Investigation of Ocular Events Associated with Taprenepag Isopropyl, a Topical EP2 Agonist in Development for Treatment of Glaucoma

Yanochko, Gina M.; Affolter, Timothy; Eighmy, Johnnie J; Evans, Mark; Khoh‐Reiter, Su; Dong, Lijie; Miller, Paul E.; Shiue, Michael H.I.; Trajkovic, Dusko; Jessen, Bart

doi:10.1089/jop.2013.0222

Cited by 13 publications

(8 citation statements)

References 16 publications

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“…A sustained‐release formulation is also being developed as AGN‐210669. This compound showed similar IOP lowering activity as that of Lumigan 0.03% but produced a high occurrence of adverse events, including increased corneal thickness as has been reported for other EP 2 receptor agonists (Yanochko et al ., ).…”

Section: Pg Analogues As Ocular Hypotensive Agentsmentioning

confidence: 97%

Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma

Impagnatiello

Bastia

Almirante

et al. 2018

British J Pharmacology

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In patients with ocular hypertension or glaucoma, all treatments aim to lower intraocular pressure (IOP) by modulating aqueous humour (AH) production and/or uveoscleral and trabecular meshwork/Schlemm's canal AH drainage. PG analogues are considered to be the 'gold standard' treatment and are the most frequently used IOP-lowering agents. Recent data support an important role for NO in regulating IOP. Thus, novel PG analogues carrying a NO-donating moiety were recently advanced. Latanoprostene bunod (LBN) and NCX 470, NO-donating derivatives of latanoprost and bimatoprost, respectively, are examples of such compounds. LBN ophthalmic solution, 0.024% (Vyzulta™), showed greater IOP-lowering efficacy compared with that of Xalatan (latanoprost ophthalmic solution, 0.005%) or 0.5% timolol maleate in clinical settings. NCX 470 was found to be more effective than bimatoprost in animal models of ocular hypertension and glaucoma. Selective EP receptor agonists (i.e. taprenepag isopropyl, omidenepag isopropyl and aganepag isopropyl) and non-selective prostanoid receptor agonists (i.e. ONO-9054, sepetaprost isopropyl) that concomitantly stimulate FP and EP receptors have also been shown to hold promise as effective IOP-lowering agents.

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Section: Pg Analogues As Ocular Hypotensive Agentsmentioning

confidence: 97%

Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma

Impagnatiello

Bastia

Almirante

et al. 2018

British J Pharmacology

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“…Such safety and side effect information have been provided for CP 533536-isopropyl ester. 14,23,24 The sponsors of taprenepag should be commended for making such information available, this is not always the case. The taprenepag side effect of greatest concern was arguably iritis and related photophobia.…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…14,23 It would seem likely that iritis is the result of off-target activity at the prostanoid DP 2 (chemoattractant receptor homologous molecule expressed on T helper type 2 cells) receptor, since this receptor promotes leukocyte infiltration and motility, plus plasma leakage. 25,26 Although cytokine release from HCEC-12 cells and monocytes and macrophages was examined, the proinflammatory implications of interleukin (IL)-6 and IL-8 release were not considered in the context of potential off-target DP 2 receptor activation 23 or the fact that latanoprost stimulates IL-6 and IL-8 release from human Tenon's capsule fibroblasts, but does not produce ocular inflammation. 27 PGN 9856 has no observable activity at the DP 2 receptor 11 and, therefore, is not likely to cause ocular inflammation.…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…11,[30][31][32][33] PGN 9856 potently inhibits cytokine release from lymphocytes and monocytes isolated from peripheral blood. 11 Taprenepag has been reported to cause increased corneal thickness, 14,23,24 which appears to be reversible and independent of any evidence for corneal epithelial or endothelial toxicity. 23 Decreased central corneal thickening has been considered a risk factor for the progression of glaucoma, [34][35][36][37] but this is not always the case.…”

Section: Pharmacokineticsmentioning

confidence: 99%

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A Highly Effective and Ultra-Long-Acting Anti-Glaucoma Drug, with a Novel Periorbital Delivery Method

