Narrow Spectrum Kinase Inhibitors Demonstrate Promise for the Treatment of Dry Eye Disease and Other Ocular Inflammatory Disorders

Hagan, Suzanne; Fyfe, Matthew C. T.; Ofori‐Frimpong, Boatemaa; Oliver, Katherine M.; Foster, Martyn; Sirohi, Sameer; Solanke, Yemisi; Doughty, Michael J.; Rowley, Adele; Taylor, Mike; Webber, Steve; Walshe, Claire A.

doi:10.1167/iovs.17-23479

Cited by 13 publications

(6 citation statements)

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“…TOP1630 is a novel agent being developed for the treatment of DED with a mechanism of action that selectively targets key kinases that play a pivotal role in signaling in numerous immune cell types from both innate and adaptive pathways. The promising preclinical profiling of NSKIs14 and mechanism of action could translate into potent and broad efficacy in patients with DED, with effects at least as pronounced as established treatments but without the associated unwanted side effects.…”

Section: Discussionmentioning

confidence: 99%

“…Inflammation has an important role in DED pathophysiology 6. Nonsystemic kinase inhibitors (NSKIs) represent a novel class of pharmacological agents that selectively target key kinases fundamental to inflammatory cell signaling in innate and adaptive immune responses 14. In DED, the NSKI targets p38α, Src family kinases (Src and Lck), and Syk are upregulated at the gene level in patients compared with healthy volunteers 14.…”

Section: Introductionmentioning

confidence: 99%

“…Nonsystemic kinase inhibitors (NSKIs) represent a novel class of pharmacological agents that selectively target key kinases fundamental to inflammatory cell signaling in innate and adaptive immune responses 14. In DED, the NSKI targets p38α, Src family kinases (Src and Lck), and Syk are upregulated at the gene level in patients compared with healthy volunteers 14. NSKIs have broad, potent anti-inflammatory effects in vitro and in vivo, exhibiting potent inhibition of cytokine release in cellular assays mimicking both innate and adaptive immune systems, as well as in vivo models 15.…”

Section: Introductionmentioning

confidence: 99%

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<p>A phase 2 randomized, double-masked, placebo-controlled study of novel nonsystemic kinase inhibitor TOP1630 for the treatment of dry eye disease</p>

Taylor¹,

Ousler²,

Torkildsen³

et al. 2019

OPTH

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Purpose To evaluate the safety and efficacy of topical TOP1630, a novel nonsystemic kinase inhibitor, in dry eye disease (DED). Patients and methods A randomized, double-masked, parallel-group trial of 0.1% TOP1630 ophthalmic solution TID or placebo (vehicle without active drug) was conducted in DED subjects (n=61). Key eligibility criteria consistent with enrolling a moderate to severe DED population included >6 months DED history; OSDI © score ≥18; Schirmer’s test score ≤10 and ≥1 mm/5 minutes; tear film break-up time >1 and <7 seconds; and dry eye exacerbation in corneal staining and ocular discomfort in a Controlled Adverse Environment (CAE ® ). After a 7-day run-in period with placebo TID, eligible subjects were randomized to TOP1630 or placebo for 28 days. No supplemental artificial tears or rescue medication were allowed. Results TOP1630 was safe, well-tolerated, and efficacious in treating DED symptoms and signs. No serious adverse events (AEs) or withdrawals due to treatment emergent AEs occurred. Drop comfort scores showed TOP1630 to be comfortable and comparable with placebo. Significant symptom improvements were seen for TOP1630 vs placebo for ocular discomfort ( P =0.02 post-CAE), grittiness/foreign body sensation (on four independent assessment scales, each P <0.05), worst DED symptom (diary, P =0.06), and ocular pain (VAS, P =0.03). Sign improvements were seen for total ocular surface (all regions), corneal sum, and conjunctival sum staining with TOP1630 compared with placebo (each P <0.05). Conclusion TOP1630 had placebo-like tolerability and produced improvements in multiple symptom and sign endpoints in both environmental and challenge settings. The emergent TOP1630 benefit–risk profile for DED treatment is highly favorable and supports further development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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<p>A phase 2 randomized, double-masked, placebo-controlled study of novel nonsystemic kinase inhibitor TOP1630 for the treatment of dry eye disease</p>

