The Discovery of N-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-((6- ((methylamino)methyl)pyrimidin-4-yl)oxy)-1H-indole-1-carboxamide (Acrizanib), a VEGFR-2 Inhibitor Specifically Designed for Topical Ocular Delivery, as a Therapy for Neovascular Age-Related Macular Degeneration

Adams, Christopher M.; Anderson, Karen; Artman, Gerald D.; Bizec, Jean-Claude; Cepeda, Rosemarie; Elliott, Jason; Fassbender, Elizabeth; Ghosh, Malay; Hanks, Shawn; Hardegger, Leo A.; Hosagrahara, Vinayak; Jaffee, Bruce; Jendza, Keith; Ji, Nan; Johnson, Leland; Lee, Wendy; Liu, Donglei; Liu, Fang; Long, Debby; Ma, Fupeng; Mainolfi, Nello; Meredith, Erik; Miranda, Karl; Yao, Peng; Poor, Stephen; Powers, James J.; Qiu, Yubin; Rao, Chang; Shen, Siyuan; Sivak, Jeremy M.; Solovay, Catherine; Tarsa, Peter B.; Woolfenden, Amber; Zhang, Chun; Zhang, Yiqin

doi:10.1021/acs.jmedchem.7b01731

Cited by 31 publications

(17 citation statements)

References 34 publications

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“…However, when it was later tested as a 10-mg/ml eye drop dosed four times daily for 12 weeks in patients with subfoveal CNV secondary to AMD, it did not decrease central retinal thickness ( 7 ). A very similar outcome was recently reported for acrizanib, a VEGF receptor-2 (VEGFR-2) inhibitor specifically designed for topical ocular delivery to treat neovascular AMD ( 8 ). The rodent CNV model (both mouse and rat) was used as the primary means of developing structure-activity relationships and screening VEGFR-2 inhibitors with potent in vitro activities for topical delivery.…”

Section: Introductionsupporting

confidence: 65%

Topical Drug Delivery to the Posterior Segment of the Eye: Addressing the Challenge of Preclinical to Clinical Translation

et al. 2018

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Topical delivery of therapeutics to the posterior segment of the eye remains the “holy grail” of ocular drug delivery. As an example, anti–vascular endothelial growth factor biologics, such as ranibizumab, aflibercept, and bevacizumab, are delivered by intravitreal injection to treat neovascular age-related macular degeneration and, although these drugs have revolutionized treatment of the disease, less invasive alternatives to intravitreal injection are desired. Multiple reports in the literature have demonstrated topical delivery of both small and large molecules to the back of the eye in small animal models. Despite this progress, successful translation to larger species, and ultimately humans, has yet to be demonstrated. Selection of animal models with relevant ocular anatomy and physiology, along with appropriate experimental design, is critical to enable more relevant feasibility assessments and increased probability of successful translation.

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Section: Introductionsupporting

confidence: 65%

Topical Drug Delivery to the Posterior Segment of the Eye: Addressing the Challenge of Preclinical to Clinical Translation

et al. 2018

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“…The limitations of current anti-VEGF-A therapies, such as treatment burden 10,11,[36][37][38][39] and ceiling effect, [40][41][42][43] in the management of nAMD has been highlighted by large real-world retrospective clinical studies. Topical delivery of several tyrosine kinase inhibitors, such as TG100801, 44 pazopanib, 45 regorafenib, 46 and acrizanib, 47 resulted in suboptimal clinical efficacy. More recently, IVT administered sustained release formulations of sunitinib and axitinib have shown preliminary efficacy and safety in phase I/IIa studies for the treatment of patients with nAMD.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Long-Lasting Potential of Suprachoroidal Axitinib Suspension Via Ocular and Systemic Disposition in Rabbits

Kansara

Muya

Ciulla

2021

Trans. Vis. Sci. Tech.

