Epimacular radiation and anti-VEGF therapy may help fill current treatment gaps

Phase 2 clinical trial shows potential for combined brachytherapy and anti-VEGF in the treatment of wet AMD.

Early evidence from a clinical trial suggests that concomitant treatment with brachytherapy and anti-VEGF agents may help address current unmet medical needs in the treatment of neovascular age-related macular degeneration.

Pravin U. Dugel

In a phase 2 multicenter study that enrolled 34 patients, treatment was administered with strontium-90 radiation via epimacular brachytherapy (NeoVista) and two doses of Avastin (bevacizumab, Genentech). At the end of 2 years, the data indicate a favorable safety profile with signs of durable clinical outcomes, according to Pravin U. Dugel, MD.

“Though anti-VEGF therapy has remarkable efficacy, it comes with a significant burden of treatment,” Dr. Dugel said. “Epimacular brachytherapy would seem to be ideal, because here you have a device that can deliver radiation exactly at the point of pathology while minimizing damage to the collateral tissue within the eye.”

Year 2 visual acuity outcomes were presented at the Retina Congress 2009, and patients will be followed for 3 years.

At 2 years, 74% of patients received no additional injections of bevacizumab beyond the protocol-mandated two loading doses, and the mean number of injections was 2.4. However, Dr. Dugel added, the trial was initiated before the advent of re-treatment guided by optical coherence tomography, and although the combined therapy protocol may reduce the overall burden of anti-VEGF therapy, it is too early to tell by how much.

“The re-treatment number using our current criteria probably would have been greater. Having said that, the visual acuity would probably have been better as well,” Dr. Dugel said.

Safety profile

While the possibility of reducing the burden of treatment in wet AMD is intriguing, the trial was designed to evaluate the preliminary safety and efficacy of the combined regimen to warrant future investigation. According to Dr. Dugel, both of these were shown in the year 2 data: There were no reports of radiation retinopathy, and by virtue of the reduced treatment burden while maintaining visual acuity outcomes, there is indication that epimacular brachytherapy can offer a broad spectrum of activity to provide positive outcomes.

A core vitrectomy is done and the NeoVista device is engaged in the midvitreous cavity. Images: NeoVista

The NeoVista device is held over the neovascular membrane for approximately 4 minutes, delivering treatment exactly at the point of the pathology.

Due to the high incidence (50%) of cataract formation related to the vitrectomy procedure performed to administer epimacular brachytherapy, a subset analysis of phakic vs. pseudophakic patients was performed. Analysis of pseudophakic participants showed that 80% lost 15 or fewer letters of visual acuity and 30% gained 15 or more letters at 24 months. The analysis of all participants showed that 64.7% of patients lost 15 or fewer letters and 20.6% gained 15 or more letters.

At baseline, a high percentage of patients were phakic, perhaps higher than might be expected in a trial evaluating therapy for wet AMD, according to Dr. Dugel. Moreover, vitrectomy, a known risk factor for cataract progression, was performed to clear the retinal space for the application of brachytherapy.

“Is [cataract progression] something to be aware of? Absolutely. Is that something that would be prohibitive for this treatment? I don’t think so,” Dr. Dugel said.

It may be necessary, for instance, to prepare phakic patients for the possibility that future cataract surgery might be necessary, something that is already routinely done with phakic patients undergoing vitrectomy during other retinal surgeries, such as for macular hole or epimacular membrane, Dr. Dugel said.

Further study

The 1-year data from this phase 2 study led to the design of the pivotal CABERNET (CNV secondary to AMD treated with beta radiation epiretinal therapy) trial. This trial will evaluate combined epimacular brachytherapy and Lucentis (ranibizumab, Genentech) vs. Lucentis alone in treatment-naïve patients.

A recent clinical trial, MERITAGE (Macular epiretinal brachytherapy for the treatment of age-related macular degeneration), has enrolled 50 patients and is designed to evaluate the initial safety and efficacy of epimacular brachytherapy in patients with persistent fluid despite continuous injections with anti-VEGF therapy for a prolonged period.

“The burden of treatment is not in treatment-naïve patients. The majority of my injections are in patients who are getting it for the third, fifth, 17th, 20th time. That’s where the treatment burden lies,” Dr. Dugel said.

It is in this group of patients that epimacular brachytherapy may offer the greatest promise, according to Dr. Dugel. Angiogenesis, he said, is the end result of a cascade of several chemical factors responding to an ischemic state within the retina.

“VEGF may be the most important of those agents, but it’s certainly not the only one. There are multiple inflammatory and immune cell systems that are involved in not only angiogenesis but in other manifestations, such as fibrosis,” Dr. Dugel said.

Fibrosis, occurring at the end stages of that cascade, is what disrupts photoreceptor cell function and results in loss of vision. The combination of epimacular brachytherapy and anti-VEGF agents has been shown to have a broader spectrum of action and enhanced outcomes in clinical oncology. Therefore, such combination therapy should potentially help combat neovascular AMD at multiple levels within the pathologic cascade, according to Dr. Dugel.

“There is compelling preliminary evidence on the safety and efficacy of epimacular brachytherapy with ongoing trials. When proven in the ongoing pivotal investigative studies, epimacular brachytherapy will change the way we treat most of our patients in a regular retina practice today,” Dr. Dugel said.

The combination therapy would seem to be ideal, he said, because of the synergistic effect of the three components: vitrectomy, which increases the oxygen retention in the retina; brachytherapy delivered exactly at the point of pathology, which is anti-inflammatory, antifibrotic and antiangiogenic; and anti-VEGF therapy, an antiangiogenic and antipermeability agent. In addition, the specific isotope used in the study, strontium-90 — which has a very short range of tissue penetration from the point of application and an expected rapid energy drop-off of about 10% for every 0.1 mm it travels — signifies the potential safety and effectiveness, Dr. Dugel said. – by Bryan Bechtel

• Pravin U. Dugel, MD, can be reached at Retinal Consultants of Arizona, 1101 E. Missouri Ave., Phoenix, AZ 85014; 602-222-2221; fax: 602-266-2044; email: pdugel@gmail.com. Dr. Dugel is a consultant for Alcon, Genentech, Macusight and NeoVista.