Woodward

Wang²,

Coleman³

et al. 2019

Journal of Ocular Pharmacology and Therapeutics

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Purpose: Two features define the future of glaucoma therapeutics: (1) greatly improved ocular hypotensive efficacy and (2) a delivery method that improves patient convenience and compliance. A highly efficacious and extraordinarily long-acting ocular hypotensive agent PGN 9856-isopropyl ester represents a potential nextgeneration anti-glaucoma drug. A new periorbital drug delivery route was also investigated. Methods: PGN 9856-isopropyl ester pharmacology was determined by employing human cells, including prostanoid receptor transfectants, and FLIPr or cellular dielectric spectroscopy technology. Intraocular pressure (IOP) was measured in conscious cynomolgus monkeys trained to accept pneumatonometry when under gentle restraint. For periorbital application, the compound was applied radially using a roller-ball device connected to a cylindrical reservoir. Pharmacokinetic data were obtained using LC/MS/MS instrumentation. Results: Single doses of PGN 9856-isopropyl ester, administered over a 0.001%-0.01% dose range, produced profound decreases in monkey IOP that persisted for at least 5 days, which was long after the drug was detectable in ocular tissues. It was not uncommon for a single eye drop to reduce IOP to the level of 4-7 mm Hg. Drug application to the periorbital dermis of ocular normotensive monkeys produced a similarly profound reduction in IOP, which was well maintained. Conclusions: PGN 9856-isopropyl ester appears to possess efficacy and duration of action properties unmatched by currently prescribed anti-glaucoma agents and by those currently undergoing clinical evaluation. In addition, application to the periorbital skin using a roller-ball device offers a more convenient method of ophthalmic drug delivery than eye drops and is noninvasive, unlike other ''dropless'' technologies.

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“…EP1AA induces apoptosis in breast cancer cells, inhibits the development of breast cancer (15) and suppresses colon cancer development in rats (16). EP2AA possesses the potential for treatment of glaucoma (17). PGE2, via EP4, stimulates anti-inflammation in the lung and provides a novel clinical perspective for chronic airway inflammatory conditions (18).…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin E2 promotes human CD34+ cells homing through EP2 and EP4 in vitro

Wang

Lai

Tang

et al. 2017

Molecular Medicine Reports

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Recently, certain studies have demonstrated in vitro that prostaglandin E2 (PGE2) promotes human cluster of differentiation (CD)34+ cell homing. However, the sub-type receptors activated by PGE2 are unknown, as the PGE2 receptor EP1-4 subtypes (EP1-4) are expressed on the membrane of human CD34+ cells. Based on the above, the present study aimed to screen the receptor subtype activity by PGE2 to promote human CD34+ cell homing. It was observed that human CD34+ cells expressed the four PGE2 sub-receptors, particularly EP2 and 4. PGE2 increased EP2 and 4 mRNA expression significantly, while EP1 and 3 mRNA exhibited no significant alteration. PGE2, EP2 agonist (EP2A), and EP4A upregulated C-X-C chemokine receptor 4 mRNA and protein expression in human CD34+ cells, and promoted stromal cell-derived factor 1α (SDF-1α) expression in bone marrow mesenchymal stem cells (BMMSCs). These phenomena were inhibited by the associated receptor antagonists. PGE2, EP2A, and EP4A facilitated human CD34+ cell migration towards SDF-1α and BMMSCs. The results of the present study suggested that PGE2 promoted human CD34+ cell homing through EP2 and 4 receptors in vitro.

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Investigation of Ocular Events Associated with Taprenepag Isopropyl, a Topical EP2 Agonist in Development for Treatment of Glaucoma

Abstract: The lack of in vivo or in vitro endothelial cytotoxicity and the reversibility of the increase in corneal thickness and iritis in the monkey provide confidence to permit further clinical development of taprenepag.

Cited by 13 publications

References 16 publications

Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma

Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma

A Highly Effective and Ultra-Long-Acting Anti-Glaucoma Drug, with a Novel Periorbital Delivery Method

Prostaglandin E2 promotes human CD34+ cells homing through EP2 and EP4 in vitro

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