Published in Retina

Anti-VEGF Therapy: An Ophthalmology Resident's Guide

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15 min read
Anti-VEGF drugs are used for ocular diseases to reduce neovascularization, vascular leakage, and scar formation. Gain an overview of the current anti-VEGF medications available to clinicians today.
Anti-VEGF Therapy: An Ophthalmology Resident's Guide
For the past two decades, researchers have been working on optimal treatments to halt the effects of vascular endothelial growth factor (VEGF) on ocular diseases. Anti-VEGF drugs are used for ocular diseases to reduce neovascularization, vascular leakage, and scar formation. These treatments are essential in managing patients with pathologies that involve abnormal angiogenesis and vascular leakage such as neovascular (wet) age-related macular degeneration (AMD) and diabetic retinopathy (DR) with diabetic macular edema (DME).
Pegaptanib (Macugen®), an aptamer that binds to VEGF-A165, was the first intravitreal drug used to treat wet AMD. Currently, VEGF inhibitors like bevacizumab (Avastin®), ranibizumab (Lucentis®), and aflibercept (Eylea®) are commonly used. Brolucizumab (Beovu®) by Novartis received FDA approval in late 2019. And more recently, Susvimo™(port delivery system with Lucentis) and Faricimab (Vabysmo®), both produced by Genentech, received FDA approval in late 2021 and early 2022, respectively.
The main challenge with anti-VEGF injections is concerning treatment burden, as some patients need intravitreal injections up to every 4 weeks. One of the primary goals of current research is to develop different treatment modalities with improved durability but equal safety and efficacy. Recent research focuses on developing implants, extended-release polymers, tyrosine kinase inhibitors, and gene therapies to prolong the time between treatments.
This article discusses the current anti-VEGF medications currently available to clinicians today.
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Pegaptanib sodium

Pegaptanib sodium (Macugen; Eyetech/Pfizer) is a pegylated RNA aptamer that binds to VEGF-165. It antagonizes the effects of VEGF and thus halts the protein’s neovascular effects. It gained FDA approval in 2004 for the treatment of wet AMD.
Pegaptanib is given as an intravitreal injection at 0.3 mg doses every 6 weeks. The VISION (Vascular Endothelial Growth Factor Inhibition Study in Ocular Neovascularization) study showed significantly better results in maintaining visual acuity over 2-year treatments for wet AMD patients than sham injections.
Similar positive results were seen in patients with diabetic macular edema (DME), where patients treated with intravitreal 0.3 mg of intravitreal injections had a positive mean change in visual acuity. Patients with DME also had decreased central retinal thickness and reduced need for subsequent photocoagulation treatment.
The drug also showed positive results in regression of retinal neovascularization in proliferative diabetic neuropathy. In a study on Pegaptanib in macular edema secondary to central retinal vein occlusion (RVO), the drug showed positive results in visual acuity and reduction in the center point and central subfield thickness. Although the drug had positive results, it quickly fell out of favor with the subsequent rise of Bevacizumab.

Bevacizumab (Avastin)

Bevacizumab (Avastin®) is a full-length murine-derived antibody that antagonizes VEGF. The FDA first approved it in 2004 for use in adenocarcinoma of the colon.
Systemic use for ocular pathologies was stopped due to adverse side effects; however, there was evidence of positive results with intraocular injections. It is given as a 1.25mg/0.05 ml intravitreal injection every 4 to 6 weeks.
Studies such as CATT (Comparison of Age-Related Macular Degeneration Treatments Trials) and IVAN (Inhibition of VEGF in Age-Related choroidal Neovascularization trial) showed improvement in visual acuity from baseline in wet AMD. It antagonizes all isoforms of VEGF-A and thus reduces angiogenesis and vascular leakage. The PACORES (Pan-American Collaborative Retina Study Group) study also showed positive results in diabetic macular edema and central vein occlusion patients.
Patients with DME had a remarkable improvement in visual acuity compared to patients treated with laser photocoagulation after 2 years. Patients with central retinal vein occlusions (CRVO) had a 19-letter improvement in visual acuity within the first year when Bevacizumab was used monthly or as needed.
Recently, Outlook Therapeutics announced it is seeking FDA approval for ONS-5010 (Bevacizumab-vikg, LytenavaTM) developed for on-label use of wet AMD, citing its NORSE study results, which showed a favorable benefit-to-risk safety profile. It is expected to be available in early 2023.

