Molecular insights and clinical experience: Extending anti-VEGF durability

A recent Ophthalmology Times Case-Based Roundtable focused on extended anti-VEGF treatment durability. Peter K. Kaiser, MD, the Chaney Family Endowed Chair in Ophthalmology Research and professor of ophthalmology at the Cleveland Clinic Lerner College of Medicine in Ohio, served as moderator.

Treatment decisions

The discussion first examined treatment choices for patients with treatment-naive age-related macular degeneration (AMD) and treatment-
naive diabetic macular edema (DME). The options depend on the region of practice and the patient’s insurance coverage, Kaiser noted.

Regarding AMD, the factors that differentiate the drugs are their ability to dry the retina and their treatment durability, Kaiser continued. However, he noted, because no available treatments provide significantly better visual acuity (VA) outcomes, the insurance companies impose step therapy, which generally begins with off-label bevacizumab (Avastin; Genentech). The results of the Comparison of Age-
related Macular Degeneration Treatments Trials (NCT00593450) and the Inhibition of VEGF in Age-related choroidal Neovascularisation (ISRCTN92166560) studies showed bevacizumab is a reasonable drug with which to start AMD treatment.

For patients with traditional Medicare and comprehensive insurance coverage, treatment typically begins with aflibercept 2 mg (Eylea; Regeneron) or the newer faricimab (Vabysmo; Genentech) and aflibercept 8 mg (Eylea HD; Regeneron).

Regarding DME, the phase 3 DRCR.net Protocol T study (NCT01627249) showed the superiority of aflibercept over bevacizumab and ranibizumab (Lucentis; Genentech).

Case 1

This man, aged 53 years, had poor blood glucose control and hypertension with a hemoglobin A_1C of 10.1. The baseline VA was 20/100. Large cystic spaces were visible in the retina, indicating chronic DME.

Given poor vision and chronic edema, and with good private insurance coverage, the patient was started on aflibercept 8 mg, achieving faster retinal drying than with aflibercept 2 mg. The DME showed good improvement after 1 month. A second injection also resulted in further improvement. However, because of the disorganization of the retinal inner layers, the patient’s disease prognosis was poor. The outer retinal changes also were a poor prognostic sign for his vision. In this case, the patient is unlikely to achieve 20/20 vision. “It is important to set expectations early for such patients,” Kaiser said.

The participants also discussed the differences between faricimab and aflibercept 8 mg. The former inhibits angiopoietin-2 and VEGF-A, and the latter blocks VEGF-A, VEGF-B, placental growth factor (PGF), and galectin. Aflibercept’s ability to block PGF and faricimab’s ability to block angiotensin-2 are important because both are elevated in AMD and especially in DME. “It is reasonable, therefore, that the newer molecules would achieve slightly better outcomes,” Kaiser said.

The participants also discussed a dexamethasone intravitreal implant (Ozurdex; AbbVie), which provides extended drug release from 4 to 6 months. A consideration in a young patient is cataract development; if the patient had not responded favorably to aflibercept, the dexamethasone implant would have been a treatment option.

Case 2

A woman aged 72 years who does not smoke and has a family history of AMD was diagnosed with new neovascular AMD. The initial treatment was 3 bevacizumab injections, which resulted in a VA of 20/30. Further treatment considerations were continuing with monthly bevacizumab or switching to another anti-VEGF drug for additional improvement.

The patient was switched to aflibercept
2 mg, resulting in a slight improvement.
However, the optical coherence tomography (OCT) images showed marginal benefit.

The patient continued aflibercept 2 mg at 6-week intervals. After 4 injections, the patient’s VA slightly declined compared with that of the previous month. Bevacizumab was restarted, with no changes observed on imaging. Despite partial responses to both agents, the retina remained exudative, and treatment was switched to faricimab.

Treatment intervals

The discussion then focused on treatment intervals. Most participants agreed that maintaining a 6-week dosing interval was the optimal approach. At that time, VA remained stable. However, imaging findings worsened after 1 injection. Six weeks following a second injection, OCT demonstrated slight improvement.

Despite stable VA, outcomes were inferior to prior aflibercept response, prompting a switch to aflibercept 8 mg. Six weeks later, the VA and OCT improved slightly. Kaiser then extended the treatment interval despite a small amount of subretinal fluid and no intraretinal fluid. When considering how aggressively to treat, the consensus was that some fluid was tolerated.