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Purpose Axitinib, a tyrosine kinase inhibitor, is a potent inhibitor of vascular endothelial growth factor (VEGF) receptors −1, −2 and −3. Suprachoroidal (SC) delivery of axitinib, combined with pan-VEGF inhibition activity of axitinib, has the potential to provide additional benefits compared to the current standard of care with intravitreal anti–VEGF-A agents. This study evaluated the ocular pharmacokinetics and systemic disposition of axitinib after SC administration in rabbits. Methods Rabbits received axitinib as either a single SC injection (0.03, 0.10, 1.00, or 4.00 mg/eye; n = 4/group) or a single intravitreal injection (1 mg/eye; n = 4/group) in three separate studies. Axitinib concentrations were measured in several ocular compartments and in plasma at predetermined timepoints for up to 91 days. The pharmacokinetics parameters were estimated by noncompartmental analysis. Results A single SC injection of axitinib suspension (1 mg/eye) resulted in an 11-fold higher mean axitinib exposure in the posterior eye cup, compared with intravitreal injection. Sustained levels of axitinib in the retinal pigment epithelium–choroid–sclera (RCS) and retina were observed throughout the duration of studies after a single SC axitinib injection (0.1 and 4.0 mg/eye), with low exposure in the vitreous humor, aqueous humor, and plasma. Axitinib levels in the RCS were 3 to 5 log orders higher than the reported in vitro (VEGF receptor–2 autophosphorylation inhibition) 50% inhibitory concentration value after 0.1 and 4.0 mg/eye dose levels throughout the 65-day and 91-day studies, respectively. Conclusions This study demonstrates that SC axitinib suspension has a favorable pharmacokinetics profile with potential as a long-acting therapeutic candidate targeted to affected choroid and retinal pigment epithelium in neovascular age-related macular degeneration. Translational Relevance Suprachoroidal axitinib suspension has potential to decrease the treatment burden in neovascular age-related macular degeneration, as a long-acting therapeutic candidate, and could yield greater efficacy, as a potent tyrosine kinase pan-VEGF inhibitor, compared with current standard anti-VEGF-A therapies.

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“…Acrizanib, a VEGFR2 inhibitor, showed impressive in vivo efficacy in the mouse CNV model, by leading to complete inhibition of neovascularization. Three times daily administration of 4 µL × 1.0% suspension/eye in the rat CNV model also resulted in 90% inhibition of neovascular area [106]. When investigated in a clinical trial Acrizanib failed to demonstrate efficacy, compared to anti-VEGF injections [115].…”

Section: Inhibitors Of Receptor Tyrosine Kinasesmentioning

confidence: 99%

Topical Drug Delivery to the Posterior Segment of the Eye

et al. 2022

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Topical drug delivery to the posterior segment of the eye is a very complex challenge. However, topical delivery is highly desired, to achieve an easy-to-use treatment option for retinal diseases. In this review, we focus on the drug characteristics that are relevant to succeed in this challenge. An overview on the ocular barriers that need to be overcome and some relevant animal models to study ocular pharmacokinetics are given. Furthermore, a summary of substances that were able to reach the posterior segment after eye drop application is provided, as well as an outline of investigated delivery systems to improve ocular drug delivery. Some promising results of substances delivered to the retina suggest that topical treatment of retinal diseases might be possible in the future, which warrants further research.

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The Discovery of N-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-((6- ((methylamino)methyl)pyrimidin-4-yl)oxy)-1H-indole-1-carboxamide (Acrizanib), a VEGFR-2 Inhibitor Specifically Designed for Topical Ocular Delivery, as a Therapy for Neovascular Age-Related Macular Degeneration

Cited by 31 publications

References 34 publications

Topical Drug Delivery to the Posterior Segment of the Eye: Addressing the Challenge of Preclinical to Clinical Translation

Topical Drug Delivery to the Posterior Segment of the Eye: Addressing the Challenge of Preclinical to Clinical Translation

Evaluation of Long-Lasting Potential of Suprachoroidal Axitinib Suspension Via Ocular and Systemic Disposition in Rabbits

Topical Drug Delivery to the Posterior Segment of the Eye

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