Pharmacokinetics,pharmacodynamics and pre-clinical characteristics of ophthalmic drugs that bind VEGF

Drugs that prevent the binding of VEGF to its trans-membrane cognate receptors have revolutionized the treatment of the most important chorioretinal vascular disorders: exudative age-related macular degeneration, diabetic macular edema, and retinal vein occlusions. Pegaptanib, which binds to VEGF₁₆₅ and longer isoforms, ranibizumab and bevacizumab, which bind all VEGF-A isoforms, and aflibercept, which binds VEGF-A, VEGF-B, and placental growth factor, all bind VEGF₁₆₅ with high affinity. The drugs have relatively long half-lives (7 to 10 days) after intravitreal depot injections and clinical durations of action that usually exceed 4 weeks. Plasma VEGF concentrations decrease after intravitreal injections of bevacizumab and aflibercept because their systemic half-lives are extended by their Fc fragments. Extensive in vitro and in vivo testing shows that the drugs prevent VEGF-mediated activation of endothelial cells while exhibiting little evidence of toxicity. Further anti-VEGF drug development is on-going.     

Pharmacogenetics of antiangiogenic and antineovascular therapies of age-related macular degeneration

Age-related macular degeneration (AMD), the most common age-related disease causing irreversible visual loss in industrialized countries, is a complex and multifactorial illness. Researchers have found components of the complement alternative pathway inside drusen and Bruch's membrane of AMD patients, underlying a possible important role of complement factor H in the pathogenesis of AMD. The neovascular (wet) AMD is the most destructive form and it is characterized by invasion of new blood vessels into subretinal spaces with subsequent exudation and bleeding, resulting in scarring of the macular region and loss of the central vision. The hallmark of the neovascular form is the choroidal neovascularization, where VEGF-A has an important role in the pathogenesis of the disease. SNPs of these genes have recently been investigated as potential pharmacogenetic markers of the antiangiogenic and antineovascular therapy of AMD, which includes verteporfin photodynamic therapy and anti-VEGF-A drugs, such as pegaptanib, bevacizumab and ranibizumab. The CFH rs1061170 CT and TT genotypes have been associated with an improvement of visual acuity in bevacizumab or ranibizumab treated patients, whereas patients harboring VEGF-A rs699946 G allele responded better to bevacizumab-based therapy if compared with patients carrying the A allele. In conclusion, the discovery of pharmacogenetic markers for the personalization of the antiangiogenic and/or antineovascular therapy could be, in the future, a key issue in ophthalmology to obtain a personalization of the therapy and to avoid unnecessary costs and adverse drug reactions.     

Aflibercept (VEGF-TRAP): the next anti-VEGF drug

The inflammatory cytokine, vascular endothelial growth factor (VEGF), plays a central role in human growth and development, and vascular maintenance. VEGF mediated angiogenesis is essential for tumor growth, as well as exudative age-related macular degeneration, proliferative diabetic retinopathy and retinopathy of prematurity, all of which are characterized by abnormal neovascularization. Ischemia and inflammation also lead to VEGF-mediated breakdown of the blood-retinal barrier, which causes vision diminishing macular edema. To combat these effects, anti-VEGF drugs (antibodies, aptamers, and tyrosine kinase inhibitors) have been developed for both systemic and local (intraocular) use. The next drug to receive regulatory approval will probably be aflibercept (VEGF-Trap), a fusion protein with high VEGF affinity attributed to binding sequences from the native receptors VEGFR1 and VEGFR2. Aflibercept monotherapy significantly reduces tumor growth and extends survival in several orthotropic animal models, and has both prevented and reduced the growth of experimental choroidal neovascularization. Ongoing phase III trials are evaluating the effectiveness of aflibercept combined with chemotherapy in patients with advanced carcinomas. The phase III VELOUR trial determined that patients receiving aflibercept with irinotecan/5-FU as second line chemotherapy for metastatic colorectal cancer experienced extended progression free survival and overall survival. Intravitreal aflibercept improved visual acuity in patients with exudative age-related macular degeneration and was non-inferior to standard therapy (ranibizumab). Ongoing phase III trials are investigating the use of aflibercept for retinal vein occlusions and diabetic macular edema. A regulatory approval application for use in exudative macular degeneration has been filed, with a decision expected by late 2011.     

