Choroidal structural changes determined by the binarization method after intravitreal aflibercept treatment in neovascular age-related macular degeneration

AIM: To assess the choroidal structural alterations after intravitreal injection of aflibercept in neovascular age-related macular degeneration (nAMD). METHODS: Fifty eyes with treatment-naïve nAMD were evaluated at baseline, 3rd, and 12th month. Fifty eyes of 50 healthy subjects were also included as controls. Choroidal thickness (CT) was measured in the subfoveal region. Total circumscribed choroidal area (CA), luminal area (LA), stromal area (SA), and choroidal vascularity index (CVI) was calculated using Image J. RESULTS: At baseline, subfoveal CT was increased in nAMD patients compared to controls (P=0.321). Eyes with nAMD had a significantly increased total circumscribed CA and SA (P=0.041, 0.005, respectively). The CVI was decreased (P=0.038). In the 3rd month, the subfoveal CT, LA, and CVI revealed a decrease (P=0.005, P=0.039, 0.043, respectively). In the 12th month, subfoveal CT, LA, and CVI were decreased in comparison to baseline measures (P<0.001, 0.006, 0.010, respectively). CONCLUSION: Significant structural alterations are found after intravitreal aflibercept treatment during the 12-month follow-up, in particular at the third month, in eyes with nAMD.     

抗VEGF类药物与传统激光疗法用于治疗糖尿病性黄斑水肿的药物经济学评价

目的从中国全社会角度出发,评价抗血管内皮生长因子(vascular endothelial growth factor,VEGF)类药物(雷珠单抗、阿柏西普)与激光光凝用于治疗糖尿病性黄斑水肿的成本-效果。方法构建Markov模型,通过随机对照试验、已发表文献和医院调研获得3种干预措施治疗糖尿病性黄斑水肿的临床疗效、健康效用及成本数据,对各干预措施下患者终身的疾病转归、质量调整生命年(QALYs)及成本进行长期模拟。计算增量成本-效果比(ICER),并进行单因素和概率敏感性分析。结果与激光光凝相比,雷珠单抗的ICER值为61174元·QALY^-1,阿柏西普的ICER值为138232元·QALY^-1,均小于我国3倍人均GDP(59660元,2017年),抗VEGF类药物具有经济性。比较雷珠单抗与阿柏西普,雷珠单抗QALY更高成本更低,占绝对优势。单因素和概率敏感性分析证明了结果的稳健性。结论雷珠单抗、阿柏西普与激光光凝相比,在治疗糖尿病性黄斑水肿方面均具有成本-效果;其中雷珠单抗效果更好成本更低,在治疗糖尿病性黄斑水肿方面占绝对优势。     

The role of Aflibercept in the management of age-related macular degeneration

ABSTRACT

Introduction: During the past decade, significant advances have occurred in the management of neovascular age-related macular degeneration (NV-AMD). The advent of anti-vascular endothelial growth factor (anti-VEGF) therapy has shifted the treatment goal of NV-AMD from merely salvaging vision to improving visual acuity and maintaining a good quality of life. Aflibercept (AFL) is a significant addition to the arsenal of anti-VEGF therapies against the NV-AMD. In the index review, pharmacology and efficacy of AFL has been reviewed.

Areas Covered: An extensive literature search was performed to identify preclinical and clinical studies performed to illustrate the role of AFL in NV-AMD. Randomized clinical trials evaluating other anti-VEGF agents were also included for comparison. Additionally, studies where AFL was employed to treat anti-VEGF-resistant cases agents have been reviewed.

Expert Opinion: AFL is an effective agent in the management of NV-AMD and its efficacy has been found to be comparable to ranibizumab (RBZ). Additionally, AFL is a good alternative agent in patients with NV-AMD resistant to RBZ and bevacizumab (BVZ), and can potentially lessen the treatment burden. As more research is conducted, the role of AFL in varying dosing regimens, as monotherapy and in combination with other agents, will become further defined.     

A mechanism-based model for the population pharmacokinetics of free and bound aflibercept in healthy subjects

AIM

Aflibercept (VEGF-Trap), a novel anti-angiogenic agent that binds to VEGF, has been investigated for the treatment of cancer. The aim of this study was to develop a mechanism-based pharmacokinetic (PK) model for aflibercept to characterize its binding to VEGF and its PK properties in healthy subjects.

METHODS

Data from two phase I clinical studies with aflibercept administered as a single intravenous infusion were included in the analysis. Free and bound aflibercept concentration−time data were analysed using a nonlinear mixed-effects modelling approach with MONOLIX 3.1.

