Multicenter Study of a Novel Topical Interleukin-1 Receptor Inhibitor, Isunakinra, in Subjects With Moderate to Severe Dry Eye Disease

Goldstein, Michael H.; Martel, James B.; Sall, Kenneth; Goldberg, Damien F.; Abrams, Marc A; Rubin, Jay M.; Sheppard, John D.; Tauber, Joseph; Korenfeld, Michael S; Agahigian, Jennifer; Durham, Todd A.; Furfine, Eric S.

doi:10.1097/icl.0000000000000276

Cited by 16 publications

(11 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…compounds 83-116 were confirmed by spectral (IR, 1 H NMR, 13 C NMR, HSQC-2D, HMBC-2D, and MS) and analytical data (Scheme 1, Section 4, and Supporting Information). The isomeric structures of compounds 72 and 99 were determined by X-ray single-crystal diffraction analysis, and the stable isomers were found to be in Z configuration.…”

Section: Chemistrymentioning

confidence: 84%

“…[10][11][12] However, only isunakinra, an IL-1β/IL-1Ra chimeric peptide, has progressed into clinical trials. [13] Small molecules offer an important cost advantage over biological drugs, and they can be more suitable for patients owing to more versatile pharmaceutical forms with better compliance. Thus, developing a safe and effective molecule capable of controlling the effects of IL-1 is of prime importance.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

5‐Fluoro/(trifluoromethoxy)‐2‐indolinone derivatives with anti‐interleukin‐1 activity

Soylu‐Eter,

Sevinçli,

Ersoy

et al. 2023

Archiv der Pharmazie

View full text Add to dashboard Cite

The pro‐inflammatory cytokine interleukin‐1 (IL‐1) drives the pathogenesis of several inflammatory diseases. Recent studies have revealed that 2‐indolinones can modulate cytokine responses. Therefore, we screened several 2‐indolinone derivatives in preliminary studies to develop agents with anti‐IL‐1 activity. First, the putative efficacies and binding interactions of 2‐indolinones were evaluated by docking studies. Second, previously synthesized 5‐fluoro/(trifluoromethoxy)−1H‐indole‐2,3‐dione 3‐(4‐phenylthiosemicarbazones) (compounds 47–69) which had the highest inhibitory effect in the screening were evaluated for inhibitory effects on the IL‐1 receptor (IL‐1R). Compounds 52 (IC50 = 0.09 µM) and 65 (IC50 = 0.07 µM) were selected as lead compounds for the subsequent synthesis of new derivatives. The novel 5‐fluoro/(trifluoromethoxy)−1H‐indole‐2,3‐dione 3‐(4‐phenylthiosemicarbazones) (compounds 70–116) were designed, synthesized, and in vitro studies were completed. The compounds 76, 78, 81, 91, 100, 105, and 107 tested showed nontoxic inhibitory effects on IL‐1R‐dependent responses in the range of 0.01–0.06 µM and stronger than the lead compounds 52 and 65. In vitro and in silico findings showed that compounds 78 (IC50 = 0.01 µM) and 81 (IC50 = 0.02 µM) had the strongest IL‐1R inhibitory effects and the most favorable drug‐like properties. Molecular modeling studies of the compounds 78 and 81 were carried out to determine the possible binding interactions at the active site of the IL‐1R.

show abstract

Section: Chemistrymentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

5‐Fluoro/(trifluoromethoxy)‐2‐indolinone derivatives with anti‐interleukin‐1 activity

Soylu‐Eter,

Sevinçli,

Ersoy

et al. 2023

Archiv der Pharmazie

View full text Add to dashboard Cite

show abstract

“…Finally, 56 articles were included in the meta-analysis. As a placebo, the studies included in this meta-analysis used saline [ 30 , 33 , 34 , 37 , 45 , 47 , 48 , 53 , 57 , 71 , 72 , 74 , 77 ] or balanced salt solution [ 35 ], vehicle drops [ 29 , 43 , 50 , 52 , 56 , 61 , 66 – 68 , 80 ], artificial tears [ 81 ], sham pulsed light treatment [ 55 , 78 ], sham acupuncture [ 92 ], an ophthalmic solution containing base only [ 36 ], oral vitamin E [ 39 ], olive oil [ 7 , 42 , 44 , 51 , 70 , 75 , 83 ], sunflower oil [ 59 , 85 ], safflower oil [ 84 ], wheat germ oil [ 65 ], corn oil [ 54 ], palm and coconut oil [ 62 , 63 ], medium-chain fatty acids [ 60 ], or tablets without the active ingredient with the same appearance as the active treatment [ 40 , 46 , 49 , 58 , 69 , 79 ], placebo beverage with a similar texture, flavour, and taste as the active agent [ 31 ],1000 IU of vitamin A in a study using 100,000 IU of vitamin A as active treatment [ 76 ], or the placebo was not exactly specified [ 9 , 41 , 73 , 82 ]. Therefore, the choice of placebo was heterogenous.…”

