Eyeing Improvement: Fine-Tuning Anti-VEGF for Macular Degeneration

A patient diagnosed with age-related macular degeneration (AMD) or diabetic macular edema (DME) is prescribed to anti-vascular endothelial growth factor (VEGF) injections—a therapy touted for its efficacy, but nonetheless a painful, constant, costly, intravitreal procedure.

The patient—likely elderly, and more susceptible to worsening vision as they age—must receive the therapy once every 5-6 weeks. As Peter Campochiaro, MD, a professor of ophthalmology and director of the Retinal Cell and Molecular Laboratory at Johns Hopkins University, suggested to MD Magazine®, the patient may break a leg. Or they could get sick, or miss their ride to the doctor’s office.

These common inconveniences aren’t options for AMD or DME patients trying to retain their best vision. Anti-VEGF therapy retention, without missed regimens, is their opportunity to limit the effects of their disease, but it’s a lifelong commitment with difficulties in convenience.

“It’s not just a matter of convenience, it’s a matter that they’re not getting sufficient treatment,” Campochiaro said to MD Mag at the annual American Academy of Ophthalmology (AAO) Annual Meeting in Chicago. “And it can result in poor outcomes.”

Treatment Burdens

Though anti-VEGF therapies have been a fixture in ophthalmological care for years now, 2018 saw a turn of conversation about the drug: is this the optimal delivery of care?According to a new study this year from the Wills Eye Hospital in Philadelphia, patients with neovascular AMD (nAMD) are not dependable to continue anti-VEGF therapy on their own—even if the treatments are further apart.

The cohort analysis of 9000-plus patients with nAMD to receive injection therapy at an urban, private retina specialist facility found that 22.2% were lost to follow-up in between 12-month intervals of anti-VEGF care. Investigators also identified patient demographics more likely to miss treatments: minority groups, patients aged 81 years or older, patients with an adjusted gross income of $75,000 or less, and those living more than 20 miles from the facility were more likely than other to be lost to follow-up.

Though investigators could not provide a definite explanation to the differing rates among patients, they suggested that a lack of immediate benefit from the therapy could influence patients’ decisions.

“Convincing patients that poor adherence will greatly counter the beneficial effects of treatment is a very important first step,” they wrote. “Helping them to act on this knowledge by using practical and feasible interventions must follow.”

That may prove more difficult, as more frequent anti-VEGF dosing in the first year of care—at least for patients with nAMD—has now been shown to be more beneficial. Retrospective data presented at the American Society of Retina Specialists (ASRS) Annual Meeting in Vancouver, BC, this year showed that newly diagnosed patients to receive a greater rate of injection therapy in their first year reported greater visual gains.

Study author Andrew A. Moshfeghi, MD, MBA, of the USC Roski Eye Institute at Keck School of Medicine, told MD Mag the study results also showed that about 80% of patients were receiving at least 7 injections in their first year, bucking against the popular notion that clinicians have been actually under-dosing patients.

Nonetheless, other investigators—including a China-based team which reported on aflibercept (Eylea) for DME this year—have cited the burdensome cost of anti-VEGF therapy outweighing the benefits of continuous care. They cited aflibercept currently costing about $2000 per dose. This same drug is heavily preferred at least among the ASRS community—72.7% of polled specialists in the US society stated it is the most effective therapy for patients with nAMD.

Though biosimilars for current anti-VEGF therapies are reaching the market, and therefore cutting down patient costs, the result could be a greater expectancy of dosing from clinicians. Alay S. Banker, MD, of the Bankers Retina Clinic & Laser Center in India, told MD Mag the introduction of proven biosimilars to the market will result in a dosing rate greater than once-monthly.

“There's a lot of office visits, office work—it's a big burden, not only to the patient but also to the support group of the patient’s relatives,” Banker acknowledged. “And you have to come down, and travel long distances. So I think issues are still there.”

The Future of Care

That’s why the greater hope is for more durable therapies.Banker said researchers are fixed on finding molecules capable of giving clinicians greater lengths of efficacy between doses, and ensure patients a more steady regimen than the preferred treat-and-extend plan.

He envisioned this coming to fruition as part of new sustained-release delivery devices, or implants that allow longer sustained duration of action on patients’ eyes.

“In the future I think it's not just going to be one drug,” Banker said. “I think we're going to play around with multiple drugs and combinations and the best way for that particular patient—which could provide the best results, with the least number of injections and the least number of clinic visits.”

Practices which would ensure fewer doses in patients’ anti-VEGF regimen were particularly researched in 2018. REGENXBIO released phase 1 results for its investigative gene therapy RGX-314, showing the drug resulted in improved protein expression levels and reduced anti-VEGF injections in frequently-treated patients with nAMD.

Another study, presented at ASRS, found that low-dose proton beam irradiation therapy could positively and safely sustain the benefits of anti-VEGF in patients with AMD when used in combination.

In the vein of Banker’s vision, the newest results from the LADDER study presented at AAO showed an implantable delivery system for ranibizumab (Lucentis) allowed some patients with nAMD to go up to 15 months without another injection dose.

Other newer innovations have fixated on the other burdens of current anti-VEGF dosing: cost and convenience. A team of Egyptian investigators recently reported that high-dose intravitreal triamcinolone acetonide could serve as low-cost alternative treatment, as it delivers a higher dosage of steroid directly to the site of care and is only needed in 4- to 6-month doses.

Perhaps even more ambitiously, a British team is working towards conducting human trials for anti-VEGF eye drop therapy. In the eyes of Felicity de Cogan, PhD, MChem, of the Institute of Microbiology and Infection, University of Birmingham, this could address all the troublesome facets of preferred AMD/DME care.

“From the outset, we realized that delivering drugs through eye drops would mean that patients can administer their treatment themselves, and this would be less costly, save time for patients and healthcare providers, and reduce the potential complications that can arise from injections,” she said in a statement.

What ophthalmology is currently facing—questions as how to better optimize its optimal therapy—is a problem less-resourced specialties may wish it could face instead of, say, limited therapy options. But with a constantly aging population in need of certain, frequent care to keep their vision, improving on current anti-VEGF therapies is a crucial goal to stay focused on in 2019.

_{This article is part of MD Magazine's This Year In Medicine 2018 series. To read more from the series, check out the links below and follow us on Twitter at @MDMagazine.Finding and Treating the Young Hepatitis C Patient}

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