Neovascular age-related macular degeneration: potential therapies

Age-related macular degeneration (AMD) affects an estimated 14 million people worldwide, and is the leading cause of severe, irreversible vision loss in individuals over the age of 50 years in Western societies. Choroidal neovascularization (CNV), the hallmark of 'wet', 'exudative' or 'neovascular' AMD, is responsible for approximately 90% of cases of severe vision loss due to AMD. Vascular endothelial growth factor (VEGF) has been shown to play a key role in the regulation of CNV and vascular permeability. Ranibizumab, the current gold standard in the US for the treatment of neovascular AMD, exerts its effect through binding and inhibition of all isoforms of VEGF. Randomized controlled clinical trials have established ranibizumab as the first US FDA-approved therapy for neovascular AMD to result in improvement in visual acuity. Despite impressive outcomes, treatment with ranibizumab requires sustained treatment regimens and frequent intravitreal injections. In this review, we discuss promising emerging therapies for neovascular AMD that aim to improve outcomes, safety and treatment burden through novel mechanisms of action. Currently in phase III clinical trials, VEGF Trap is a receptor decoy that targets VEGF with higher affinity than ranibizumab and other currently available anti-VEGF agents. Another promising therapeutic strategy is the blockade of VEGF effects by inhibition of the tyrosine kinase cascade downstream from the VEGF receptor; such therapies currently in development include vatalanib, TG100801, pazopanib, AG013958 and AL39324. Small interfering RNA technology-based therapies have been designed to downregulate the production of VEGF (bevasiranib) or VEGF receptors (AGN211745) by degradation of specific messenger RNA. Other potential therapies include pigment epithelium-derived factor-based therapies, nicotinic acetylcholine receptor antagonists, integrin antagonists and sirolimus.     

Ranibizumab: the evidence of its therapeutic value in neovascular age-related macular degeneration

INTRODUCTION: Neovascular age-related macular degeneration (AMD) is the leading cause of severe, irreversible visual impairment in people over 60 years of age. Neovascular AMD is characterized by abnormal growth of blood vessels under the retina, specifically the macula. These vessels leak blood and fluids, damaging the retina and its photoreceptors, resulting in permanent loss of central vision. Vascular endothelial growth factor-A (VEGF-A) has been shown to play a critical role in the pathogenesis of neovascular AMD. In the US, ranibizumab, a VEGF-A blocker, is approved and indicated for the treatment of patients with neovascular AMD. AIMS: To review the clinical evidence for ranibizumab in the treatment of neovascular AMD. EVIDENCE REVIEW: Phase III clinical trial data have established ranibizumab as a safe and well-tolerated treatment for neovascular AMD. Monthly intravitreal injections of ranibizumab result in a statistically significantly greater proportion of patients losing <15 letters of visual acuity (VA) and statistically significant increases in the mean number of letters gained compared with controls. Anatomically, ranibizumab results in stabilization in the mean area of choroidal neovascularization (CNV) and statistically significant reductions in the mean area of leakage compared with controls. Although there is limited economic evidence available, ranibizumab therapy for neovascular AMD appears to deliver a significant degree of value gain in terms of quality of life when compared with other neovascular AMD interventions. PLACE IN THERAPY: Clinical evidence establishes ranibizumab as a first-line therapy option for virtually all treatable neovascular AMD patients. Updating neovascular AMD treatment guidelines to reflect the evidence base for ranibizumab as a preferred first-line therapy would be beneficial for physicians in making informed treatment choices and ultimately helping to ensure the best care for patients.     

