A Phase 1 Study of Intravitreous E10030 in Combination with Ranibizumab in Neovascular Age-Related Macular Degeneration

Jaffe, Glenn J.; Eliott, Dean; Wells, John A.; Prenner, Jonathan L.; Papp, András; Patel, Sudi

doi:10.1016/j.ophtha.2015.09.004

Cited by 83 publications

(40 citation statements)

References 26 publications

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“…There are several alternative antiangiogenic ocular drugs under development. Fovista (E10030; Ophthotech, New York, NY), 36 CrossMAb (RG7716; Roche, Basel, Switzerland), 28 Conbercept (KH902; Chengdu Kanghong Biotech Co, Ltd, Sichuan, China), 37 Pazopanib (GW786034; GlaxoSmithKline, Research Triangle Park, NC), 38 AdPEDF (GenVec, Inc, Gaithersburg, MD), 39 and many others are showing interesting outcomes. In the future, we likely will have a combination of angiogenesis inhibitors, or a more effective one, that concurrently addresses various vasogenic mediators and pathways.…”

Section: Discussionmentioning

confidence: 99%

Bevacizumab Injection in Patients with Neovascular Age-Related Macular Degeneration Increases Angiogenic Biomarkers

Cabral

Lima

Mello

et al. 2018

Ophthalmology Retina

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Purpose To evaluate the expression of 19 angiogenic biomarkers in the aqueous humor before and after intravitreal bevacizumab injection (IVB) in eyes with neovascular age-related macular degeneration (AMD). Design Prospective, noncomparative, interventional case series. Participants Twenty-three eyes of 23 treatment-naïve patients with choroidal neovascularization (CNV) secondary to neovascular AMD. Methods Eyes were diagnosed with CNV secondary to neovascular AMD and were treated with 3 monthly IVBs. Aqueous humor samples were obtained by anterior chamber paracentesis at baseline and immediately before each intravitreal bevacizumab injection. Main Outcome Measures Aqueous humor levels of 19 angiogenic biomarkers (angiopoietin 2, bone morphogenetic protein 9 [BMP-9], epidermal growth factor [EGF], endoglin, endothelin 1, fibroblast growth factor [FGF]-1 and FGF-2, follistatin, granulocyte colony-stimulating factor [GCSF], heparin-binding EGF-like growth factor [HB-EGF], hepatocyte growth factor [HGF], interleukin 8, leptin, placental growth factor [PLGF], vascular endothelial growth factor [VEGF]-A, VEGF-C, VEGF-D, and tissue inhibitor of metalloproteinases [TIMP]-1 and TIMP-2) were measured. Best-corrected visual acuity (BCVA), spectral-domain OCT parameters, and intraocular pressure also were evaluated. Results Baseline aqueous VEGF-A expression was elevated in all study eyes before treatment initiation. A statistically significant decrease of VEGF-A was observed at the 1- and 2-month follow-ups. A statistically significant increased concentration was observed in 7 biomarkers: VEGF-C, angiopoietin 2, endothelin 1, follistatin, HB-EGF, HGF, and interleukin 8. The other 11 study biomarker levels (VEGF-D, BMP-9, EGF, endoglin, FGF-1, FGF-2, GCSF, leptin, PLGF, TIMP-1, and TIMP-2) did not show any significant difference during follow-up. The BCVA statistically improved significantly at 2 months. Spectral-domain OCT parameters improved significantly at all follow-ups. Mean intraocular pressure values were not statistically different during the study period. Conclusions Despite a decrease in VEGF-A, the aqueous levels of VEGF-C, angiopoietin 2, endothelin 1, follistatin, HB-EGF, HGF, and interleukin 8 increased significantly after intravitreal injection of bevacizumab. These upregulated angiogenic biomarkers may represent new therapeutic targets in exudative AMD.