Section: Resultsmentioning

confidence: 99%

Section: Study Selectionmentioning

confidence: 99%

Placebo administration for dry eye disease: a level I evidence based systematic review and meta-analysis

et al. 2022

View full text Add to dashboard Cite

Background The efficacy of various common treatment options for dry eye disease (DED) has been investigated against placebo. However, the potential beneficial effect of placebo in the management of DED is still unclear. Aim This meta-analysis investigated the impact of placebo administration in DED in Ocular Surface Disease Index (OSDI), Schirmer I test (SIT), tear breakup time (TBUT), corneal staining, and complications. Method This meta-analysis and systematic review was conducted according to the 2020 PRISMA guidelines. In March 2022, Pubmed, Web of Science, Google Scholar, and Embase were accessed. All the randomised clinical trials which investigated any active treatment against a placebo control group were considered. The following data were extracted at baseline and at last follow-up: Ocular Surface Disease Index (OSDI), tear breakup time test (TBUT), Schirmer I test (SIT), corneal staining. Results Data from 56 studies (12,205 patients) were retrieved. Placebo administration is not effective in improving TBUT (P = 0.3), OSDI (P = 0.2), SIT (P = 0.1) and corneal staining (P = 0.1) from baseline to last follow-up. Active treatment led to a higher TBUT and SIT compared to placebo administration (P < 0.0001). The active treatment resulted in a lower OSDI compared to placebo administration (P = 0.0005). Five studies reported data on the corneal staining. No difference was found between placebo administration and active treatment (P = 0.8). Conclusion Placebo administration does not impact symptoms of DED and can be successfully employed to evaluate the efficacy of active treatments.

show abstract

“…Additionally, insunakinra (EBI-005) is an IL-1 receptor antagonist (IL-1Ra) that has been demonstrated to reduce inflammation of the ocular surface by blocking the IL-1 receptor [ 11 , 163 ]. IL-1 is a potent pro-inflammatory cytokine that mediates inflammation of the ocular surface by promoting the migration of immune cells into the site of inflammation in the conjunctiva.…”

Section: Potential Therapeutic Targetsmentioning

confidence: 99%

Therapeutic Targets in Allergic Conjunctivitis

Labib

Chigbu

2022

Pharmaceuticals

View full text Add to dashboard Cite

Allergic conjunctivitis (AC) is a common condition resulting from exposure to allergens such as pollen, animal dander, or mold. It is typically mediated by allergen-induced crosslinking of immunoglobulin E attached to receptors on primed conjunctival mast cells, which results in mast cell degranulation and histamine release, as well as the release of lipid mediators, cytokines, and chemokines. The clinical result is conjunctival hyperemia, tearing, intense itching, and chemosis. Refractory and chronic cases can result in ocular surface complications that may be vision threatening. Patients who experience even mild forms of this disease report an impact on their quality of life. Current treatment options range from non-pharmacologic therapies to ocular and systemic options. However, to adequately control AC, the use of multiple agents is often required. As such, a precise understanding of the immune mechanisms responsible for this ocular surface inflammation is needed to support ongoing research for potential therapeutic targets such as chemokine receptors, cytokine receptors, non-receptor tyrosine kinases, and integrins. This review utilized several published articles regarding the current therapeutic options to treat AC, as well as the pathological and immune mechanisms relevant to AC. This review will also focus on cellular and molecular targets in AC, with particular emphasis on potential therapeutic agents that can attenuate the pathology and immune mechanisms driven by cells, receptors, and molecules that participate in the immunopathogenesis and immunopathology of AC.

show abstract

Multicenter Study of a Novel Topical Interleukin-1 Receptor Inhibitor, Isunakinra, in Subjects With Moderate to Severe Dry Eye Disease

Abstract: Isunakinra was safe, well tolerated and showed clinically meaningful improvements in signs and symptoms of DED. These results encouraged the design of an adequately powered study to characterize the safety and efficacy of isunakinra in ocular surface diseases.

Cited by 16 publications

References 16 publications

5‐Fluoro/(trifluoromethoxy)‐2‐indolinone derivatives with anti‐interleukin‐1 activity

5‐Fluoro/(trifluoromethoxy)‐2‐indolinone derivatives with anti‐interleukin‐1 activity

Placebo administration for dry eye disease: a level I evidence based systematic review and meta-analysis

Therapeutic Targets in Allergic Conjunctivitis

Contact Info

Product

Resources

About