Vascular endothelial growth factor (VEGF) is a key angiogenesis regulator that promotes vascular endothelial cells' growth. Overexpression of VEGF is implicated in various retinal diseases, including diabetic retinopathy, age-related macular degeneration (AMD), and retinal vein occlusion. Anti-VEGF therapies prevent the binding of VEGF to its receptors, resulting in a reduction in abnormal blood vessel formation, vascular leak, and scar formation.
Pegaptanib (Macugen), an aptamer targeting VEGF-A165, was the first intravitreal drug approved for treating wet AMD. In recent years, VEGF inhibitors such as bevacizumab (Avastin), ranibizumab (Lucentis), and aflibercept (Eylea) have been commonly used in clinical practice.
More recent developments in the field of anti-VEGF agents have focused on biosimilar products. Biosimilar anti-VEGF agents are biologic drugs that are highly similar to existing anti-VEGF therapies. These biosimilars are designed to have the same mechanism of action, efficacy, and safety profile as their reference products, but they are typically more affordable and aim to provide broader patient access to these essential treatments.
Unlike generic drugs, which are exact chemical copies of small-molecule drugs, biosimilars are not identical to their reference biologics. Instead, biosimilars are made to be “highly similar” to their reference products regarding structure, function, and clinical effect.
This article discusses the current anti-VEGF medications available to clinicians today.
Ranibizumab (Lucentis)
Ranibizumab (Lucentis) was developed by Genentech, Inc. and received FDA approval for neovascular AMD (nAMD), followed by expanded indications for diabetic macular edema (DME), retinal vein occlusion (RVO), and myopic choroidal neovascularization (mCNV).1 This molecule is a recombinant humanized IgG1 kappa isotype monoclonal antibody fragment.
It consists of a Fab region specifically targeting VEGF isoforms 121, 165, and 189. Its relatively small molecular size (48-kD) and lack of an Fc region facilitates enhanced retinal penetration compared to full-length antibodies.
MARINA and ANCHOR clinical trials
Two pivotal phase III clinical trials, MARINA and ANCHOR, established ranibizumab’s efficacy in AMD. The MARINA trial evaluated monthly intravitreal ranibizumab injections (0.3mg or 0.5mg) versus sham injections over 24 months. Results demonstrated significant visual acuity improvement and prevention of vision loss that persisted throughout the study.
The ANCHOR trial compared ranibizumab against verteporfin photodynamic therapy for predominantly classic choroidal neovascularization, with ranibizumab showing superior outcomes in visual acuity preservation and reduced choroidal neovascularization area.2
Long-term outcomes were assessed in the SEVEN-UP non-interventional cohort study, which followed ANCHOR and MARINA participants for 7 to 8 years post-treatment. Results revealed that approximately ⅓ of patients maintained favorable visual outcomes, while another ⅓ experienced significant visual decline, highlighting the need for ongoing monitoring despite initial therapeutic success.3
Clinical trials on ranibizumab for DME
For diabetic macular edema, the RISE and RIDE phase III trials demonstrated ranibizumab’s efficacy through rapid and substantial visual acuity improvements, reduced vision loss progression, and decreased macular edema.4
Similarly, the BRAVO and CRUISE phase III trials established ranibizumab’s effectiveness in treating macular edema secondary to branch and central retinal vein occlusion, respectively, with both studies showing rapid resolution of macular edema.5,6
Following the expiration of ranibizumab’s patent in June 2020, several biosimilar products have been developed, promising to expand treatment accessibility. These biosimilars are discussed below.
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Anti-VEGF Cheat Sheet
Download this cheat sheet to navigate the many new anti-VEGF medications in development and soon to come to market!
Ranibizumab-nuna (Byooviz)
Ranibizumab-nuna (Byooviz) was the first FDA-approved biosimilar to reference ranibizumab, developed by Samsung Bioepis and marketed by Biogen Inc. The FDA approved September 2021 nAMD, ME, following RVO and mCNV.
The recommended dosing regimen is 0.5mg administered monthly via intravitreal injection. Notably, it provides a significant cost advantage, with approximately 40% reduction compared to reference ranibizumab.
