The best treat-and-extend regimens for wet AMD

Boston-When treating patients with wet age-related macular degeneration (AMD), regular monthly therapy with anti-vascular endothelial growth factor (VEGF) therapies or patient monitoring results in optimal visual outcomes.

The more recently discussed treat-and-extend regimens offer a proactive approach to minimize the treatment burden with good visual outcomes. Difficult cases may benefit from combination therapy according to Jeffrey Heier, MD.

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Anti-VEGF agents have been the mainstay of AMD therapy for more than a decade. Over that time, clinicians have evaluated the strengths and weaknesses of the drugs and the dosing regimens in which the drugs are administered.

Dr. Heier, professor of ophthalmology, Tufts University School of Medicine and Harvard University Medical School, Boston, evaluated the currently used regimens to determine the ideal approaches for these patients.

Numerous studies have identified the efficacy and safety similarities achieved with ranibizumab (Lucentis, Genentech), bevacizumab (Avastin, Genentech), and aflibercept (Eylea, Regeneron Pharmaceuticals) in patients treated for wet AMD.

“The studies showed that regular anti-VEGF therapy is outstanding in maintaining visual acuity (VA) and very good for recovering vision,” he said. “However, deviations from regular therapy results in decreased VA, with longer-term follow-up of patients causing increased concerns.

“When we evaluate a regimen, the goal should be to maximize visual outcomes and minimize treatment burden,” he emphasized.

NEXT: Breaking the regimens down

Evaluations of as-needed dosing have shown that the results can approach the outcomes achieved with regular monthly therapy. These goals were apparent in the Comparison of AMD Treatment Trial, year 2 of the VIEW Study, and the Harbor Study. The caveat is that those regimens required monthly follow-up with strict re-treatment guidelines. When clinicians deviate from the guidelines, the VA gains often can be lost, as became apparent in the VIEW Extension Study when regular follow-up was not maintained, Dr. Heier said.

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As-need dosing regimens can work, but monthly patient monitoring and strict re-treatment guidelines are necessary.

“Our concern is that this regimen carries the greatest risk of a catastrophic ocular events, that is, large submacular hemorrhages,” he specified, and pointed to 5-year follow-up of patients receiving as-needed therapy in which treatment gains were not achieved and patients were maintained, meaning that they lost less than three lines of vision.

Treat-and-Extend Regimen

The Preferences and Trends Survey in 2014 indicated that almost 80% of U.S. clinicians adhere to the treat-and-extend regimen, as do about 60% of their foreign counterparts.

“The treat-and-extend regimen is considered a continuous proactive approach that minimizes recurrences, setbacks, and overtreatment,” Dr. Heier explained.

An important study of the treat-and-extend approach performed at the Wills Eye Institute evaluated patients treated monthly with bevacizumab and ranibizumab until all signs of choroidal neovascularization (CNV) activity resolved. The regimen was then extended by 2-week intervals. If there was a CNV recurrence, the regimen was shortened by 2 weeks.

 In 210 patients followed for 12 months and 60 patients followed for 3 years, the functional vision was found to approach the results seen in randomized clinical trials and the anatomic outcomes were good. In the LUCAS trial, in which ranibizumab and bevacizumab were compared in a treat-and-extend regimen, the results also were comparable to other randomized clinical trials.

NEXT: Combination Therapy

“These treatments may synergistically target different pathways,” Dr. Heier said. “They may increase the durability of current therapies, decrease the number of injections, which perhaps will lead to increased safety.”

The combination of photodynamic therapy (PDT) and anti-VEGF injections is one example. The drugs have different mechanisms of action, in that PDT selectively destroys CNV and anti-VEGF drugs inhibit VEGF.

“A number of studies have reported positive vision and safety outcomes, especially of the so-called triple therapy, which includes PDT, an anti-VEGF drug, and a steroid,” Dr. Heier recounted.

However, the results of the randomized, controlled Denali and Mont Blanc studies, and the positive results of triple therapy previously reported did not pan out. In addition, a review of PDT and ranibizumab used in seven randomized controlled trials also showed no benefit associated with the combination therapy.

Investigators saw a trend toward the need for fewer injections, but better vision was achieved with monotherapy.

An exception to these disappointing results was a study of combination therapy of PDT and anti-VEGF therapy for polypoidal choroidal vasculopathy. In this study, which had guidelines for identification of the CNV and laser therapy, the VA outcomes trended toward the combination therapy having an advantage compared with monotherapy. Triple therapy regimens that included steroids did not show an advantage in larger trials and the efficacy was similar to monotherapy.

The Evaluation of Ranibizumab with Implantable Dexamethasone in Wet AMD study evaluated the dexamethasone implant (Ozurdex, Allergan) as an adjunctive therapy to ranibizumab. Ranibizumab was the initial treatment and patients then were randomly assigned to either the implant and ranibizumab or sham and ranibizumab. Patients were followed to the first needed ranibizumab injection, and the time to needing the first injection was later with the combined therapy. Patients receiving the combination therapy were more likely to receive no or one injection along with a small VA increase.

NEXT: Gene Therapy

Another combination therapy includes a strategy of attacking pericytes to prevent vessel maturation and/or resistance in the Ophthtec study.

“Animal models have suggested that the anti-platelet-derived growth factor and anti-VEGF treatments would work synergistically,” he said.

Gene Therapy

Gene therapy is an option to establish sustained drug delivery.

“Our current therapies are limited by the peaks and troughs of first-order pharmacokinetics,” Dr. Heier said. “The rationale for gene therapy is that a therapeutic level could be delivered in a steady state.

“This may offer efficacy, safety, and compliance benefits,” he continued.

Avalanche and Genzyme are studying subretinal and intravitreal routes of an adeno-associated virus vector with DNA encoding for a soluble VEGF receptor protein.