Intraocular Sustained-Release Delivery Systems for Triamcinolone Acetonide

Recently, the use of triamcinolone acetonide (TA) injection has increased dramatically in treatment for several ocular diseases. Among them, macular diseases such as macular edema due to diabetic retinopathy, venous occlusive diseases, ocular inflammation and age-related macular degeneration (AMD) are very common vision threatening disorders and are great challenges to treat. In these types of chronic retinal diseases, repeated intraocular injections of TA are often required which increases the likelihood of complications. In order to achieve sustained-release, maintain therapeutic levels of TA over longer times and reduce frequency of intravitreal injections, researchers are investigating different implantable devices or injectable systems. However, as of yet, there is no sustained-release product for TA available on the commercial market. This review discusses and compares different sustained-release devices or injectable systems that are currently being developed. Supported by the Discovery Eye Foundation, Henry L. Guenther Foundation, Iris and B. Gerald Cantor Foundation and the Research to Prevent Blindness Foundation.     

Aflibercept for the treatment of neovascular age-related macular degeneration

Age-related macular degeneration (AMD) can have devastating effects on vision, especially in its neovascular form. In the last decade, the use of intravitreal pharmacotherapy targeted to vascular endothelial growth factor (VEGF) has significantly improved the visual outcomes in patients with neovascular AMD. Although we have become accustomed to these unprecedented improvement outcomes, maintaining good visual results with anti-VEGF therapy requires tremendous effort, time and cost, typically involving monthly clinic visits and intravitreal injections. The introduction of aflibercept, an anti-VEGF drug that targets all isoforms of VEGF as well as placenta growth factor, has shown promise throughout recent clinical trials as an equally effective treatment for neovascular AMD that requires less frequent dosing than either ranibizumab or bevacizumab. Based on clinical trial results, the U.S. Food and Drug Administration approved aflibercept in November 2011 for use in neovascular AMD, giving patients the hope of alleviating some of the burden associated with treatment.     

Anti-angiogenesis drugs in diabetic retinopathy

The vascular endothelial growth factor (VEGF) plays a key role in the development of proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME), resulting in a significant visual loss among patients with diabetes mellitus. Systemic VEGF-A and the interplay between membrane-bound VEGF receptors and VEGF-R1 (soluble form) are key to angiogenesis and vasculogenesis. Furthermore, patients with diabetes have a higher risk of hypertension and proteinuria, two surrogate markers of systemic VEGF inhibition. Pegaptanib, ranibizumab, bevacizumab and roboxistaurin are the currently available anti-VEGF agents. Agents with activity occurring later down the angiogenic pathway and those drugs with potential to synergize with anti-VEGF-A technologies are being developed. In recent years, inhibition of ocular VEGF has emerged as a promising treatment modality for diabetes and is currently undergoing evaluation in clinical trials. A potential role for these anti-VEGF agents in the prevention of PDR and DME are also emerging.     

Ranibizumab and diabetic macular oedema: after laser therapy

Diabetic retinopathy is sometimes accompanied by macular oedema, leading to a marked decline in visual acuity. The standard treatment, in addition to glycaemic and blood pressure control, is laser photocoagulation, despite its modest efficacy. Ranibizumab (Lucentis, Novartis), a VEGF (vascular endothelial growth factor) inhibitor, was initially authorised for age-related macular degeneration (AMD) in the European Union. It is now also approved for the treatment of visual loss due to macular oedema in diabetic patients. In this setting, clinical evaluation of ranibizumab is mainly based on two double-blind randomised trials comparing ranibizumab + laser photocoagulation versus placebo + laser photo-coagulation in a total of about 1000 patients. Compared with placebo, addition of ranibizumab to laser therapy led to a marked improvement in visual acuity in approximately 15% of patients after 12 months of treatment. The improvement appeared to persist after 24 months of treatment. In a trial that included a group treated with ranibizumab alone, efficacy did not differ from that of the ranibizumab + laser combination. Uncertainties remain concerning the long-term efficacy of ranibizumab and its benefits in patients with poorly controlled diabetes or proliferative retinopathy. The adverse effect profile of ranibizumab in patients with diabetic macular oedema is similar to that reported in patients with AMD, and mainly includes ocular adverse effects such as pain, bleeding and increased intraocular pressure. A risk of systemic adverse effects, particularly cardiovascular disorders, should be kept in mind in case of long-term treatment. Ranibizumab can cause birth defects, even after intravitreal injection during pregnancy. Monthly treatment with ranibizumab is inconvenient, difficult and expensive. In practice, laser therapy remains the standard treatment for diabetic patients with significantly reduced visual acuity due to macular oedema. Ranibizumab, which requires intravitreal injections, should be restricted to second-line use.     

