The Pharmacologic Assessment of A Novel Lymphocyte Function-Associated Antigen-1 Antagonist (SAR 1118) for the Treatment of Keratoconjunctivitis Sicca in Dogs

Murphy, Christopher J.; Bentley, Ellison; Miller, Paul E.; McIntyre, K. B.; Leatherberry, Gary; Dubielzig, Richard R.; Giuliano, Elizabeth A.; Moore, Cecil P.; Phillips, Thomas E.; Smith, P.Blaise; Prescott, Elizabeth; Miller, Jacqueline M.; Thomas, Peter T.; Scagliotti, R. H.; Esson, Doug W.; Gadek, Thomas R.; O’Neill, Charles

doi:10.1167/iovs.09-5078

Cited by 73 publications

(88 citation statements)

References 21 publications

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“…Lifitegrast is a novel small molecule integrin antagonist, currently under development for the treatment of DED 5 . Lifitegrast targets the inflammatory pathways involved in the disease by blocking the binding of intercellular adhesion molecule 1 (ICAM-1) to the integrin lymphocyte function-associated antigen 1 (LFA-1) on the T cell surface 6 , and inhibiting subsequent T cell-mediated inflammation associated with DED. Preclinical evidence confirms the potent dose-dependent inhibition of lifitegrast on T cell-mediated inflammatory processes 6,7 .…”

Section: Introductionmentioning

confidence: 99%

“…Lifitegrast targets the inflammatory pathways involved in the disease by blocking the binding of intercellular adhesion molecule 1 (ICAM-1) to the integrin lymphocyte function-associated antigen 1 (LFA-1) on the T cell surface 6 , and inhibiting subsequent T cell-mediated inflammation associated with DED. Preclinical evidence confirms the potent dose-dependent inhibition of lifitegrast on T cell-mediated inflammatory processes 6,7 . Currently available treatment approaches for DED include artificial tear substitutes, lubricant gels and ointments, topical cyclosporine, topical corticosteroids, and punctal plugs 8 .…”

Section: Introductionmentioning

confidence: 99%

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Lifitegrast clinical efficacy for treatment of signs and symptoms of dry eye disease across three randomized controlled trials

Holland

Whitley

Sall

et al. 2016

Current Medical Research and Opinion

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Objective: Report efficacy findings from three clinical trials (one phase 2 and two phase 3 [OPUS-1, OPUS-2]) of lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease (DED). Research design and methods: Three 84-day, randomized, double-masked, placebo-controlled trials. Adults (!18 years) with DED were randomized (1:1) to lifitegrast 5.0% or matching placebo. Changes from baseline to day 84 in signs and symptoms of DED were analyzed. Main outcome measures: Phase 2, pre-specified endpoint: inferior corneal staining score (ICSS; 0-4); OPUS-1, coprimary endpoints: ICSS and visual-related function subscale (0-4 scale); OPUS-2, coprimary endpoints: ICSS and eye dryness score (EDS, VAS; 0-100). Results: Fifty-eight participants were randomized to lifitegrast 5.0% and 58 to placebo in the phase 2 trial; 293 to lifitegrast and 295 to placebo in OPUS-1; 358 to lifitegrast and 360 to placebo in OPUS-2. In participants with mild-to-moderate baseline DED symptomatology, lifitegrast improved ICSS versus placebo in the phase 2 study (treatment effect, 0.35; 95% CI, 0.05-0.65; p ¼ 0.0209) and OPUS-1 (effect, 0.24; 95% CI, 0.10-0.38; p ¼ 0.0007). Among more symptomatic participants (baseline EDS !40, recent artificial tear use), lifitegrast improved EDS versus placebo in a post hoc analysis of OPUS-1 (effect, 13.34; 95% CI, 2.35-24.33; nominal p ¼ 0.0178) and in OPUS-2 (effect, 12.61; 95% CI, 8.51-16.70; p < 0.0001). Limitations: Trials were conducted over 12 weeks; efficacy beyond this period was not assessed. Conclusions: Across three trials, lifitegrast improved ICSS in participants with mild-to-moderate baseline symptomatology in two studies, and EDS in participants with moderate-to-severe baseline symptomatology in two studies. Based on the overall findings from these trials, lifitegrast shows promise as a new treatment option for signs and symptoms of DED. ARTICLE HISTORY

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lifitegrast clinical efficacy for treatment of signs and symptoms of dry eye disease across three randomized controlled trials

Holland

Whitley

Sall

et al. 2016

Current Medical Research and Opinion

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“…11,12 The most common cause of canine KCS is a defect in autoimmunity causing an insufficient production of the aqueous component by the lacrimal and accessory lacrimal glands (Schirmer tear test of <10 mm/min) due to a lymphocytic attack on these tear glands. 6,7,[13][14][15] In most cases (80%), the histopathologic evidence of lacrimal gland mononuclear cell infiltration and acinar atrophy, presence of circulating autoantibodies, and concurrent immune disease suggest an autoimmune etiology to canine KCS. 13,14,16 Cyclosporine A interferes with the proliferation and activity of T-lymphocytes and the macrolide calcineurin inhibitor tacrolimus also reduces lymphocyte activity.…”

