Overcoming anti-VEGF treatment burden and adherence challenges

Bios Dr. Zafar is a vitreoretinal surgery fellow at Wills Eye Hospital/Mid Atlantic Retina in Philadelphia. Dr. Gupta is a retina specialist and surgeon at Wills Eye Hospital/Mid Atlantic Retina in Philadelphia. DISCLOSURES: The authors have no relevant financial disclosures.

Intravitreal anti-VEGF injections are now the accepted standard of care and are commonly used for the treatment of a myriad of retinal vascular diseases, including choroidal neovascularization, diabetic retinopathy, diabetic macular edema, retinal vein occlusions and retinopathy of prematurity. The approval of the first anti-vascular endothelial growth factor product in 2004 transformed the field of retina. Macugen (pegaptanib sodium injection), a VEGF165 inhibitor developed by Eyetech Pharmaceuticals, was the first anti-angiogenic molecule to demonstrate decreased vision loss in patients with neovascular age-related macular degeneration in Phase II and III clinical trials.¹ Since then, multiple anti-VEGF products have been developed and have gained FDA approval,² with over 17.5 million intravitreal injections performed in the United States between 2014 and 2019.³

Here, we review the shortcomings of anti-VEGFs, how novel therapies are improving patients’ adherence and visual outcomes, and what the future has in store for the management of retinal vascular diseases.

Treatment burden of anti-VEGFs

While anti-VEGF therapy remains the standard of care for treatment of the above-mentioned conditions, real-world clinical setting studies have repeatedly demonstrated outcomes are often poorer compared to the clinical trials, with undertreatment a significant contributor to suboptimal outcomes.⁴ In clinical practice, anti-VEGF frequencies for eyes with DME, for example, range from 2.2 to 4.4 injections each year.^5,6 In contrast, eyes enrolled in clinical trials receive an average of nine to 12 injections per year.

Similar findings have also been reported for nAMD and RVOs.⁷ Treatment patterns outside clinical trials, however, are multifactorial. While provider clinical decision-making based on treatment response certainly plays a role, follow-up visits after treatment are also imperative to optimize visual outcomes. In a large retrospective study of more than 9,000 patients with treatment-naïve nAMD, the lost to follow-up (LTFU) rate was 22.2 percent.⁸ In another cross-sectional study conducted in Germany, the LTFU rate was 18.9 percent among 95 patients with nAMD. An analysis of 2,595 patients with non-proliferative DR and DME found approximately one in four patients were LTFU, and a similar LTFU rate (22 percent) was also noted among 1,718 patients with proliferative DR.^9,10

Understanding the prevalence and reasons behind nonadherence and noncompliance is important, in that they remain significant barriers to optimizing outcomes for patients with retinal vascular disorders receiving anti-VEGF therapy. High intravitreal injection treatment burden significantly impacts patient lives, with many factors affecting adherence, which is influenced by financial costs, time constraints and patient perspectives on their treatment response.^11,12 While attempts to limit treatment burden through the adoption of different protocols such as treat-and-extend and pro re nata have been used, fewer injections have been associated with worse visual acuity outcomes.¹³ Patients with chronic conditions such as diabetes often need frequent visits to other health-care providers, which adds to their health-care visit burden.

LTFU rates also vary by race/ethnicity, with white patients having the lowest rates of nonadherence. Among patients with DME or nAMD, LTFU rates were reported to vary from 27 to 30 percent among Black patients and 38 percent among Hispanics compared to 19 to 20 percent for white patients.^9,10 Increasing age has also been associated with increasing LTFU rates, with the risk increasing per decade of life.¹⁴ A possible explanation for this may be the increasing prevalence of systemic comorbidities among older patients which can potentially limit an individual’s ability to operate independently. Indeed, in a systemic review, almost a quarter of patients cited the lack of a caretaker who could take them to their appointments as a barrier to anti-VEGF adherence.¹⁴ Greater socioeconomic disadvantage, lack of transport or distance to the eye clinic are among other factors that have been reported as barriers to patient compliance.^9,10

Port Delivery System with ranibizumab (PDS) implant. (A) Port Delivery System with ranibizumab implant showing four key components: the extrascleral flange that anchors the implant in the sclera, the self-sealing septum that allows for implant refills, the implant body that contains the drug reservoir for the ranibizumab formulation, and the release control element that controls the rate of ranibizumab diffusion from the implant into the vitreous. Patient images from a PDS-implanted patient with (B) eye in primary position (implant not visible), (C) eye looking up with implant visible through dilated pupil and (D) eye looking down to visualize PDS septum. Campochiaro PA, et al. (Creative Commons license: https://creativecommons.org/licenses/by-nc-nd/4.0/)

Safety and efficacy of Susvimo

While anti-VEGF treatment has revolutionized how we manage retinal and choroidal vascular diseases, significant limitations still exist, including the need for repeat injections, the potential for disease rebound upon discontinuing treatment, and that not all patients respond adequately to treatment. Therefore, there’s a need for developing both longer-acting therapies as well as novel therapies.

The Port Delivery System with ranibizumab, or Susvimo (Roche/Genentech), is a long-acting drug delivery system that provides continuous delivery of a customized formulation of ranibizumab (100 mg/mL) into the vitreous.¹⁵ The implant contains a refillable reservoir that’s surgically inserted through a small incision in the sclera and pars plana. Ranibizumab moves by passive diffusion down a concentration gradient from the implant reservoir, through a porous metal release control element specifically designed for ranibizumab, and into the vitreous cavity.¹⁵ By sustained intravitreal VEGF suppression, it has the potential to reduce treatment burden while maintaining optimal vision outcomes.