Clinical trials demonstrating therapeutic equivalence to ranibizumab
The similarity of ranibizumab-nuna to reference ranibizumab was established through comprehensive clinical evaluation. A pivotal phase III randomized clinical trial in 2020 demonstrated therapeutic equivalence in patients with nAMD. The study showed comparable improvements in best-corrected visual acuity and optical coherence tomography central subfield thickness between ranibizumab-nuna and reference ranibizumab groups.7
A subsequent clinical trial in 2021 further validated the biosimilarity through a detailed analysis of efficacy, safety, immunogenicity profiles, and pharmacokinetics. The study confirmed equivalent visual efficacy endpoints and revealed similar adverse event profiles between treatment groups.
Pharmacokinetic analyses demonstrated comparable mean serum concentrations, while immunogenicity assessment showed no significant differences between groups in antidrug and neutralizing antibodies.9
A 2023 phase III post-hoc analysis provided additional supporting evidence for biosimilarity, reinforcing the therapeutic equivalence of ranibizumab-nuna to reference ranibizumab in all evaluated parameters.8
Ranibizumab-eqrn (Cimerli)
Ranibizumab-eqrn (Cimerli), developed by Coherus BioSciences, received FDA approval in August 2022 as a biosimilar to reference ranibizumab. It is indicated for all five FDA-approved indications of the reference product: nAMD, ME following RVO, DME, diabetic retinopathy (DR), and mCNV. The drug is available in two strengths of 0.3mg and 0.5mg for monthly intravitreal administration.
Clinical trials establishing biosimilarity to ranibizumab
The COLUMBUS-AMD phase III clinical trial established the biosimilarity of ranibizumab-eqrn to reference ranibizumab in patients with nAMD. This randomized, double-masked study demonstrated therapeutic equivalence between the biosimilar and reference product.
Results showed comparable clinical efficacy regarding best-corrected visual acuity (BCVA) improvements. The study also confirmed equivalent ocular and systemic safety profiles between ranibizumab-eqrn and reference ranibizumab, with similar adverse events and immunogenicity rates.10
Faricimab-svoa (Vabysmo)
Faricimab-svoa (Vabysmo), developed by Genentech, represents a novel bispecific antibody with a molecular weight of 150kDa. It is the first bispecific antibody approved for ocular use, uniquely targeting VEGF-A isoforms and angiopoietin-2 (Ang-2).
The Ang-2 inhibition component modulates the Tie2 receptor pathway, thereby reducing vascular permeability, endothelial cell proliferation, and inflammation. The FDA approved it for nAMD, DME, and ME following RVO.
Clinical trials that established the efficacy of Vabysmo
The efficacy of faricimab in nAMD was established through two pivotal phase III clinical trials, TENAYA and LUCERNE. These studies demonstrated that faricimab achieved comparable BCVA improvements to aflibercept while showing superior anatomic outcomes when administered at 8-week intervals. The 2-year follow-up data revealed sustained BCVA improvements equivalent to aflibercept, with a significant proportion of patients maintaining results with extended treatment intervals.11
For DME, the phase III YOSEMITE and RHINE trials compared faricimab administered every 8 weeks or at personalized treatment intervals against aflibercept every 8 weeks. The studies demonstrated that faricimab could maintain vision gains and anatomical improvements with dosing intervals of up to 16 weeks, suggesting enhanced treatment durability compared to existing options.12
The BALATON and COMINO trials evaluated faricimab's efficacy in retinal vein occlusion, comparing it with aflibercept over 24 weeks. Results showed non-inferior BCVA changes through week 24 compared to aflibercept, with a favorable safety profile.13
Trials investigating Vabysmo for wet AMD
A 2023 study investigated faricimab's potential in treating highly treatment-resistant choroidal neovascularization in wet AMD, defined as persistent retinal fluid despite intensive anti-VEGF therapy and/or combination treatment with steroids.
The study demonstrated significant anatomic improvement in these resistant cases, suggesting faricimab's potential as a therapeutic option for patients who have exhausted other treatments.14 Further evidence of faricimab's clinical utility came from a 2023 retrospective study of nAMD patients previously treated with anti-VEGF therapy who received at least three intravitreal faricimab injections.
