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Preclinical aspects of anti-VEGF agents for the treatment of wet AMD: ranibizumab and bevacizumab.

ABSTRACT: Three anti-vascular endothelial growth factor (VEGF) therapies are currently used for the treatment of patients with wet age-related macular degeneration (AMD): pegaptanib, ranibizumab, and bevacizumab. Ranibizumab is an antibody fragment approved for the treatment of wet AMD. Bevacizumab is a full-length antibody registered for use in oncology but unlicensed for wet AMD. However, it is used off-label worldwide not only for wet AMD but also for various other ocular diseases associated with macular edema and abnormal vessel growth. We consider aspects of ranibizumab and bevacizumab in relation to their molecular characteristics, in vitro and in vivo properties, and preclinical safety data. Before 2009, most studies described the short-term toxicity of bevacizumab in multiple cell types of the eye. Since 2009, an increasing number of studies have compared the properties of ranibizumab and bevacizumab and investigated their impact on retinal cell functioning. Compared with bevacizumab, ranibizumab neutralizes VEGF better at low concentrations, maintains efficacy for longer, and has a higher retinal penetration and potency. Studies in animals demonstrate ranibizumab to be better localized to the injected eye, whereas bevacizumab appears to have a greater effect in the fellow eye. In humans, a localized and systemic effect has been reported for both molecules. In conclusion, overlapping yet distinct pharmacological properties of ranibizumab and bevacizumab indicate that safety or efficacy data from one cannot be extrapolated to the other.

SUBMITTER: Meyer CH

PROVIDER: S-EPMC3178135 | biostudies-other | 2011 Jun

REPOSITORIES: biostudies-other

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Development of an inducible anti-VEGF rAAV gene therapy strategy for the treatment of wet AMD.

Project description:Vascular endothelial growth factor (VEGF) is a key mediator in the development and progression of choroidal neovascularization (CNV) in patients with wet age-related macular degeneration (AMD). As a consequence, current treatment strategies typically focus on the administration of anti-VEGF agents, such as Aflibercept (Eylea), that inhibit VEGF function. While this approach is largely successful at counteracting CNV progression, the treatment can require repetitive (i.e. monthly) intravitreal injections of the anti-VEGF agent throughout the patient's lifetime, imposing a substantial financial and medical burden on the patient. Moreover, repetitive injection of anti-VEGF agents over a period of years may encourage progression of retinal and choroidal atrophy in patients with AMD, leading to a decrease in visual acuity. Herein, we have developed a single-injection recombinant adeno-associated virus (rAAV)-based gene therapy treatment for wet AMD that prevents CNV formation through inducible over-expression of Eylea. First, we demonstrate that by incorporating riboswitch elements into the rAAV expression cassette allows protein expression levels to be modulated in vivo through oral supplementation on an activating ligand (e.g. tetracycline). We subsequently utilized this technology to modulate the intraocular concentration of Eylea following rAAV delivery, leading to nearly complete (p = 0.0008) inhibition of clinically significant CNV lesions in an established mouse model of wet AMD. The results shown in this study pave the way for the development of a personalized gene therapy strategy for the treatment of wet AMD that is substantially less invasive and more clinically adaptable than the current treatment paradigm of repetitive bolus injections of anti-VEGF agents.

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Project description:Data from real-world studies of ranibizumab in neovascular (wet) age-related macular degeneration suggest that outcomes in clinical practice fail to match those seen in clinical trials. These real-world studies follow treatment regimens that differ from the fixed dosing used in the pivotal clinical trial programme. To better understand the effectiveness of ranibizumab in clinical practice, we conducted a comprehensive evaluation of 12-month outcomes reported in peer-reviewed 'real-world' publications. Key measures included in our analysis were mean change in visual acuity (VA) and the proportion of patients gaining ?15 letters or losing ?15 letters. Twenty studies were eligible for inclusion in our study, with 18?358 eyes having sufficient data for analysis of 12-month outcomes. Mean baseline VA ranged from 48.8 to 61.6 Early Treatment Diabetic Retinopathy Study letters. Mean change in VA was between -2.0 and +5.5 letters, with a grand mean of +2.9±3.2, and a weighted mean (adjusted for the number of eyes in the study) of +1.95. Eleven studies reported that 19±7.5 (mean value) of patients gained ?15 letters, while in 12 studies the mean percentage of patient losing ?15 letters was 89±6.5%. Our comprehensive analysis of real-world ranibizumab study data confirm that patient outcomes are considerably poorer than those reported in randomised control trials of both fixed and pro re nata regimens.

| S-EPMC4763117 | biostudies-literature

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Pharmacogenetics of Complement Factor H Y402H Polymorphism and Treatment of Neovascular AMD with Anti-VEGF Agents: A Meta-Analysis.

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| S-EPMC4585967 | biostudies-literature

Evaluation of Aflibercept Treatment Responses in Eyes with Bevacizumab/Ranibizumab-resistant Wet Age-related Macular Degeneration.