Ranibizumab (Lucentis)

Ranibizumab (Lucentis®) was produced by Genentech, Inc to treat wet AMD. Since its inception, it has also been approved for DME, RVO, and myopic choroidal neovascularization (CNVM). Ranibizumab is a fragment of a recombinant humanized IgG1 kappa isotype monoclonal antibody fragment.
The fragment consists of a 48-kD Fab region of the A4.6.1 antibody, targeting VEGF121, VEGF165, and VEGF189. Without an Fc region, it is much smaller than the typical antibody allowing it to absorb into the retina more easily.
ANCHOR and MARINA were two-year clinical trial studies that evaluated the difference in treatment for wet AMD with 0.3 mg and 0.5 mg monthly injections of ranibizumab. The conclusion of the MARINA study indicated improvement of visual acuity with the prevention of vision loss. ANCHOR tested between ranibizumab versus verteporfin therapy.
Ranibizumab was shown to decrease the area of choroidal neovascularization, whereas verteporfin led to an increase in the area of choroidal neovascularization.
RISE and RIDE were double-masked studies in which 759 patients were randomized to receive a sham injection (control) or 0.3 mg and 0.5 mg monthly intravitreal injections of ranibizumab for diabetic macular edema. Patients in the treatment group showed significant improvements since enrollment in the study.
BRAVO and CRUISE were double-masked studies in which 789 patients were randomized to receive a sham injection (control) or 0.3 mg and 0.5 mg intravitreal injections of ranibizumab for retinal vein occlusion. BRAVO was used to assess branched retinal vein occlusion, while CRUISE was used to evaluate central retinal vein occlusion. Both studies established a significant improvement in the treatment of macular edema associated with retinal vein occlusion.
The patent for Ranibizumab expired in June 2020. Thus, several Ranibizumab biosimilars are on the horizon and are expected to be available in the United States soon. CHS-201 (FYB201) from Coherus BioSciences and BYOOVIZ (SB11) from Samsung Bioepis are two examples of Ranibizumab biosimilars being studied.

Aflibercept (Eylea)