The study documented improvements in both BCVA and central subfield thickness. Notably, the mean interval between consecutive faricimab injections was significantly longer compared to ranibizumab or aflibercept, suggesting the potential for reduced treatment burden.15
Pegaptanib sodium (Macugen)
Pegaptanib Sodium (Macugen), developed by Eyetech/Pfizer, is an RNA aptamer designed to target VEGF-165, inhibiting this isoform's neovascular activity.
It achieved historical significance as the first anti-VEGF therapy approved by the FDA in 2004 to treat nAMD. The approved dosing regimen consists of 0.3mg intravitreal injections administered every 6 weeks.
Clinical trials demonstrating the efficacy of pegaptanib
The VISION clinical trials established pegaptanib's efficacy in nAMD, demonstrating superior maintenance of visual acuity over a 2-year treatment period compared to sham injections. These pivotal studies led to its initial FDA approval and set the stage for future anti-VEGF therapies.16
Beyond nAMD, pegaptanib showed promise in several other ocular conditions. A 2006 phase II trial investigating its use in DME demonstrated improvements in visual acuity outcomes and reductions in central retinal thickness. The study also noted a decreased need for supplementary photocoagulation therapy during follow-up.17
Further applications were explored in 2009 through two significant studies. The first compared pegaptanib with panretinal laser photocoagulation in active proliferative diabetic retinopathy, demonstrating substantial and rapid regression of neovascularization.18 A concurrent study evaluated its efficacy in macular edema secondary to central retinal vein occlusion (CRVO), showing both visual and anatomical benefits in treated eyes.19
Bevacizumab (Avastin)
Bevacizumab (Avastin) is a full-length humanized monoclonal antibody that targets all isoforms of vascular endothelial growth factor-A (VEGF-A). Initially approved by the FDA in 2004 for the treatment of metastatic colorectal cancer, its potential in ophthalmology was discovered through off-label use.
While systemic administration for ocular conditions was discontinued due to adverse effects, intravitreal administration showed promising results. The commonly used off-label dosing regimen consists of 1.25mg/0.05ml intravitreal injections administered every 4 to 6 weeks.
Clinical trials on bevacizumab
Two landmark clinical trials established bevacizumab's efficacy in nAMD. The CATT (Comparison of Age-Related Macular Degeneration Treatments Trials) and IVAN (Inhibition of VEGF in Age-Related Choroidal Neovascularization Trial) both demonstrated significant improvements in visual acuity over 2 years.20
Long-term follow-up at 5 years revealed that while initial vision gains were not fully maintained, 50% of patients retained visual acuity of 20/40 or better, supporting the drug's long-term efficacy.21
The PACORES (Pan-American Collaborative Retina Study Group) trial provided evidence for bevacizumab's efficacy in DME, demonstrating superior outcomes compared to conventional laser photocoagulation.22
The study also showed significant benefits in CRVO, with patients achieving an impressive 19-letter improvement in visual acuity when bevacizumab was administered either monthly or as needed.
Bevacizumab-vikg (ONS-5010/LYTENAVA)
Bevacizumab-vikg (ONS-5010/LYTENAVA), developed by Outlook Therapeutics, is a recombinant humanized monoclonal antibody formulated explicitly for ophthalmic use. It selectively binds with high affinity to all human VEGF isoforms, neutralizing VEGF's biological activity by blocking its binding to receptors Flt-1 (VEGFR-1) and KDR (VEGFR-2) on endothelial cells.
The development of bevacizumab-vikg addresses a significant clinical need, as currently, there are no FDA-approved ophthalmic formulations of bevacizumab. Clinicians rely on off-label, repackaged intravenous bevacizumab from compounding pharmacies, presenting concerns regarding sterility, potency consistency, and product availability. Bevacizumab-vikg aims to provide the first FDA-approved on-label bevacizumab option for nAMD.
Clinical trials showing efficacy of bevacizumab-vikg
The efficacy and safety of bevacizumab-vikg have been evaluated through a series of clinical trials. The NORSE-ONE proof-of-concept trial compared bevacizumab-vikg with ranibizumab, providing initial evidence supporting its safety and efficacy profile.
The pivotal phase III NORSE-TWO trial compared monthly bevacizumab-vikg administration against the ranibizumab PIER dosing regimen (three monthly doses followed by quarterly treatment). Results demonstrated superior efficacy for bevacizumab-vikg, with patients achieving a mean gain of 11.2 letters compared to 5.8 letters in the ranibizumab group.