Aflibercept (VEGF Trap-Eye) for the treatment of exudative age-related macular degeneration

Aflibercept, a soluble receptor molecule that binds VEGF, has been recently approved for the treatment of exudative age-related macular degeneration. This fusion protein with binding sequences from VEGF receptors 1 and 2 possesses high binding affinity for isomers of VEGF-A, VEGF-B and PlGF, and prevents VEGF from initiating proliferation and migration of vascular endothelial cells. Phase III trials showed that intravitreal aflibercept given monthly or every 2 months produces visual improvement and decrease in macular thickness comparable with monthly ranibizumab. The second year of the trials demonstrated that as-needed aflibercept maintained vision with few required injections. Aflibercept promises to decrease the treatment burden faced by patients with exudative age-related macular degeneration.     

Antineovascular agents in the treatment of eye diseases

Neovascularization is a common and potentially visually threatening complication of eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). An antiangiogenic therapy is aimed at inhibiting the growth of new blood vessels and should prevent onset or progression of neovascularization. Accumulated evidence indicates that growth factors, endothelial cell surface receptors, and extracellular matrix (ECM) proteins are major mediators of neovascularization and appealing targets for pharmacotherapeutical intervention. Vascular endothelial growth factor (VEGF) plays a critical role in the pathogenesis of retinal neovascularization (in linking tissue ischemia to angiogenesis), and is likely to contribute also significantly to choroidal neovascularization (CNV). Several antineovascular agents antagonize the function of VEGF, by blocking its proangiogenic activity. Indeed, VEGF targeting or disruption of VEGF signalling is the most effective strategy known so far in the pharmacological treatment of ocular neovascularization. Other compounds such as pigment epithelium-derived factor (PEDF) either aim at balancing the levels of pro-angiogenic and angiostatic molecules, target inflammation (cyclooxygenase inhibitors, steroids) or comprise modifiers of the ECM such as inhibitors of matrix metalloproteinases (MMPs) and agents that block the action of integrins. Vascular targeting agents (combretastatin) promote removal of newly formed vessels. This review provides an update on recent investigations directed at the pharmacotherapeutical management of ocular neovascular diseases, placing special emphasis on the underlying target molecules and relevant intracellular signalling pathways.     

Ranibizumab: the evidence of its therapeutic value in neovascular age-related macular degeneration

Introduction:

Neovascular age-related macular degeneration (AMD) is the leading cause of severe, irreversible visual impairment in people over 60 years of age. Neovascular AMD is characterized by abnormal growth of blood vessels under the retina, specifically the macula. These vessels leak blood and fluids, damaging the retina and its photoreceptors, resulting in permanent loss of central vision. Vascular endothelial growth factor-A (VEGF-A) has been shown to play a critical role in the pathogenesis of neovascular AMD. In the US, ranibizumab, a VEGF-A blocker, is approved and indicated for the treatment of patients with neovascular AMD.

Aims:

To review the clinical evidence for ranibizumab in the treatment of neovascular AMD.