Aflibercept (Eylea®) made by Regeneron is another anti-VEGF treatment available. It is a recombinant fusion protein with human VEGF-1 and VEGF-2 Fab linked to an IgG1 Fc region delivered through intravitreal injection. Aflibercept serves as a decoy receptor to which VEGF-A and PIGF bind with greater affinity than their natural targets. This then inhibits any effect VEGF may have if bound to its innate receptor resulting in a decrease in angiogenesis and vascular permeability.
VIEW 1 and VIEW 2 were two double-masked, parallel-group, active-controlled phase 3 clinical trials in which 2,457 patients were randomized to test the efficacy of aflibercept for the treatment of neovascular AMD. Various doses of intravitreal aflibercept were compared to a standard 0.5mg intravitreal dose of ranibizumab. Results comparing the proportion of patients maintaining vision showed clinical equivalence between aflibercept and ranibizumab; however, aflibercept Q8 allowed for five fewer injections compared to ranibizumab Q4.
VIVID and VISTA were two double-masked, laser-controlled phase 3 studies in which 872 patients were randomized into either a laser control or aflibercept treatment group to test the efficacy of aflibercept for diabetic macular edema.
In the VIVID trial, administration of 2 mg q4 weeks and 2 mg q8 weeks showed a 32.4% and 33.3% improvement in gaining > 15 letters, respectively, whereas the laser control group had a 9.1% improvement at 52 weeks. At 100 weeks, administration of 2 mg q4 weeks and 2 mg q8 weeks showed a 38.2% and 31.1% improvement of gaining > 15 letters, respectively, whereas the laser control group had a 12.1% improvement.
In the VISTA trials, administration of 2 mg q4 weeks and 2 mg q8 weeks showed 41.6% and 31.1% improvement in gaining > 15 letters, whereas the laser control group had a 7.1% improvement at 52 weeks. At 100 weeks, administration of 2 mg q4 weeks and 2 mg q8 weeks showed a 38.3% and 33.1% improvement of gaining > 15 letters, respectively, whereas the laser control group had a 13.0% improvement.
COPERNICUS and GALILEO were two double-masked, sham-controlled phase 3 studies in which 361 patients were randomized in the two trials for the efficacy of aflibercept in treating macular edema secondary to retinal vein occlusion.
In the COPERNICUS trial, 2 mg q4 weeks administration showed a 56.1% increase of gaining > 15 ETDRS letters, whereas the sham control group had a 12.3 % improvement at 24 weeks. At 52 weeks, 2 mg q4 weeks administration showed a 55.3% increase in gaining > 15 ETDRS letters. From 24-52 weeks, the sham group then received 2 mg intravitreal aflibercept as needed, resulting in a 30.1% increase in gaining > 15 ETDRS letters.
Aflibercept’s patent expires in 2023, and thus biosimilars to this are being developed. SB15 from Samsung Bioepis, ABP938 from Amgen, SOK583A1 from Novartis, MYL-1701P from Mylan Pharmaceuticals Inc are aflibercept-biosimilars being currently studied.

Brolucizumab (Beovu, Novartis)

Brolucizumab (Beovu® , Novartis) is a single-chain variable fragment that targets VEGF-A primarily. It was approved in October 2019 and is given as a 6mg intravitreal injection every 8 to 12 weeks. The treatment regimen begins with a 6 mg injection monthly for 3 months as a loading dose. In the HAWK and HARRIER (Efficacy and Safety of Brolucizumab Versus Aflibercept) trials, Brolucizumab demonstrated non-inferiority compared to aflibercept.
Brolucizumab also showed improved resolution (compared to aflibercept) in the intra-retinal and subretinal fluid, a marker for wet AMD progression. Brolucizumab’s most common side effects are elevated intraocular pressure, iritis, and uveitis, which are usually mild and self-limiting. However, the drug has the potential to cause more severe side effects.
Three trials, MERLIN, RAPTOR, and RAVEN, were discontinued due to a 9.3% intraocular inflammation rate seen in monthly injections after the loading dose. Novartis now recommends against injections less than 2 months apart after the loading period due to the risk of intraocular inflammation.

Faricimab (Vabysmo, Genentech)

Faricimab (Vabysmo®, Genentech) is a new FDA-approved anti-VEGF monoclonal antibody that inhibits VEGF-A and Ang-2. Preclinical studies showed a marked reduction in neovascularization, fibrosis, and inflammation.
Through its phase 3 clinical trials, TENAYA and LUCERNE, faricimab showed safety, efficacy, and noninferiority in the treatment of wet AMD when compared to aflibercept. The YOSEMITE, RHINE, and RHONE studies all showed the safety and effectiveness of faricimab in the treatment of DME.
In the extension studies, RHONE X for wet AMD has an expected end date of August 2023, and AVONELLE X for DME has August 2024. COMINO and BALATON trials are currently evaluating the effectiveness of faricimab in treating CRVO and BRVO, which will go on until its expected end during the fall of 2023.