The NORSE-THREE open-label safety study, conducted to support the Biologics License Application (BLA) submission, further confirmed the favorable safety profile of bevacizumab-vikg for ophthalmic use.23
To read about findings from the NORSE-EIGHT clinical evaluating ONS-5010 for wet AMD, check out Outlook Therapeutics releases 12-week data on bevacizumab formulation for AMD!
Aflibercept (Eylea)
Aflibercept (Eylea), developed by Regeneron Pharmaceuticals, is a recombinant fusion protein engineered to function as a high-affinity decoy receptor. It uniquely targets VEGF-A and placental growth factor (PlGF), binding these proteins with greater affinity than their natural receptors.
This dual mechanism effectively inhibits VEGF signaling, reducing angiogenesis and vascular permeability.
Trials demonstrating efficacy of aflibercept for nAMD
The efficacy of aflibercept in nAMD was established through two pivotal phase III trials, VIEW-1 and VIEW-2. These studies compared various aflibercept dosing regimens against monthly 0.5mg ranibizumab injections.
Results demonstrated clinical equivalence between the drugs, with a notable advantage for aflibercept: the 8-week dosing schedule required five fewer injections than monthly ranibizumab while maintaining comparable efficacy.24
For DME, the phase III VIVID and VISTA trials compared aflibercept with macular laser photocoagulation. The studies evaluated three treatment arms: 2mg aflibercept every 4 weeks, 2mg aflibercept every 8 weeks following five monthly loading doses, and laser control. At 148 weeks, both aflibercept regimens demonstrated significant visual improvements. Additionally, aflibercept treatment showed positive effects on diabetic retinopathy severity scale (DRSS) scores.25
The COPERNICUS and GALILEO phase III trials established aflibercept's efficacy in treating macular edema secondary to CRVO. Both studies demonstrated significant improvements in visual acuity and reductions in central retinal thickness compared to sham treatment.26
Following the patent expiration for aflibercept in 2023, several biosimilar products have entered development.
Aflibercept 8mg High Dose (Eylea HD)
Aflibercept 8 mg (Eylea HD), developed by Regeneron Pharmaceuticals and Bayer, received FDA approval in August 2023 for the treatment of DME and nAMD. This high-dose formulation was designed to maintain efficacy while reducing treatment burden through extended dosing intervals.
Two pivotal phase III trials, PHOTON (for DME) and PULSAR (for nAMD), evaluated the efficacy of high-dose aflibercept against standard dosing. These studies compared three treatment regimens: standard 2mg dose every 8 weeks (2q8), high-dose 8mg every 12 weeks (8q12), and high-dose 8mg every 16 weeks (8q16).
Both trials demonstrated that the 8q12 and 8q16 regimens achieved non-inferior BCVA gains compared to the standard 2q8 dosing, with comparable ocular safety profiles across all groups.27 These groundbreaking studies were the first to show that patients could initiate treatment with extended 12- or 16-week dosing intervals after initial monthly doses while maintaining clinically meaningful outcomes.28
Additional evidence came from the phase II CANDELA trial, which compared 8mg and 2mg aflibercept doses in nAMD treatment. While the study showed a trend toward superior fluid resolution in the central subfield at week 16 with the higher dose, this difference did not reach statistical significance.
Notably, both doses demonstrated similar safety profiles, supporting the viability of the high-dose formulation.29
To read about recent phase 3 data on Eylea HD check out New phase 3 data supports Eylea HD for macular edema following RVO!
Aflibercept-jbvf (Yersafil)
Aflibercept-jbvf (Yesafili), developed by Mylan Pharmaceuticals, Inc. and Biocon Biologics, Inc., received FDA approval in May 2024 as the first interchangeable biosimilar to reference aflibercept (Eylea). Like its reference product, it functions as a VEGF inhibitor and received approval for all indications of the reference product: nAMD, ME following RVO, DME, and DR.
The approved dosing regimen mirrors reference aflibercept: 2mg intravitreal injections administered every 4 weeks for the first 3 months, followed by 2mg every 8 weeks for maintenance therapy. The biosimilarity of aflibercept-jbvf was established through the INSIGHT clinical trial, which evaluated its efficacy and safety against reference aflibercept in DME treatment.