Taylor¹,

Ousler²,

Torkildsen³

et al. 2019

OPTH

Self Cite

View full text Add to dashboard Cite

show abstract

“…The next gene was SYK (ENSP00000364898), which contributes to the regulation of cellular responses, including proliferation, differentiation, and phagocytosis in B, T and myeloid cells ( Luger et al, 2013 ; Hauck et al, 2015 ; Wang et al, 2015 ). For its specific contribution on the pathogenesis of uveitis, SYK/CARD9 signaling axis participates in the pathogenesis of autoimmune eye diseases, including ocular inflammatory disorders, uveitis, and dry eye disease ( Lee et al, 2016 ; Hagan et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Use of Laplacian Heat Diffusion Algorithm to Infer Novel Genes With Functions Related to Uveitis

Zhao

Wang

et al. 2018

Front. Genet.

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Uveitis is the inflammation of the uvea and is a serious eye disease that can cause blindness for middle-aged and young people. However, the pathogenesis of this disease has not been fully uncovered and thus renders difficulties in designing effective treatments. Completely identifying the genes related to this disease can help improve and accelerate the comprehension of uveitis. In this study, a new computational method was developed to infer potential related genes based on validated ones. We employed a large protein–protein interaction network reported in STRING, in which Laplacian heat diffusion algorithm was applied using validated genes as seed nodes. Except for the validated ones, all genes in the network were filtered by three tests, namely, permutation, association, and function tests, which evaluated the genes based on their specialties and associations to uveitis. Results indicated that 59 inferred genes were accessed, several of which were confirmed to be highly related to uveitis by literature review. In addition, the inferred genes were compared with those reported in a previous study, indicating that our reported genes are necessary supplements.

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“…Similar to EAAU, aqueous humor inflammation can be examined, however, EIU cellular responses are mediated mainly by polymorphonuclear cells and macrophages of the innate immune system (56). The EIU model has successfully been used to demonstrate anti-inflammatory properties of a clinical stage narrow spectrum kinase inhibitor, TOP1362 (Topivert), compared to a topical steroid (57). TOP1362 and the steroid dose-dependently reduced LPS-induced inflammatory cell infiltration and ocular pro-inflammatory cytokine expression.…”

Section: Introductionmentioning

confidence: 99%

Translational Preclinical Pharmacologic Disease Models for Ophthalmic Drug Development

et al. 2019

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Preclinical models of human diseases are critical to our understanding of disease etiology, pathology, and progression and enable the development of effective treatments. An ideal model of human disease should capture anatomical features and pathophysiological mechanisms, mimic the progression pattern, and should be amenable to evaluating translational endpoints and treatment approaches. Preclinical animal models have been developed for a variety of human ophthalmological diseases to mirror disease mechanisms, location of the affected region in the eye and severity. These models offer clues to aid in our fundamental understanding of disease pathogenesis and enable progression of new therapies to clinical development by providing an opportunity to gain proof of concept (POC). Here, we review preclinical animal models associated with development of new therapies for diseases of the ocular surface, glaucoma, presbyopia, and retinal diseases, including diabetic retinopathy and age-related macular degeneration (AMD). We have focused on summarizing the models critical to new drug development and described the translational features of the models that contributed to our understanding of disease pathogenesis and establishment of preclinical POC.

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Narrow Spectrum Kinase Inhibitors Demonstrate Promise for the Treatment of Dry Eye Disease and Other Ocular Inflammatory Disorders

Abstract: TOP1362 is a potent inhibitor of kinases upregulated in DED and markedly attenuates proinflammatory cytokine release in vitro and in vivo, highlighting the therapeutic potential of NSKIs for treating ocular inflammation, such as that observed in DED.

Cited by 13 publications

References 50 publications

<p>A phase 2 randomized, double-masked, placebo-controlled study of novel nonsystemic kinase inhibitor TOP1630 for the treatment of dry eye disease</p>

<p>A phase 2 randomized, double-masked, placebo-controlled study of novel nonsystemic kinase inhibitor TOP1630 for the treatment of dry eye disease</p>

Use of Laplacian Heat Diffusion Algorithm to Infer Novel Genes With Functions Related to Uveitis

Translational Preclinical Pharmacologic Disease Models for Ophthalmic Drug Development

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