RESULTS

The best structural model involved two compartments for free aflibercept and one for bound aflibercept, with a Michaelis–Menten type binding of free aflibercept to VEGF from the peripheral compartment. The typical estimated clearances for free and bound aflibercept were 0.88 l day⁻¹ and 0.14 l day⁻¹, respectively. The central volume of distribution of free aflibercept was 4.94 l. The maximum binding capacity was 0.99 mg day⁻¹ and the concentration of aflibercept corresponding to half of maximum binding capacity was 2.91 µg ml⁻¹. Interindividual variability of model parameters was moderate, ranging from 13.6% (V_max) to 49.8% (Q).

CONCLUSION

The present PK model for aflibercept adequately characterizes the underlying mechanism of disposition of aflibercept and its nonlinear binding to VEGF.     

VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade

VEGF is the best characterized mediator of tumor angiogenesis. Anti-VEGF agents have recently demonstrated impressive efficacy in human cancer trials, but the optimal dosing of such agents must still be determined empirically, because biomarkers to guide dosing have yet to be established. The widely accepted (but unverified) assumption that VEGF production is quite low in normal adults led to the notion that increased systemic VEGF levels might quantitatively reflect tumor mass and angiogenic activity. We describe an approach to determine host and tumor production of VEGF, using a high-affinity and long-lived VEGF antagonist now in clinical trials, the VEGF Trap. Unlike antibody complexes that are usually rapidly cleared, the VEGF Trap forms inert complexes with tissue- and tumor-derived VEGF that remain stably in the systemic circulation, where they are readily assayable, providing unprecedented capability to accurately measure VEGF production. We report that VEGF production is surprisingly high in non-tumor-bearing rodents and humans, challenging the notion that systemic VEGF levels can serve as a sensitive surrogate for tumor load; tumor VEGF contribution becomes significant only with very large tumor loads. These findings have the important corollary that anti-VEGF therapies must be sufficiently dosed to avoid diversion by host-derived VEGF. We further show that our assay can indicate when VEGF is optimally blocked; such biomarkers to guide dosing do not exist for other anti-VEGF agents. Based on this assay, VEGF Trap doses currently being assessed in clinical trials are in the efficacious range.     

Comparison of efficacy of conbercept, aflibercept, and ranibizumab ophthalmic injection in the treatment of macular edema caused by retinal vein occlusion: a Meta-analysis

AIM: To evaluate and compare the anatomical and functional outcomes and negative effects of the three anti-vascular endothelial growth factor (VEGF) drugs in the treatment of macular edema (ME) due to retinal vein occlusion (RVO) based on the evidence pooled from current clinical trials and observational studies. METHODS: A systematic literature search was conducted on nine online databases from inception until April 30, 2022. The main endpoints were best corrected visual acuity (BCVA), central macular thickness (CMT), and adverse events (AEs). Cumulative Meta-analysis was conducted to synthesize the outcomes of the drugs. The retrieved data were analyzed using Stata software (version 12.0). RESULTS: A total of 20 studies comprising 1674 eyes met the inclusion criteria to the Meta-analysis. It was observed that conbercept and aflibercept had better visual acuity effects compared with ranibizumab at 1mo [weight mean difference (WMD)=-0.03, P=0.001; WMD=-0.05, P=0.019], but the effects were not different from that of ranibizumab at 6mo. Moreover, there was not statistically significant difference in the proportion of patients gaining ≥15 letters at 12-24mo between aflibercept and ranibizumab [odds ratio (OR)=1.16, P=0.427]. Conbercept had higher mean CMT change effects at 1mo (WMD= -14.43, P=0.014) and 6mo (WMD=-35.63, P≤0.001) compared with ranibizumab. Meanwhile, the mean CMT change effects at 1mo (WMD=-10.14, P=0.170), 6mo (WMD=-26.98, P=0.140) and 12-24mo (WMD=-12.34, P=0.071) were comparable among the groups. Similarly, AEs were not significantly different among the treatments (OR=0.75, P=0.305; OR=1.04, P=0.89). The stability of effect size of mean BCVA and CMT improved with the increase in sample size. Aflibercept and conbercept required fewer injections compared with ranibizumab. CONCLUSION: This is the first study to evaluate the efficacy and AEs of intravitreal administration of conbercept, ranibizumab, and aflibercept in the treatment of RVO-ME. Intravitreal aflibercept or conbercept results in better mean change in vision and CMT reduction compared with ranibizumab. Conbercept can be considered to be a promising and innovative drug with good anti-VEGF effects.     

Safety of monoclonal antibodies and related therapeutic proteins for the treatment of neovascular macular degeneration: addressing outstanding issues

Introduction: The vascular endothelial growth factor (VEGF) inhibitors most widely used to treat neovascular age-dependent macular degeneration (nAMD) are different proteins with structural features potentially relevant to adverse effects (AEs). Two of these are also established in cancer therapy (with higher dosages and AEs). The importance of ocular AE and extraocular activities is still a subject of controversy and ongoing research.