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Section: Discussionmentioning

confidence: 99%

Bevacizumab Injection in Patients with Neovascular Age-Related Macular Degeneration Increases Angiogenic Biomarkers

Cabral

Lima

Mello

et al. 2018

Ophthalmology Retina

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“…AXT107 also reduces ligand-induced phosphorylation of c-Met and PDGFRβ, which may also contribute. Combined neutralization of VEGF and PDGF-BB results in significantly greater suppression of murine choroidal NV and regression of choroidal NV with superior vision outcomes in patients with NVAMD than suppression of VEGF alone ( 45–47 ). Because AXT107 inhibits both VEGFR2 and PDGFRβ signaling and causes regression of choroidal NV, similar superior outcomes in NVAMD as those seen with combination therapy might be expected with injection of a single small peptide.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine kinase blocking collagen IV–derived peptide suppresses ocular neovascularization and vascular leakage

et al. 2017

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Vascular endothelial growth factor (VEGF)–neutralizing proteins provide benefit in several retinal and choroidal vascular diseases, but some patients still experience suboptimal outcomes, and the need for frequent intraocular injections is a barrier to good outcomes. A mimetic peptide derived from collagen IV, AXT107, suppressed subretinal neovascularization (NV) in two mouse models predictive of effects in neovascular age-related macular degeneration (NVAMD) and inhibited retinal NV in a model predictive of effects in ischemic retinopathies. A combination of AXT107 and the current treatment aflibercept suppressed subretinal NV better than either agent alone. Furthermore, AXT107 caused regression of choroidal NV. AXT107 reduced the VEGF-induced vascular leakage that underlies macular edema in ischemic retinopathies and NVAMD. In rabbit eyes, which are closer to the size of human eyes, intraocular injection of AXT107 significantly reduced VEGF-induced vascular leakage by 86% at 1 month and 70% at 2 months; aflibercept significantly reduced leakage by 69% at 1 month and did not reduce leakage at 2 months, demonstrating the longer effectiveness of AXT107. AXT107 reduced ligand-induced phosphorylation of multiple receptors: VEGFR2, c-Met, and PDGFRβ. Optimal signaling through these receptors requires complex formation with β3 integrin, which was reduced by AXT107 binding to αvβ3. AXT107 also reduced total VEGFR2 levels by increasing internalization, ubiquitination, and degradation. This biomimetic peptide is a sustained, multitargeted therapy that may provide advantages over intraocular injections of specific VEGF-neutralizing proteins.

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“…Notably, preliminary data from ongoing clinical trials have been reported to show beneficial additive effects of fovista treatment in combination with antieVEGF-A therapies in patients with neovascular AMD. 12,15 …”

Section: Discussionmentioning

confidence: 99%

Targeting Platelet-Derived Growth Factor Receptor β+ Scaffold Formation Inhibits Choroidal Neovascularization

Strittmatter

Pomeroy

Marneros

2016

The American Journal of Pathology

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Neovascular age-related macular degeneration is among the most common causes of irreversible blindness and manifests with choroidal neovascularization (CNV). Anti-vascular endothelial growth factor-A therapies are only partially effective and their chronic administration may impair functions of the choriocapillaris and retina. Thus, novel therapeutic targets are needed urgently. We have observed in a laser-induced model of CNV that a platelet-derived growth factor receptor β positive (PDGFRβ(+)) scaffold is formed before infiltration of neovessels into this scaffold to form CNV lesions, and that this scaffold limits the extent of neovascularization. Based on these observations we hypothesized that ablation of proliferating PDGFRβ(+) cells to prevent the formation of this scaffold might inhibit CNV growth and present a novel therapeutic approach for neovascular age-related macular degeneration. To test this hypothesis we targeted proliferating PDGFRβ(+) cells through independent distinct approaches after laser injury: i) by using an inducible genetic model to inhibit specifically proliferating PDGFRβ(+) cells, ii) by treating mice with a neutralizing anti-PDGFRβ antibody, iii) by administering an anti-PDGF-AB/BB aptamer, and iv) by using small chemical inhibitor approaches. The results show that therapeutic targeting of proliferating PDGFRβ(+) cells potently inhibits the formation of the pericyte-like scaffold, with concomitant attenuation of CNV. Moreover, we show that early inhibition of PDGFRβ(+) cell proliferation before neovessel formation is sufficient to inhibit scaffold formation and neovascularization.

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A Phase 1 Study of Intravitreous E10030 in Combination with Ranibizumab in Neovascular Age-Related Macular Degeneration

Cited by 83 publications

References 26 publications

Bevacizumab Injection in Patients with Neovascular Age-Related Macular Degeneration Increases Angiogenic Biomarkers

Bevacizumab Injection in Patients with Neovascular Age-Related Macular Degeneration Increases Angiogenic Biomarkers

Tyrosine kinase blocking collagen IV–derived peptide suppresses ocular neovascularization and vascular leakage

Targeting Platelet-Derived Growth Factor Receptor β+ Scaffold Formation Inhibits Choroidal Neovascularization

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