at a concentration of 5% dosed twice a day was selected. OPUS-1 was conducted from 2011 to 2012 involving 13 sites enrolling 588 dry eye patients. Patients were randomized at a ratio of 2:1 (lifitegrast:placebo) and used the eye drops twice a day for 12 weeks. The primary objective outcome measure was inferior corneal fluorescein staining and the primary subjective outcome measure was visual-related function subscale of the Ocular Surface Disease Index (VR-OSDI). The visual-related function involved questions six to nine on the OSDI. Unlike the Phase II study, the CAE was used during the screening process, but not once patients were on treatment. Objective findings including corneal fluorescein staining and conjunctival lissamine green staining were significantly reduced in the lifitegrast group as compared to placebo. There was symptomatic improvement in ocular discomfort and dryness in the treatment group. However, the co-primary endpoint of VS-OSDI was not met.^5,12

OPUS-2 was then conducted from 2012 to 2013 at 30 sites involving 718 dry eye patients. Participants were randomized to use either lifitegrast 5% or placebo twice a day for 12 weeks. The subjective primary outcome measure was altered from VR-OSDI to Eye Dryness Score (EDS), which assesses seven subject-reported symptoms using a visual analog scale for each item with zero representing no discomfort and 100 indicative of maximum discomfort. The subjective primary outcome measure was a single score that combined the EDS from both eyes. In contrast to OPUS-1, OPUS-2 demonstrated significant improvement in the subjective endpoint (i.e., eye dryness), but failed to show significant improvement in the objective measure of corneal fluorescein staining.^6,12 

SONATA was a multicenter (23 sites) Phase III safety study enrolling 331 dry eye patients conducted from 2012 to 2014. Patients were randomized; 220 received lifitegrast and 111 received placebo. Patients used the eye drops twice a day for one year. No serious ocular adverse events occurred in either group; however, those receiving lifitegrast had more ocular and nonocular adverse events than the placebo group. Approximately half the study subjects reported adverse events, with the most common being dysgeusia and irritation upon instillation. Secondary safety measures showed no significant changes, including plasma concentration.^12,13 

OPUS-3 concluded in October. This Phase III study involved 41 sites enrolling 711 patients. Like prior OPUS studies, dry eye patients either received lifitegrast or placebo twice a day for 12 weeks; however, the main difference in this study compared with the others is the inclusion of just a single primary outcome measure—the subjective eye dryness score.¹² Preliminary results from this study released on October 27 indicated that the primary endpoint was met with significant improvement in patient-reported symptoms in the group receiving lifitegrast. Other key secondary endpoints evaluating symptoms at days 14 and 42 were also met. Shire reportedly plans to resubmit the lifitegrast NDA to the FDA in the first quarter of 2016.  

For now, the waiting continues. These positive results from OPUS-3 will hopefully address the FDA’s concerns and ultimately give us a new first-in-class medication to offer relief of both the signs and symptoms of dry eye.  

1. FDA Grants Priority Review to Lifitegrast NDA for Treatment of Dry Eye Disease in Adults. Available at https://www.shire.com/newsroom/2015/april/fda-grants-priority-review-to-lifitegrast-nda-for-treatment-of-dry-eye-disease-in-adults. Accessed Oct 5, 2015.
2. FDA Declines Approval of Shire’s Eye Drug Lifitegrast. Available at http://www.techtimes.com/articles/96514/20151017/fda-declines-approval-of-shires-eye-drug-lifitegrast.htm. Accessed Oct 19, 2015.
3. Lifitegrast Heads Up Promising Dry Eye Pipeline.  Available at: http://ois.net/lifitegrast-heads-up-promising-dry-eye-pipeline/. Accessed Oct 5, 2015.
4. Press Release: Shire Provides Update on Next Steps for Lifitegrast in Light of FDA Complete Response Letter. Available at: https://www.shire.com/newsroom/2015/october/shire-provides-update-on-next-steps-for-lifitegrast-in-light-of-fda-complete-response-letter. Accessed Oct 19, 2015.
5. Sheppard JD, Torkildsen GL, Lonsdale JD, D’Ambrosio FA, et al. Lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease: results of the OPUS-1 phase 3 study. Ophthalmology. 2014 Feb;121(2):475-83.
6. Tauber J, Karpecki P, Latkany R, Luchs J, et al. Lifitegrast ophthalmic solution 5.0% versus placebo for treatment of dry eye disease. Results of the randomized phase III OPUS-2 study. Ophthalmology. 2015 Sep 10. pii: S0161-6420(15)00777-0.
7. Semba CP, Swearingen D, Smith VL, et al. Safety and pharmacokinetics of a novel lymphocyte function-associated antigen-1 antagonist ophthalmic solution (SAR 1118) in healthy adults. J Ocul Pharmacol Ther. 2011 Feb;27(1):99-104.
8. Zhong M, Gadek Tr, Bui M, et al. Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye. ACS Med Chem Lett. 2012 Jan;31;3(3):203-6. 
9. Millard M, Odde S, Neamati N. Integrin Targeted Therapeutics. Theranostics. 2011;1:154-188.
10. Takada Y, Ye X, Simon S. The integrins. Genome Biology. 2007; 8(5):215.
11. Ousler GW, Gomes PJ, Welch D, Abelson MB. Methodologies for the Study of Ocular Surface Disease. The Ocular Surface. 2005 July;3(3):143–154. 
12. ClinicalTrials.gov. Accessed: Oct 19, 2015.
13. SONATA: 50% Adverse Event Rate Reported for Lifitegrast. Available athttp://www.medscape.com/viewarticle/8443968_print. Accessed: Oct 5, 2015.