Evidence review:

Phase III clinical trial data have established ranibizumab as a safe and well-tolerated treatment for neovascular AMD. Monthly intravitreal injections of ranibizumab result in a statistically significantly greater proportion of patients losing <15 letters of visual acuity (VA) and statistically significant increases in the mean number of letters gained compared with controls. Anatomically, ranibizumab results in stabilization in the mean area of choroidal neovascularization (CNV) and statistically significant reductions in the mean area of leakage compared with controls. Although there is limited economic evidence available, ranibizumab therapy for neovascular AMD appears to deliver a significant degree of value gain in terms of quality of life when compared with other neovascular AMD interventions.

Place in therapy:

Clinical evidence establishes ranibizumab as a first-line therapy option for virtually all treatable neovascular AMD patients. Updating neovascular AMD treatment guidelines to reflect the evidence base for ranibizumab as a preferred first-line therapy would be beneficial for physicians in making informed treatment choices and ultimately helping to ensure the best care for patients.     

VEGF Trap-Eye for the treatment of neovascular age-related macular degeneration

Background: Age-related macular degeneration (AMD) affects > 14 million individuals worldwide. Although 90% of patients with AMD have the dry form, neovascular AMD accounts for the vast majority of patients who develop legal blindness. Until recently, few treatment options existed for treatment of neovascular AMD. The advent of anti-VEGF therapy has significantly improved the safe and effective treatment of neovascular AMD. In addition to two anti-VEGF drugs currently in widespread use, ranibizumab and bevacizumab, a number of medications that interrupt angiogenesis are currently under investigation. One promising new drug is aflibercept (VEGF Trap-Eye), a fusion protein that blocks all isoforms of VEGF-A and placental growth factors-1 and -2. Objective: To review the current literature and clinical trial data regarding VEGF Trap-Eye for the treatment of neovascular AMD. Methods: Literature review. Results/conclusion: VEGF Trap-Eye is a novel anti-VEGF therapy, with Phase I and II trial data indicating safety, tolerability and efficacy for the treatment of neovascular AMD. Two Phase III clinical trials (VIEW-1 and VIEW-2) comparing VEGF Trap-Eye to ranibizumab are currently continuing and will provide vital insight into the clinical applicability of this drug.     

Blockade of nitric-oxide synthase reduces choroidal neovascularization

Nitric oxide (NO) promotes retinal and choroidal neovascularization, although different isoforms of nitric-oxide synthetase (NOS) are critical in each. Deficiency of endothelial NOS (eNOS) suppresses retinal but not choroidal neovascularization, whereas deficiency of neuronal NOS (nNOS) or inducible NOS (iNOS) suppresses choroidal, but not retinal neovascularization. In this study, we investigated the effect of N(G)-monomethyl-L-arginine (L-NMMA), a nonspecific NOS inhibitor, in three models of ocular neovascularization. Oral administration of L-NMMA caused significant inhibition of choroidal neovascularization in mice with laser-induced rupture of Bruch's membrane and significantly inhibited subretinal neovascularization in transgenic mice with expression of vascular endothelial growth factor (VEGF) in photoreceptors (rho/VEGF mice) but did not inhibit retinal neovascularization in mice with ischemic retinopathy. By extensive mating among mice deficient in NOS isoforms, triple homozygous mutant mice deficient in all three NOS isoforms were produced. These mice had marked suppression of choroidal neovascularization at sites of rupture of Bruch's membrane and near-complete suppression of subretinal neovascularization in rho/VEGF mice but showed no difference in ischemia-induced retinal neovascularization compared with wild-type mice. These data indicate that NO is an important stimulator of choroidal neovascularization and that reduction of NO by pharmacologic or genetic means is a good treatment strategy. However, the situation is more complex for ischemia-induced retinal neovascularization for which NO produced in endothelial cells by eNOS is stimulatory, but NO produced in other retinal cells by iNOS and/or nNOS is inhibitory. Selective inhibitors of eNOS may be needed for treatment of retinal neovascularization.     

