Targeting VEGF: The future is now

In the future, there will be a massive paradigm shift in terms of the durability of our therapies for wet macular degeneration and expansion of therapies for dry macular degeneration.

Reviewed by David Maberley MD, FRCPC

The “long-standing enemy” in retinal disease is vascular endothelial growth factor (VEGF) as it drives the angiogenic pathway, and there are numerous established therapies that target VEGF, according to David Maberley MD, FRCPC, head, Department of Ophthalmology, Ottawa Hospital, Ottawa, Ontario, Canada.

Ophthalmologists have learned to optimize their use of traditional anti-VEGF therapies and are now incorporating newer therapies like brolucizumab for managing retinal diseases, and in the not-so-distant future they can look forward to gaining familiarity with faricimab and using a new delivery system for ranibizumab. Further down the road, they should be on the lookout for new treatments for geographic atrophy, according to Maberley.

Delivering a talk about what is on the cutting edge for medical retina at the annual Sally Letson Symposium held recently in Ottawa, Ontario, Canada, Maberley described several innovations that ophthalmologists will be able to embrace.

“There will be a massive paradigm shift that we will see in terms of the durability of our therapies for wet macular degeneration and expansion of therapies for dry macular degeneration,” Maberley explained.

David Maberley MD, FRCPC

IOI events with brolucizumab

Some of the advantages of 1 of the newer therapies to treat retinal conditions, brolucizumab, is its low molecular weight, improved penetration of the retina, and ability to dry the retina better than aflibercept or ranibizumab, noted Maberley.

The issue that has arisen with the use of brolucizumab is the development of

intraocular inflammatory events, which occur in about 5% of cases, said Maberley.

“The main concern has been the development of retinal vasculitis and retinal occlusive disease, which can be the cause of very severe vision loss,” Maberley added.

Most patients who had developed intraocular inflammatory events with brolucizumab in the HAWK (NCT02307682)and HARRIER (NCT02434328) clinical trials had experienced these events in the first 6 months of the trial, had resolution of these events by the end of the 2 clinicals trials, and had been able to continue with treatment in the clinical trials, according to Maberley.

“Current guidance now is to carefully examine your patient before using this drug and make sure that there is no active inflammation before you start,” Maberley explained. “Monitor your patients closely for active inflammation, especially in the first 6 months, and educate your patients about the symptoms of intraocular inflammation.”

Should anterior uveitis develop with brolucizumab, topical drops are needed, and if posterior uveitis develops, systemic treatment and/or intravitreal steroids may be warranted, according to Maberley.

The efficacy of brolucizumab has been impressive in postmarketing studies for improving the OCT status of patients who did not respond to other anti-VEGF treatments and reducing the size of pigment epithelial detachments.

“In the REBA study, every single patient in the first 3 months of treatment had their retinas become completely dry,” Maberley added.

New agent for nAMD and new formulation of aflibercept

Faricimab has been approved for the treatment of neovascular age-related macular degeneration (nAMD) as of July 2022 by the FDA and in Canada by Health Canada as of the end of August 2022, noted Maberley.

“It is important because this treatment blocks VEGF and Ang-2. Ang-2 promotes inflammation and enhances VEGF activity,” he said, noting faricimab is a durable treatment.

In terms of toxicity, there are intraocular events, but there appear to be fewer serious inflammatory events observed with faricimab use compared with the toxicities associated with brolucizumab, according to Maberley.

While it is not a new treatment, aflibercept will become available in a prefilled syringe in an 8-mg dose. The Candela study (NCT04126317) demonstrated that 12-week dosing was more likely with the higher dose of aflibercept, noted Maberley.

“There were significant reductions in central retinal thickness with the 8-mg dose compared to the 2-mg dose through week 44 from baseline,” he pointed out. “It did dry better than the 2-mg dose.”

Lengthening the interval between dosing

There is always a goal to reduce the frequency of dosing, and 1 of the ways it may be achieved is via a depot that can slowly elute drugs into the eye.

Maberley pointed to ranibizumab’s port delivery system, which was investigated in the Archway study (NCT03677934). The therapy will require implantation every 6 months, and data suggest few patients, less than 5%, need “top-up therapy” over 6 months. Some toxicities of concern will include endophthalmitis, implant dislocation, and conjunctival bleb or bleb leak.

Novel approaches in geographic atrophy

As there is complement dysregulation involved in the pathogenesis of geographic atrophy, novel treatments like pegcetacoplan and avacincaptad pegol are addressing this dysregulation, according to Maberley.

Pegcetacoplan has shown clinically meaningful decreases in central and non-central geographic atrophy lesion growth in clinical trials, but there were no visual acuity gains reported.

“We don’t yet know if these reductions in lesion size are clinically significant,” Maberley added.

From a toxicity perspective, the biggest threat of pegcetacoplan is the development of exudative age-related macular degeneration, Maberley said.

Avacincaptad pegol, a complement 5 inhibitor, demonstrated decreases in geographic area growth in non-central geographic atrophy, said Maberley.

Biosimilars on the horizon

Biosimilars for established drugs like aflibercept and ranibizumab are being introduced in North America, and Maberley warned that biosimilars are not identical to brand-name drugs.

“The immunogenicity of the biosimilar agents cannot be assumed to be similar,” he said.

There are concerns that cost containment pressures by third-party payers may affect the range of therapies patients can access, said Maberley.

“We’re going to need to be stronger advocates for our role in the decision of which drugs we choose,” Maberley concluded. “And we need to be actively out there, lobbying for our patients’ rights to maintain therapies that they are successful with. We also need to be lobbying for our patients that may benefit from these newer therapeutics, which have prolonged durability, or new therapeutic benefits, such as in geographic atrophy.”

David Maberley MD, FRCPC

P: 604-875-4199

Maberley sits on advisory boards for Novartis, Bayer, Roche, Apellis, and Alcon. He receives research support from Regenxbio, Apellis, Ionis, and Opthea.