Susvimo (Port Delivery System with ranibizumab, Genentech)

Susvimo(Port Delivery System with ranibizumab, Genentech) recently received FDA approval in early 2022. This method allows for a port delivery system to be surgically placed within the eye allowing for the continued delivery of the anti-VEGF agent into the vitreous, requiring refills of ranibizumab in the clinic up to every 6 months.
The implant showed promising results in the multicentered Phase III Archway study. Patients had improved vision and maintained that gain equivalent to monthly injections. These results were held after 72 weeks. 98% of patients with the implant could go through 6 months without supplemental injections.
The current challenge with the implant is the significantly higher risk (3-fold) of endophthalmitis. In addition, there was a higher risk of conjunctival retraction and erosion with Susvimo compared to monthly injections.
Three other current studies address the long-term safety and efficacy of the implant (Portal study), a 9-month refill interval (Velodrome), and an evaluation of the implant for diabetic macular edema and diabetic retinopathy.
A phase 2 clinical trial compared the effects of the port delivery system filled with ranibizumab doses (10mg/ml, 40mg/ml, and 10 mg/ml) with monthly intravitreal injections of 0.5mg ranibizumab. Compared to formulations, the port delivery system with 100 mg/ml has shown efficacious results and is well tolerated. Archway, a phase 3 clinical trial for the port delivery system of ranibizumab, demonstrated non-inferiority and equivalent efficacy compared to monthly injections.

Don't forget to download our Anti-VEGF Medication Cheat Sheet!

The future of anti-VEGF

Beyond these approved and available medications, further medications are in the pipeline in the form of other intravitreal biosimilars, gene therapy (e.g. ADVM-022 by Adverum, RGX-314 by REGENXBIO), and sustained-release therapies.
Mark Shokralla, BA
About Mark Shokralla, BA

Mark Shokralla, BA, is a third-year medical student at William Carey University College of Osteopathic Medicine. He graduated in 2019 with a BA in Biology from the University of North Texas.

Mark Shokralla, BA
Sergio Karageuzian, BS
About Sergio Karageuzian, BS

Sergio Karageuzian, BS, is a third-year medical student at A.T. Still University School of Osteopathic Medicine in Arizona. In 2018, he graduated from the University of California, Davis with a B.S. in Microbiology.

Sergio Karageuzian, BS
Harris Ahmed DO, MPH
About Harris Ahmed DO, MPH

Harris Ahmed DO, MPH is a resident physician in ophthalmology at the Loma Linda University Eye Institute. He is a leader in health policy, serving in national leadership positions in multiple organizations including the AMA, AOCOOHNS, and AOA and has authored many publications and given lectures on public health advocacy and health policy, specializing in topics such as scope of practice, physician distribution, and medical education.

Harris Ahmed DO, MPH
David RP Almeida, MD, MBA, PhD
About David RP Almeida, MD, MBA, PhD

David Almeida MD MBA PhD is a vitreoretinal eye surgeon offering a unique voice that combines a passion for ophthalmology, vision for business innovation, and expertise in ophthalmic and biomedical research. He is part of Erie Retinal Surgery, a retina-only private practice with an esteemed reputation for excellence in Pennsylvania. Dr. Almeida and Erie Retinal Surgery diagnose and treat all medical and surgical conditions of the vitreous, retina and macula.

David RP Almeida, MD, MBA, PhD
Eric K Chin, MD
About Eric K Chin, MD

Dr. Eric K Chin is a board-certified ophthalmologist in the Inland Empire of Southern California. He is a partner at Retina Consultants of Southern California, and an Assistant Professor at Loma Linda University and the Veterans Affair (VA) Hospital of Loma Linda. He is a graduate of University of California Berkeley with a bachelor’s of science degree in Bioengineering. Dr. Chin received his medical degree from the Chicago Medical School, completed his ophthalmology residency at the University of California Davis, and his surgical vitreoretinal fellowship at the University of Iowa. During his residency and fellowship, he was awarded several accolades for his teaching and research in imaging and novel treatments for various retinal diseases.

Eric K Chin, MD
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