Areas covered: Potential risks of intraocular VEGF inhibition based on prospective studies, in vitro investigations, pharmacokinetics, and hints from anti-cancer treatment.

Expert opinion: nAMD is a frequently observed chronic clinical condition severely affecting the visual function of elderly persons. Intravitreal injection of VEGF-inactivating proteins is highly effective to prevent loss of vision. Anti-VEGF therapy is well tolerated, and low rates of ocular and systemic AEs in smaller trials suggest a very high benefit/risk ratio. The proteins established in nAMD therapy show similar efficacies. In the controversy over the off-label use of bevacizumab purely on grounds of much lower cost, the small, but potentially relevant differences between the available drugs are easily either dramatized (by pharmaceutical companies) or trivialized (by health insurances) and even political interference is involved. Facing the lack of a convincing body of evidence regarding safety, further long-term study results seem necessary.     

5-Fluorouracil derivatives: a patent review (2012 – 2014)

Introduction: 5-Fluorouracil (5-FU)-based chemotherapy is the most widely prescribed treatment for gastrointestinal solid tumors, but there are several drawbacks such as toxicities, lack of selectivity and effectiveness as well as the development of resistance that need to be overcome.

Areas covered:In this review, the authors present the latest innovations in 5-FU derivatives or combinations with: i) other chemotherapeutic drugs; ii) novel targeted compounds; iii) radiotherapy; iv) mAbs; v) siRNA strategies; and vi) traditional Chinese medicine extracts. Moreover, advances to overcome or determine 5-FU adverse effects and effectiveness are described. Finally, the authors introduce the ongoing clinical trials and highlight the main challenges to be addressed in the future.

Expert opinion: Although in the past few years there has been a great advancement in the antitumor effectiveness and selectivity of 5-FU-based therapies, it is envisaged that future approaches using ‘omics’ technologies that could determine the tumor heterogeneity may help in identifying additional candidate genes, microRNAs or cytokines involved in both the path mechanisms of 5-FU-related toxicity and its therapeutic efficacy. Moreover, the development of novel targeted 5-FU derivatives or 5-FU-based therapies tailored to individual patients opens up new possibilities in the improvement of the quality of life and survival for those suffering from this devastating disease.     

雷珠单抗和阿柏西普对年龄相关性黄斑变性患者外层视网膜管状结构的影响

目的　分析雷珠单抗和阿柏西普对年龄相关性黄斑变性（age-related macular degeneration,AMD）患者外层视网膜管状结构（outer retinal tubulation,ORT）的影响。方法　收集2016年2月至2018年1月医院收治的110例（142眼）AMD患者的临床资料，按治疗方式分为雷珠单抗组（65例82眼）与阿柏西普组（45例60眼），均完成术后2 a随访，记录治疗前后两组患者视力、黄斑中心凹厚度（central foveal thickness,CFT）及ORT的变化。结果　基线、治疗后6个月两组治疗眼数比较差异均无统计学意义（均为P>0.05），治疗后12个月、24个月雷珠单抗组治疗眼数比例（86.59%、26.83%)均高于阿柏西普组（55.00%、0,均为P<0.05）。两组治疗后6个月、12个月、24个月最佳矫正视力均有不同程度上升［雷珠单抗组:77.18±10.21、74.24±12.46、73.36±10.71；阿柏西普组:75.45±13.56、75.71±14.74、72.65±11.99］，均高于同组治疗前［59.15±13.92、59.21±14.01］（均为P<0.05），但组间差异均无统计学意义（均为P>0.05）。两组治疗后6个月、12个月、24个月CRT［雷珠单抗组:（345.22±30.71）μm、（340.37±41.05）μm、（341.67±42.02）μm；阿柏西普组:（346.87±29.68）μm、（341.65±42.65）μm、（343.41±40.87）μm］均较治疗前［（389.57±58.65）μm、（388.67±57.54）μm］降低（均为P<0.05），但组间不同时间点比较差异均无统计学意义（均为P>0.05）。治疗后6个月、12个月、24个月两组ORT（雷珠单抗组:34.15%、46.34%、60.98%；阿柏西普组:40.00%、60.00%、68.33%）均较基线上升（18.29%、23.33%），但组间比较差异均无统计学意义（均为P>0.05）。结论　湿性AMD患者ORT患病率随时间的推移增加，抗VEGF药物治疗可改善患者视力及黄斑形态，但无法抑制ORT进展，必须重视鉴别ORT与视网膜下液及水肿，减少过度治疗。