The study demonstrated therapeutic equivalence between aflibercept-jbvf and reference aflibercept through 52 weeks of treatment. Comprehensive analysis showed comparable outcomes across multiple parameters, including BCVA improvements across various baseline subgroups, safety profiles, immunogenicity, and pharmacokinetics.30
Opuviz (aflibercept-yszy)
Aflibercept-yszy (Opuviz), developed by Samsung Bioepis Co., Ltd., received FDA approval in May 2024 as an interchangeable biosimilar to reference aflibercept (Eylea). Along with Yesafili, it represents one of the first FDA-approved aflibercept biosimilars, marking a significant advancement in expanding treatment accessibility for retinal disorders.
The biosimilarity of aflibercept-yszy was established through a comprehensive phase III clinical trial comparing it with reference aflibercept in patients with nAMD. The study's primary efficacy endpoint evaluated BCVA changes from baseline to week 8. Results demonstrated comparable efficacy between treatment groups that were maintained through week 32.31
The trial also established equivalent safety profiles, with no clinically relevant differences in treatment-emergent adverse events between aflibercept-yszy and reference aflibercept. Further supporting its biosimilarity, pharmacokinetic analyses showed comparable serum concentration profiles and immunogenicity assessments revealed similar cumulative incidences of antidrug antibody development between the biosimilar and reference product.
Aflibercept-abzv (Enzeevu)
Aflibercept-abzv (Enzeevu), developed by Sandoz, received FDA approval in August 2024 as a biosimilar to reference aflibercept (Eylea). The approval covers all significant indications of the reference product: nAMD, macular edema following RVO, DME, and DR.
The approved dosing regimen follows the established protocol of reference aflibercept: 2mg intravitreal injections administered every 4 weeks for the first 3 months, followed by 2mg every 8 weeks for maintenance therapy.
The biosimilarity of aflibercept-abzv was established through the Mylight clinical trial, specifically designed to evaluate clinical equivalence with reference aflibercept. The study provided comprehensive evidence demonstrating that aflibercept-abzv matched reference aflibercept across multiple parameters, including efficacy outcomes, safety profile, and pharmacokinetic properties.32
Aflibercept-ayyh (Pavblu)
Aflibercept-ayyh (Pavblu), developed by Amgen, received FDA approval in September 2024 as the fifth biosimilar to reference aflibercept (Eylea). The approval encompasses all significant indications of the reference product: nAMD, macular edema following RVO, DME, and DR.33
The approved dosing regimen follows the established protocol of reference aflibercept: 2mg intravitreal injections administered every 4 weeks for the first 3 months, followed by 2mg every 8 weeks for maintenance therapy.
Clinical evaluation of aflibercept-ayyh focused on its use in nAMD treatment, comparing its performance with reference aflibercept. The study demonstrated no clinically meaningful differences between the biosimilar and reference product across evaluated parameters, establishing the biosimilarity of aflibercept-ayyh to reference aflibercept.
Aflibercept-mrbb (Ahzantive)
Aflibercept-mrbb (Ahzantive), developed by Formycon, is the latest biosimilar to receive FDA approval for reference aflibercept (Eylea). Like other approved aflibercept biosimilars, it is indicated for the treatment of nAMD, macular edema following RVO, DME, and DR.34
The approved dosing regimen follows the established protocol of reference aflibercept: 2mg intravitreal injections administered every 4 weeks for the first 3 months, followed by 2mg every 8 weeks for maintenance therapy.
The MAGELLAN-AMD phase III clinical trial provided the primary evidence supporting biosimilarity by comparing aflibercept-mrbb with reference aflibercept in nAMD treatment. The study demonstrated comparable efficacy between the biosimilar and reference products, establishing the therapeutic equivalence of aflibercept-mrbb.
Brolucizumab (Beovu)
Brolucizumab (Beovu), developed by Novartis, represents an innovation in anti-VEGF therapy as a humanized single-chain antibody fragment specifically targeting VEGF-A. The FDA approved in October 2019 to treat nAMD.
The approved dosing regimen consists of 6mg intravitreal injections every 8 to 12 weeks, following an initial loading phase of monthly 6 mg injections for three months.