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confidence: 99%

Preformulation Studies of a Liposomal Formulation Containing Sirolimus for the Treatment of Dry Eye Disease

Linares-Alba

Gómez-Guajardo²,

Fonzar

et al. 2016

Journal of Ocular Pharmacology and Therapeutics

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Purpose: The aim of this study was to develop and characterize a liposomal product containing sirolimus to be administered subconjunctivally for the treatment of nonresponsive keratoconjunctivitis sicca (KCS) or dry eye. Methods: Formulations were prepared using an ethanol injection method and an adaptation of the heating method in pursuance of the most suitable methodology for future industrial production. Liposomes were loaded with either a high dose of 1 mg/mL of sirolimus or a less toxic dose of 0.4 mg/mL. The effects of critical process and formulation parameters were investigated. Liposomes were characterized in terms of size, zeta potential, polydispersity, differential scanning calorimetry, morphology, entrapment efficiency, phospholipid content, thermal stability, and sterility. The formulation was evaluated clinically in dogs with spontaneous KCS. Results: Sterile liposomal dispersions with sizes ranging from 140 to 211 nm, were successfully obtained. High entrapment efficiency of 93%-98% was achieved. The heating method allowed an easier production of liposomes with high entrapment efficiency, to significantly shorten production time and the elimination of the use of alcohol. The poor stability of the obtained liposomes in aqueous dispersion made the inclusion of a lyophilization step necessary to the manufacturing process. In vivo testing of the liposomal sirolimus formulations in the spontaneous KCS dog model have produced promising results, particularly with a sirolimus dose of 1 mg/mL, indicating the need for further development and study of proposed formulations in the treatment of canine KCS. Clinical improvement in tear production in dogs with spontaneous KCS treated with the 1 mg/mL dose product was observed. Conclusions: The heating method allowed easier production of high entrapment efficiency liposomes to significantly shorten production time and the elimination of the use of alcohol. Tear production was increased in dogs administered with the formulation.

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“…22 In particular, releases of inflammatory cytokines, such as interferon γ (IFNγ), macrophage inflammatory protein-1α (MIP-1α), interleukin-1α (IL-1α), IL-1β, IL-6, and IL-10, which well correlate with the clinical severity of human KCS when present in tears, are strongly inhibited. 23 Subsequently, a number of potent compounds, including 1b−c, 1g, 1l−n, 1q, and 1t, were selected for ADME evaluations.…”

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confidence: 99%

“…Moreover, 1g exhibited a good in vitro safety profile, such as being negative in the Ames test and having low potency in both cytochrome P450 (CYP) inhibition (3A4, IC 50 >20 μM, and 2C9, IC 50 = 3.0 μM) and the human ether-a-go-go-related gene (hERG) (patch clamp, IC 50 >20 μM) assays. A 14 C-labeled 1g at the carbonyl of the central THIQ residue was topically administered as an ophthalmic solution to both rats 24 and dogs 22 to evaluate the corresponding ocular PK profile. Maximal concentrations with good exposure levels were achieved 30 min postdose in all ocular tissues, particularly in bulbar conjunctiva, palpebral conjunctiva, and cornea, of these two species, while having quick initial and slow terminal elimination rates by tears.…”

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confidence: 99%

Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye

Zhong

Gadek²,

Bui

et al. 2012

ACS Med. Chem. Lett.

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LFA-1/ICAM-1 interaction is essential in support of inflammatory and specific T-cell regulated immune responses by mediating cell adhesion, leukocyte extravasation, migration, antigen presentation, formation of immunological synapse, and augmentation of T-cell receptor signaling. The increase of ICAM-1 expression levels in conjunctival epithelial cells and acinar cells was observed in animal models and patients diagnosed with dry eye. Therefore, it has been hypothesized that small molecule LFA-1/ICAM-1 antagonists could be an effective topical treatment for dry eye. In this letter, we describe the discovery of a potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonist (SAR 1118) and its development as an ophthalmic solution for treating dry eye.

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The Pharmacologic Assessment of A Novel Lymphocyte Function-Associated Antigen-1 Antagonist (SAR 1118) for the Treatment of Keratoconjunctivitis Sicca in Dogs

Abstract: SAR 1118 appears to be an effective anti-inflammatory treatment for KCS. Additional studies are warranted to establish the efficacy of SAR 1118 for the treatment of KCS in humans.

Cited by 73 publications

References 21 publications

Lifitegrast clinical efficacy for treatment of signs and symptoms of dry eye disease across three randomized controlled trials

Lifitegrast clinical efficacy for treatment of signs and symptoms of dry eye disease across three randomized controlled trials

Preformulation Studies of a Liposomal Formulation Containing Sirolimus for the Treatment of Dry Eye Disease

Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye

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