Welcome back to Retina Mentor Moments! As a brief reminder, this series is hosted by John W. Kitchens, MD, a retina specialist and practice partner at Retina Associates of Kentucky, and features curated discussions between retina specialists on mentorship in ophthalmology, compelling research, and novel disease treatments.
In the first episode of 2025, Dr. Kitchens is joined by Michael Klufas, MD, to discuss applications of second-generation anti-vascular endothelial growth factor (VEGF) agents, such as their role in retinopathy of prematurity (ROP) and how they can reduce treatment burden in diabetic patients.
Dr. Klufas is a retina specialist at Mid Atlantic Retina and Wills Eye Hospital and is an assistant professor of ophthalmology at Thomas Jefferson University in Philadelphia, Pennsylvania. He has authored over 75 scientific publications and textbook chapters on vitreoretinal diseases.
What you need to know about next-generation anti-VEGF drugs
In 2004, the FDA approved the first anti-VEGF medication for ophthalmic use with pegaptanib (Macugen) for age-related macular degeneration (AMD) after two large studies led by the VEGF Inhibition Study in Ocular Neovascularization (VISION) Clinical Trial Group demonstrated its efficacy.1
Since then, several more anti-VEGF drugs have received FDA approval, revolutionizing the treatment options for retinal vascular diseases such as neovascular AMD (nAMD), diabetic macular edema (DME), retinal vein occlusion (RVO), and ROP.
These first-generation of anti-VEGF drugs include:2
- Bevacizumab (Avastin, Genentech/Roche)
- Aflibercept 2mg (Eylea, Regeneron)
- Ranibizumab (Lucentis, Genentech/Roche)
Continued innovations in the anti-VEGF landscape have led to the FDA approval of second-generation agents, including faricimab-svoa (Vabysmo, Genentech/Roche) and aflibercept 8mg (Eylea HD, Regeneron).2
Clinical trial data for these drugs have reported increased time intervals between injections with noninferior outcomes for nAMD and DME:3-6
- Faricimab
- nAMD
- TENAYA (NCT03823287) and LUCERNE (NCT03823300)
- DME
- YOSEMITE (NCT03622580) and RHINE (NCT03622593)
- nAMD
- Aflibercept 8mg
- nAMD
- PULSAR (NCT04423718)
- DME
- PHOTON (NCT04429503)
- nAMD
As such, these interventions have the potential to reduce the treatment burden of patients with retinal vascular disorders.
Using second-generation anti-VEGF agents for ROP
While the current standard treatment for ROP is laser photocoagulation of the peripheral avascular retina, anti-VEGF agents have emerged as a promising treatment alternative.7 Dr. Klufas noted that in his experience, as small as a quarter dose (ex., 0.3mg of Lucentis) for ROP patients can be effective in providing regression.
He added that considering safety risks is paramount in neonatal patients, as studies have reported systemic absorption of anti-VEGF drugs can cause a reduction in VEGF serum levels, which may lead to abnormal organogenesis or neurodevelopment.8
Of note, aflibercept 2mg received FDA approval for ROP in 2023. Dr. Klufas remarked that his practice has primarily shifted to using high-dose aflibercept in ROP patients. Usually, he treats one eye and then follows up after 1 to 2 days to check for regression in the other eye, which may indicate systemic absorption.
In addition, Dr. Klufas typically recommends laser photocoagulation at some point after anti-VEGF injections, particularly if there is significant posterior disease, media opacity, anterior plus disease, or iris engorgement.
To learn why Dr. Klufas prefers to follow-up anti-VEGF treatments with laser for ROP patients, watch the full interview!
Next-generation anti-VEGF therapies for DME
Recently, Dr. Klufas co-authored a literature review of anti-VEGF treatment extension protocols for DME in Current Opinion in Ophthalmology that highlighted a paradigm shift toward less frequent injections.9
Earlier trials established the foundation for DME treatment regimens by demonstrating sustained visual gains with continuous treatment, including:10-12
- Ranibizumab
- RISE (NCT00473382) and RIDE (NCT00473330)
- LUCIDATE (NCT01223612)
- Aflibercept
- VISTA (NCT01363440) and VIVID (NCT01331681)
Yet, newer trials (listed below) have revealed that less frequent dosing of various anti-VEGF agents can maintain similar visual acuity and anatomical outcomes to traditional monthly injections:4,6,13,14
- Aflibercept, bevacizumab, or ranibizumab
- PROTOCOL T (NCT01627249)
- Brolucizumab
- KESTREL (NCT03481634) and KITE (NCT03481660)
- Faricimab
- YOSEMITE and RHINE
- Aflibercept 8mg
- PHOTON
In Dr. Klufas’ opinion, aflibercept is arguably one of the best compounds for DR and DME, as he has seen significant regressions, and many patients on aflibercept 2mg usually get out to 10 weeks on average between injections. He has also found that these have been prime patients to convert to aflibercept 8mg, wherein he has observed better disease control and extensions that are approaching 24 weeks in some patients.
Watch the interview for more reflections on the literature review and pearls for prescribing anti-VEGF injections for DME!
Reducing treatment burden with next-generation anti-VEGFs
Dr. Klufas discussed an example of how newer anti-VEGF therapies have decreased treatment burdens with a 90-year-old patient he has been treating for 8 years who is now monocular and has persistent exudation. The patient received aflibercept 2mg injections in 12-week intervals, and unfortunately, was not a good candidate for surgery.
To address the residual exudation and increase the interval between injections, Dr. Klufas recommended the patient start aflibercept 8mg, as clinical trial data has demonstrated efficacy with 20- to 24-week dosing.6 This allowed the patient to come in half as often without sacrificing visual acuity.
What to look out for in the retina pipeline
New interventions and therapies for retinal diseases that Dr. Klufas is keeping an eye on include:
- Revakinagene taroretcel-Iwey (ENCELTO, Neurotech Pharmaceuticals)
- This allogeneic encapsulated cell therapy implant secretes ciliary neurotrophic factor (CNTF) and was recently approved by the FDA for the treatment of idiopathic macular telangiectasia type 2 (MacTel)15
- Gene therapies for retinal vascular diseases, including subretinal gene therapies16
- Ranibizumab injection 100mg/mL (SUSVIMO, Genentech/Roche) for DME
- Of note, SUSVIMO received FDA approval for DME earlier this year
- While Dr. Klufas is cautious about placing a permanent piece of hardware in a patient’s eye for 20+ years, he has seen interest in SUSVIMO from diabetic patients seeking an alternative treatment to monthly or bimonthly injections
Conclusion
The recent innovations in anti-VEGF therapies provide physicians with even more options to reduce treatment burden in patients with retinal vascular diseases via longer injection intervals with comparable visual acuity outcomes to earlier anti-VEGF drugs.
Dr. Kitchens highlighted that retina specialists, patients, and trainees alike can be excited by the variety of new therapies in development and with recent FDA approvals that address unmet needs.