Project description:To evaluate anatomic and functional results after switching from intravitreal bevacizumab or ranibizumab treatment to aflibercept for wet (neovascular) age-related macular degeneration.This retrospective study included 22 eyes of 22 patients resistant to treatment with at least 6 injections of bevacizumab or ranibizumab. The first three injections had been applied monthly, the others pro re nata (PRN). Outcome measures were follow-up period, injection number, best corrected visual acuity (BCVA), central retinal thickness (CRT) and pigment epithelial detachment (PED) height. Dosing regimen of aflibercept was determined PRN. The patients were examined monthly. In all visits, BCVA and optical coherence tomography results were assessed together and injections were applied according to these findings. Patients with at least three months of follow-up were included in the study.Twenty-two eyes of 22 patients treated with bevacizumab or ranibizumab were switched to aflibercept therapy. Seven patients had serous PED and 4 patients had fibrovascular PED. The mean follow-up periods for these groups were 20.59±6.76 months and 8.68±3.79 months, respectively. The mean injection numbers were 10.5±3.61 vs 4.54±1.56. Statistically significant reductions were noted in CRT (533.86±164.06 µm vs 412.04±143.86 µm, p<0.05). BCVA levels were almost equal before and after switching (0.18±0.17 vs 0.18±0.14). Serous and fibrovascular PED heights decreased suboptimally from 460±281.51 µm to 282.42±175.76 µm (p>0.05) for serous PEDs and 251.25±43.85 µm to 225.75±73.09 µm (p>0.05) for fibrovascular PEDs.Switching to aflibercept resulted in significant improvement in CRT, but not in BCVA or PED heights.

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Project description:Inhibition of vascular endothelial growth factor is the mode of action for several approved therapies, including aflibercept, for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Lack of compliance due to the frequent intravitreal dosing requirements may result in inadequately treated disease, leading to irreversible vision impairment. To date, the majority of gene therapy clinical trials providing sustained anti-VEGF levels in the retina have been limited to subretinal injections requiring a vitrectomy. A single intravitreal injection of a gene therapy product could drastically reduce the treatment burden and improve visual outcomes. ADVM-022, an adeno-associated virus vector encoding aflibercept, has been optimized for intravitreal delivery and strong protein expression. Long-term expression and efficacy of ADVM-022-derived aflibercept were evaluated in a laser-induced choroidal neovascularization (CNV) model in non-human primates. Ocular safety was evaluated following long-term suppression of VEGF by clinical scoring (inflammatory parameters) as well as optical coherence tomography (OCT) and electroretinography (ERG). Intravitreal administration of ADVM-022 was well tolerated and resulted in sustained aflibercept levels in ocular tissues. In addition, ADVM-022 administration 13 months before laser-induced CNV prevented the occurrence of clinically relevant CNV lesions, to the same degree as a bolus of aflibercept delivered at the time of laser. These results demonstrate that a single intravitreal administration of ADVM-022 may provide a safe and effective long-term treatment option for nAMD and DME, and may ultimately improve patients' visual outcomes. Clinical trials are currently underway, evaluating safety and efficacy following a single intravitreal injection of ADVM-022.

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Project description:Data comparing systemic exposure and systemic vascular endothelial growth factor (VEGF) suppression of ranibizumab, bevacizumab and aflibercept following intravitreal injection are lacking.Fifty-six patients with wet age-related macular degeneration received intravitreal ranibizumab (0.5?mg), bevacizumab (1.25?mg), or aflibercept (2.0?mg). Serum pharmacokinetics and plasma free VEGF were evaluated after the first and third injections.Following the first dose, systemic exposure to aflibercept was 5-, 37-, and 9-fold higher than ranibizumab, whereas, bevacizumab was 9-, 310-, and 35-fold higher than ranibizumab, based on geometric mean ratio of peak and trough concentrations and area under the curve, respectively. The third dose showed accumulation of bevacizumab and aflibercept but not ranibizumab. Aflibercept substantially suppressed plasma free VEGF, with mean levels below lower limit of quantitation (10?pg/mL) as early as 3?h postdose until ?7?days postdose. Mean free (unbound) VEGF levels with ranibizumab were largely unchanged, with mean trough level of 14.4?pg/mL compared with baseline of 17?pg/mL.There are notable differences in systemic pharmacokinetics and pharmacodynamics among anti-VEGF treatments after intravitreal administration. All three agents rapidly moved into the bloodstream, but ranibizumab very quickly cleared, whereas bevacizumab and aflibercept demonstrated greater systemic exposure and produced a marked reduction in plasma free VEGF.NCT02118831.

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Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab.

Project description: Not available

| S-EPMC3338918 | biostudies-literature

VEGF-R2/Caveolin-1 Pathway of Undifferentiated ARPE-19 Retina Cells: A Potential Target as Anti-VEGF-A Therapy in Wet AMD by Resvega, an Omega-3/Polyphenol Combination.

Project description:Age-related macular degeneration (AMD) is one of the main causes of deterioration in vision in adults aged 55 and older. In spite of therapies, the progression of the disease is often observed without reverse vision quality. In the present study, we explored whether, in undifferentiated ARPE-19 retinal cells, a disruption of the VEGF receptors (VEGF-R)/caveolin-1 (Cav-1)/protein kinases pathway could be a target for counteracting VEGF secretion. We highlight that Resvega®, a combination of omega-3 fatty acids with an antioxidant, resveratrol, inhibits VEGF-A secretion in vitro by disrupting the dissociation of the VEGF-R2/Cav-1 complex into rafts and subsequently preventing MAPK activation. Moreover, DNA ChIP analysis reveals that this combination prevents the interaction between AP-1 and vegf-a and vegf-r2 gene promoters. By these pathways, Resvega could present a potential interest as nutritional complementation against AMD.

| S-EPMC8234996 | biostudies-literature

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