Therapeutic anti-VEGF antibodies

Vascular endothelial growth factor (VEGF-A) is a key cytokine in the development of normal blood vessels as well as the development of vessels in tumors and other tissues undergoing abnormal angiogenesis. Here, we review the molecular engineering of two humanized antibodies derived from a common mouse anti-VEGF antibody--bevacizumab, a full-length IgG1 approved for the treatment of specified cancer indications, and ranibizumab, an affinity-matured antibody Fab domain approved for use in age-related macular degeneration (AMD). In clinical trials and as FDA-approved therapeutics, these two anti-VEGF antibodies, bevacizumab (Avastin anti-VEGF antibody) and ranibizumab (Lucentis anti-VEGF antibody), have demonstrated therapeutic utility in blocking VEGF-induced angiogenesis.     

Anti-VEGF compounds in the treatment of neovascular age related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness among elderly patients in developed countries. Although the pathogenesis of AMD is still largely unknown, it is now well known that vascular endothelial growth factor (VEGF) plays a pivotal role in the growth of the abnormal blood vessels (i.e. choroidal neovascularization, CNV) which characterizes the "wet form" of this ocular disease. Therefore, inhibiting VEGF has turned out to be a good way of more effectively controlling neovascular AMD. VEGF is a heparin-binding glycoprotein with potent angiogenic, mitogenic and vascular permeability-enhancing activities specific for endothelial cells. Currently two anti-VEGF compounds have been approved by the US Food and Drug Administration (FDA) for the treatment of neovascular AMD: pegaptanib and ranibizumab. Off-label usage of bevacizumab, an anti-VEGF agent similar to ranibizumab, has also become fairly common. The substantial improvement of visual acuity noticed in patients treated with ranibizumab has made this drug the gold standard for AMD therapy. However, as with many new therapies, there are unresolved issues, including safety, cost, and dosing frequency. This review describes in details the properties and efficacy of the three anti-VEGF agents in use in clinical practice. Promising emerging anti-VEGF strategies (VEGF-trap, small interfering RNA, tyrosine kinase inhibitors) which aim to improve outcomes, safety and treatment burden through novel mechanisms of action are also discussed.     

Emerging treatments for wet age-related macular degeneration

Introduction: Wet or exudative age-related macular degeneration (AMD) is the leading cause of blindness in the United States for individuals over the age of 65 years. Wet AMD is characterized by the formation of choroidal neovascularization, which can lead to edema, hemorrhage and scarring of the macula. This leads to metamorphopsia and vision loss. Without treatment, the loss of vision is permanent. The current gold standard treatment of wet AMD consists of intravitreal injections of anti-vascular endothelial growth factor (VEGF) medications.

Areas covered: Numerous new therapies in the drug pipeline aim at addressing limitations of current treatments. Future therapies involve novel compounds that attack different parts of the VEGF cascade, novel delivery systems aimed at reducing the frequency of intraocular injections, combination therapies and the use of radiation in conjunction with intravitreal therapies.

Expert opinion: Limitations of current treatments include the need for repeated injections, the high financial costs and treatment burdens of repeated injections, the risk of adverse ocular and systemic adverse events, and the inability to completely reverse the disease process of wet AMD. There are many new therapies and approaches in the pipeline which hold promise for improving the treatment of wet AMD.     

贝伐珠单抗应用于眼器官疾病的安全信号检测与分析

目的：挖掘贝伐珠单抗治疗眼器官疾病的药品不良事件（ADE）信号,为其眼部超说明书用药管理提供参考。方法：采用报告比值比法（ROR）结合压缩估计对美国不良反应数据库2010第1季度~2021年第1季度中适应症为眼器官疾病的贝伐珠单抗报告进行数据挖掘和安全信号检测。结果：共得到贝伐珠单抗相关的8056个报告,涉及2431份病例,病例数位列前5位的适应症为：年龄相关性黄斑变性、糖尿病性视网膜病变、视网膜静脉阻塞、黄斑水肿、脉络膜新生血管。其中女性（45.37%）多于男性（37.15%）且老年患者居多。总体共得119个ADE信号,涉及18个系统/器官,主要是眼器官。报告数及信号强度均在前30的信号中,眼内炎、失明、玻璃体飞蛾症、视网膜剥离、眼部感染发生最多;脑血管意外、心肌梗死、神经系统病变、动脉血栓形成是死亡风险高且报告数/信号强度在前30的信号。结论：贝伐珠单抗治疗眼器官疾病的ADE信号集中在眼部,可造成不同程度的视力损伤,而生命威胁大的事件多在眼外器官/系统,临床对其在眼病的超适应症使用应更为慎重且应严格管理。     