Clinical trials on the efficacy of brolucizumab
The efficacy of brolucizumab was established through two pivotal phase III trials, HAWK and HARRIER. These studies demonstrated non-inferiority to aflibercept in visual outcomes. Notably, brolucizumab showed superior efficacy in reducing intra-retinal and subretinal fluid compared to aflibercept, suggesting enhanced fluid resolution capabilities.35
However, significant safety concerns emerged during subsequent clinical investigations. The MERLIN, RAPTOR, and RAVEN trials were prematurely terminated due to an unexpectedly high rate of intraocular inflammation (9.3%) observed with monthly injections following the loading phase.36
These findings led to a critical modification in the treatment protocol: brolucizumab injections are now contraindicated at intervals shorter than 8 weeks after loading to minimize the risk of adverse events.
Susvimo ocular implant
Susvimo (ranibizumab injection) is a VEGF inhibitor indicated for the treatment of nAMD in patients who have previously responded to at least two intravitreal injections of a VEGF inhibitor. Approval of Susvimo was based on the phase 3 Archway study for eyes with previously treated nAMD.
Susvimo is delivered through an ocular implant. The recommended dosage is 2mg continuously delivered with refills every 24 weeks.37 Supplemental treatment with 0.5mg intravitreal ranibizumab injection may be administered if necessary. This delivery system is unique and provides patients with a way to receive VEGF treatment without repeated retinal injections and the associated discomfort.
Complications related to the Susvimo implant include:
- Endophthalmitis
- Rhegmatogenous retinal detachment
- Implant dislocation
- Septum dislodgement
- Vitreous hemorrhage
- Conjunctival retraction
- Conjunctival erosion
- Conjunctival bleb
- A decrease in visual acuity usually occurs over the first 2 months post-operatively
Note it has been associated with a 3-fold higher rate of endophthalmitis compared to monthly intravitreal injections of ranibizumab. In clinical trials, 2% of patients receiving an implant experienced an episode of endophthalmitis. To minimize the risk of vitreous hemorrhage, it is recommended to discontinue antithrombotic medication prior to implant insertion.38
Conclusions
Anti-VEGF therapy continues to evolve rapidly, with significant advances in both therapeutic options and delivery mechanisms. The field has progressed substantially from the first FDA-approved anti-VEGF agent, pegaptanib, to the current landscape featuring multiple approved medications and biosimilars.
Several key developments characterize the current state of anti-VEGF therapy:
- First, the introduction of biosimilars, particularly for ranibizumab (Byooviz, Cimerli) and aflibercept (Yersafili, Opuviz, Enzeevu, Pavblu, Ahzantive), has expanded treatment accessibility while maintaining comparable efficacy to reference products. These biosimilars offer potential cost advantages while demonstrating therapeutic equivalence in clinical trials.
- Second, novel therapeutic approaches have emerged, including bispecific antibodies like faricimab (Vabysmo) that target both VEGF-A and Ang-2. This dual mechanism of action shows promise in extending treatment intervals while maintaining efficacy.
- Third, innovations in drug delivery systems, such as the Susvimo ocular implant, offer alternatives to frequent intravitreal injections, potentially improving treatment adherence and reducing the burden of care.
- However, these advances come with their considerations, including surgical risks and the need for careful patient selection. The introduction of high-dose formulations, exemplified by Eylea HD (aflibercept 8mg), demonstrates the field's continued evolution toward optimizing treatment intervals while maintaining efficacy. Clinical trials have shown that extended dosing intervals are possible without compromising visual outcomes.
As we look to the future, several challenges and opportunities remain, including the need to balance treatment efficacy with patient burden and healthcare costs, the importance of personalized treatment regimens based on individual disease characteristics and response patterns, the ongoing development of novel therapeutic targets and delivery mechanisms, and the integration of biosimilars into clinical practice while ensuring maintained quality and safety standards.
These developments collectively suggest a promising future for anti-VEGF therapy, with increasing options for physicians and patients. Continued research and clinical experience will refine our understanding of optimal treatment strategies and patient selection criteria for these therapeutic options.
The field of anti-VEGF therapy remains dynamic, with ongoing research and development promising to bring additional innovations in both therapeutic agents and delivery systems. As our understanding of retinal disease mechanisms continues to expand, we can anticipate further advances to enhance our ability to preserve and improve vision for patients with retinal disorders.
