Sunday, November 23, 2014

Lifitegrast | Treatment for Dry Eyes | LFA-1/ICAM-1 Antagonist | Lymphocyte Function-Associated Antigen-1 Inhibitor


Lifitegrast [N-{[2-(1-Benzofuran-6-ylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl]carbonyl}-3-(methylsulfonyl)-L-phenylalanine] is a potent novel small molecule lymphocyte function-associated antigen-1 (LFA-1/ICAM-1) antagonist for a broad range of ocular inflammatory conditions including dry eye and diabetic macular edema. It represents a first-in-class integrin anti-inflammatory specifically engineered for ophthalmic use [1].
Lifitegrast is designed with the hypothesis that inhibition of the LFA-1/ICAM-1 interaction may be an appropriate pharmacologic target for breaking the constant cycle of T-cell-mediated inflammation associated with dry eye. The anti-inflammatory effects of LFA-1 inhibition have been biologically validated in experimental models of chronic inflammation, including uveitis, diabetic retinopathy, and keratoconjunctivitis.
Lifitegrast: 2D and 3D Structure

Lifitegrast is an ICAM-1 decoy and prevents binding of LFA-1 to native ICAM-1 expressed on the surface of inflamed epithelial, endothelial, and antigen presenting cells. It is a member of a series of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists, which were shown to bind the I-domain of the CD11α subunit of LFA-1 and serve as direct competitive antagonists of LFA-1 binding to ICAM-1 [2, 3].
On July 11, 2016 Lifitegrast was approved as a twice-daily eye drop solution indicated for the treatment of the signs and symptoms of dry eye disease in adult patients.

Dry Eye [keratoconjunctivitis sicca (KCS), keratitis sicca, or xerophthalmia]
Dry eye is a complex disorder of the ocular surface characterized by symptoms of discomfort, decreased tear quality, and chronic inflammation. Although the cause of dry eye is multifactorial, a common pathway is the establishment of a proinflammatory state leading to activation of T-cell-mediated immune responses, cytokine release, and hyperosmolar tears. The resulting inflammatory milieu stimulates corneal neural fibers resulting in sensations of ocular discomfort and dryness.
Activation and homing of lymphocytes to the ocular surface are central to the chronic inflammatory process and influenced by the binding of the T-cell integrin, lymphocyte function antigen-1 (LFA-1; CD11α /CD18; αLβ2), to its cognate ligand, intercellular adhesion molecule-1 (ICAM-1; CD54) expressed on the cell surface of inflamed epithelium.7 Increased expression of ICAM-1 is demonstrated at both the mRNA and protein levels in conjunctival epithelial/lacrimal acinar cells in patients with dry eye,10 along with elevated levels of inflammatory T-cell-mediated cytokines in the tear film.11

Lifitegrast (0.5%) as a topically administered LFA-1 inhibitor 
Phase III study demonstrated superiority of Lifitegrast 5.0% in reducing ocular surface epithelial lesions compared with placebo. These findings were supported by statistically significant improvements observed in the superior and total corneal regions after 84 days of treatment. Furthermore, benefits in corneal fluorescein staining were supported by improvements in conjunctival lissamine staining in the nasal and total conjunctival regions with statistical significance observed as early as day 14 and benefit maintained through day 84.
The study provides evidence that use of Lifitegrast, a topically administered LFA-1 inhibitor, can reduce inflammatory changes of the ocular surface associated with dry eye disease as early as week 2 when administered twice daily over a 12-week treatment period.
Lifitegrast demonstrated evidence of reduced ocular surface inflammation as early as day 14 as measured by lissamine. The relatively rapid onset of action may be attributable to broad inhibition of inflammatory cytokines associated with dry eye and maintenance of sustained inhibitory concentrations of drug in the tear film up to 24 hours after a single dose. Human clinical data of Lifitegrast have demonstrated that a compound possessing great potency against the biological target, good intrinsic solubility, poor oral bioavailability, and fast clearance can also be developed into a safe and efficacious ophthalmic treatment.

Dosages and Approvals:
Lifitegrast 5%ophthalmic solution (Tradename:  Xiidra) was approved by the U.S. Food and Drug Administration (FDA) on July 11, 2016 as a twice-daily eye drop solution indicated for the treatment of the signs and symptoms of dry eye disease in adult patients. Xiidra is the only prescription eye drop indicated for the treatment of both signs and symptoms of this condition. It is dosed twice per day, approximately 12 hours apart, in each eye. Shire plc is credited with discovery and development of Lifitegrast. Shire expects to launch Xiidra in the United States in the third quarter of 2016.

Reported Activities for Lifitegrast
IC50 (Inhibition of Binding of Hut-78 cells to Immobilized ICAM-1) = 0.009 uM
IC50 (Inhibition of Jurkat T-cell Attachment to ICAM-1) = 2.98 nM

Common name: SAR 1118; SAR-1118; SAR1118; Lifitegrast
Trademarks: Xiidra
Molecular Formula: C29H24Cl2N2O7S
CAS Registry Number: 1025967-78-5
CAS Name: N-{[2-(1-Benzofuran-6-ylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl]carbonyl}-3-(methylsulfonyl)-L-phenylalanine
Molecular Weight: 615.48
InChI: InChI=1S/C29H24Cl2N2O7S/c1-41(38,39)20-4-2-3-16(11-20)12-23(29(36)37)32-27(34)25-22(30)13-19-15-33(9-7-21(19)26(25)31)28(35)18-6-5-17-8-10-40-24(17)14-18/h2-6,8,10-11,13-14,23H,7,9,12,15H2,1H3,(H,32,34)(H,36,37)/t23-/m0/s1
Mechanism of Action: LFA-1/ICAM-1 antagonists; Lymphocyte function-associated antigen-1 Inhibitor
Activity: Treatment of Dry Eyes; Treatment of Keratoconjunctivitis Sicca (KCS), Keratitis Sicca, or Xerophthalmia; Ophthalmic Agents
Status: Launched 2016 (US)
Chemical Class: Tetrahydroisoquinoline; Amides; Amino Acids; Chlorobenzenes; Small-molecules; Chlorine containing; Methylsulfonyl containing; L-phenylalanine
Originator: Shire Pharmaceuticals
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