VEGF inhibitors for the treatment of neovascular age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world for those patients aged 50 years or older. Neovascular AMD, a subtype characterized by the growth of new, pathologic blood vessels, results in most of the cases of severe and rapid vision loss associated with AMD. A critical activator of angiogenesis in neovascular AMD is VEGF. Several therapies have been and are now being developed for neovascular AMD, with the goal of inhibiting VEGF. These VEGF inhibitors include the RNA aptamer pegaptanib, partial and full-length antibodies ranibizumab and bevacizumab, VEGF receptor decoy VEGF Trap, small interfering RNA-based therapies bevasiranib and AGN211745, sirolimus, and tyrosine kinase inhibitors including vatalanib, pazopanib, TG100801, TG101095, AG013958 and AL39324. At present, established therapies have met with great success in reducing the vision loss associated with neovascular AMD, whereas those still investigational in nature offer the potential for further advances.     

Therapeutic efficacy of bevacizumab for age-related macular degeneration: what are the implications of CATT for routine management?

CATT (Comparison of Age-related macular degeneration [AMD] Treatment Trials) examined the efficacy of ranibizumab and bevacizumab for the treatment of neovascular AMD. This prospective, randomized, but unblinded trial revealed a significant improvement in vision with both treatments in terms of visual acuity; importantly, patients with juxtafoveal choroidal neovascularization (CNV) and retinal pigment epithelial detachments were not excluded from the study. Monthly treatment with the drugs resulted in similar increases in visual acuity, although angiograms indicated that ranibizumab was superior in terms of reducing retinal fluid and leakage. As the study also differentiated between a fixed regimen and an as-needed (pro re nata [PRN]) dosing regimen, a larger sample size and Bonferroni statistical correction were necessary. The equivalence of the PRN dosing of bevacizumab to the monthly treatment could not be confirmed. Almost all of the frequent deviations from the protocol (referring to retreatment criteria: 25.7-28.5%) resulted in under-treatment. Since this applied to both drugs equally, under-treatment alone could not explain the larger loss of visual acuity observed in the bevacizumab PRN arm. The PRN regimen was generally associated with a larger lesion size after 12 months compared with the fixed treatment regimens. The investigators accepted the drawbacks of an incomplete masking to allow co-payment by Medicare. As assessments of drug trials are often politically motivated, the higher demands of a non-inferiority trial compared with a superiority design must be emphasized. A comparison of the per-protocol and last-observation-carried-forward analysis has not yet been published; ongoing subgroup analysis might highlight the impact of different lesion characteristics. While CATT provided further evidence for the efficacy of bevacizumab treatment, differences in adverse events between the two treatments (e.g. a higher rate of serious adverse events with bevacizumab compared with ranibizumab) were reported; however, these still have to be analysed, with the larger sample sizes of previous ranibizumab studies needing to be taken into account. Preclinical studies imply some differences between the drugs in terms of their adverse event profiles. A possible increased risk of adverse events could not be ruled out by previous clinical case series and CATT because the sample sizes and the follow-up intervals were not adequate. The large discrepancy in the price of bevacizumab versus ranibizumab in the US means a cost-benefit analysis is warranted. A lack of quality-of-life data has prevented calculation of an appropriate bevacizumab price in the context of its performance in the ophthalmological setting. Thus, CATT suggests that a favourable visual acuity might be achieved by very frequent administration of bevacizumab in patients with neovascular AMD. Although there are certain safety caveats, increased focus on subgroup analyses and obtaining longer follow-up data are expected to yield additional information of clinical relevance.