Susvimo gained FDA approval for the treatment of nAMD in 2021 based on the results of the Phase II LADDER trial and the Phase III ARCHWAY trial.^15,16 In the ARCHWAY trial, the PDS arm was noninferior and had equivalent VA efficacy compared to monthly intravitreal anti-VEGF injections.¹⁶ Most patients (98.4 percent) didn’t require supplemental treatment before the first refill-exchange at week 24.¹⁶ However, as with any innovation, challenges are expected. Initial rates of vitreous hemorrhage with PDS implantation were high at 50 percent. Modifying the surgical technique by addition of prophylactic laser ablation of the pars plana after scleral dissection reduced VH rates to around 4.5 to 5.2 percent.¹⁷

In 2022, the device underwent a voluntary recall for cases of septum dislodgement. Manufacturing process improvements and component-level changes were made to address this issue, with the updated PDS implant receiving FDA approval in July 2024, and since then, has been reintroduced in the United States for clinical use.¹⁸

On February 4, 2025, Susvimo received FDA approval for DME based on findings from the PAGODA trial and most recently on May 22, 2025, was FDA approved for DR. In the PAVILION trial for DR, 80 percent of patients in the PDS arm (refill exchange every nine months) achieved at least a two-step Diabetic Retinopathy Severity Scale improvement from baseline versus 9 percent in the control group.¹⁹ Rates of DME and PDR were also significantly lower in the PDS group versus the control group (7.1 percent vs. 47 percent). In terms of safety prolife in the PDS arm, the retinal detachment rate was 1 percent and no endophthalmitis cases were seen,¹⁹ which is unlike the number of cases observed in the LADDER (n=3; 1.7 percent) and ARCHWAY (n=4; 1.6 percent) trials.^15,16 The PAGODA trial similarly established noninferiority of PDS (refill exchange every six months) to monthly anti-VEGF injections for treatment of DME. No cases of endophthalmitis or retinal detachment were reported.²⁰

Anti-VEGFs in the pipeline

Gene therapy for continued VEGF suppression is another avenue actively being explored. It offers the potential for a one-time treatment, shifting the paradigm from maintenance to prevention. ABBV-RGX-314 is an adeno-associated virus serotype 8 vector (AAV8) that expresses an anti-VEGF-A antigen-binding fragment and provides potential for continuous VEGF-A suppression after a single subretinal injection.²¹ It was well-tolerated in Phase I/IIa trials with no serious intraocular inflammation events reported. In the bilateral dosing study, 78 percent of patients were injection-free at the nine-month mark, and there was a 97-percent reduction in overall treatment burden. ABBV-RGX-314 is currently being studied in a pair of Phase III pivotal trials, ATMOSPHERE and ASCENT. Two Phase II trials evaluating delivery of this therapeutic to the suprachoroidal space are also underway.

Ixoberogene soroparvovec (ixo-vec, formerly ADVM-022), is another gene therapy product currently under investigation for nAMD. Ixo-vec is delivered via a single, in-office, intravitreal injection. It uses a novel vector capsid, AAV2.7m8, with administration resulting in long-term, stable expression of aflibercept.²² In the OPTIC study, a Phase I trial involving 30 participants, the mean annualized VEGF injections were reduced by 80 percent in the lower dose group and 98 percent in the higher dose group. At Week 104, 53 percent of participants in the lower dose group and 80 percent in the higher dose group were supplemental injection-free.²² Adverum Biotechnologies. is conducting a Phase III ARTEMIS trial evaluating Ixo-vec administration compared to aflibercept.

Developed by 4D Molecular Therapeutics, 4D-150 combines an intravitreal vector, R100, and a transgene cassette that expresses both aflibercept and a VEGF-C inhibitory RNAi.²³ This dual-transgene payload inhibits four members of the VEGF angiogenic family: VEGF A; B; C; and Placental Growth Factor (PlGF). In a Phase IIb trial, 4D-150 administration resulted in an 89 percent overall reduction in annual injections with 70 percent of patients remaining injection-free through 52 weeks.²³

Tyrosine kinase inhibitors represent a possibly promising, novel therapeutic targeting angiogenesis. Compared to anti-VEGF medications which primarily inhibit VEGF-A extracellularly, TKIs are smaller molecules capable of diffusing into cells and inhibiting all VEGF receptor isoforms as well as other TK receptors such as fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR).²⁴ Several TKI products are currently in development including EYP-1901 (vorolanib; EyePoint Pharmaceuticals) and CLS-AX (axitinib; Clearside Biomedical). EYP-1901 administration resulted in approximately 44 percent of patients remaining injection-free through 14 months in the Phase II DAVIO2 trial.²⁵ Data from the ODYSSEY, a Phase IIb trial, showed CLS-AX injection was associated with an 84-percent reduction in injection burden and 67 percent of patients required no supplemental therapy out to six months.²⁶

These pipeline trials provide insight into the scope of anti-VEGF treatments that’ll be available in the future. After more than two decades of research, development and FDA approvals, this treatment space continues to thrive and provide promising results for patients with retinal vascular diseases.

Bottom line

Anti-VEGF therapy is effective. However, the need remains to develop longer-acting anti-angiogenic therapies that reduce injection burden, alleviate the visit burden on patients and their caregivers, improve treatment adherence and optimize visual outcomes. Several therapies are currently under development which hold the promise of heralding our field into a new exciting era. Susvimo, which requires a refill exchange every six to nine months, is now FDA approved for the treatment of nAMD, DME and DR. Results from the early phase gene therapy and TKI trials have been promising but continued research is necessary before they can become a reality. RS

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