This article is from October 2010 and may contain outdated material.
Can the unruly tangle of abnormal choroidal vessels that wreak havoc in wet AMD be zapped into submission? The creators of two new radiotherapy devices, now in clinical trials, are betting the answer is yes.
The idea of treating wet AMD with radiation is not new. The literature is replete with false starts. One literature search yielded more than two dozen radiation studies between 1996 and 2007.1 Those earlier attempts succumbed to problems with dosing, targeting, collateral damage and the burdens of working with radioactive material. “It was a good idea, but it didn’t work because the targeting was imprecise,” said Peter K. Kaiser, MD, professor of ophthalmology at Cleveland Clinic. “People are scared of radiation, and it has this stigma in macular degeneration that it didn’t work.”
Perhaps the world is ready for a better mousetrap. And trials for two new systems—IRay stereotactic radiotherapy by Oraya Therapeutics and Vidion Antineovascular (ANV) Therapy from NeoVista—may determine whether the world will beat a door to a new generation of this approach.
For Dr. Kaiser, the question is: Can combination therapy with IRay perform as well or better than ranibizumab (Lucentis) alone, the current standard of care? The same may be asked of the Vidion system, which is going head-to-head with Lucentis at 25 hospitals in the United Kingdom. (Both devices have already received a CE mark, the European equivalent of FDA approval.)
“Currently, our problem with age-related macular degeneration is that we have a disease with a good treatment in Lucentis, but we’re finding we need to do monthly injections for an extended period of time to achieve excellent results,” Dr. Kaiser said. “Since most patients have stable or improved vision, any new treatment would have to be as good or better, with hopefully fewer injections and a more defined endpoint.”
Radiation, Good and Bad
Several types of radiation have been deployed in the battle against AMD: radioisotope, proton beam, external beam and brachytherapy. “Theoretically, the type of radiation doesn’t matter, as long as are you able to target and deliver it in a reproducible, safe manner,” said Darius M. Moshfeghi, MD, associate professor of ophthalmology at Stanford University.
The upside. Radiation attacks AMD on three fronts, Dr. Moshfeghi explained. It acts on angiogenesis, inflammation and fibrosis. “All three of those processes play a role in the development and maintenance of wet macular degeneration.”
While the main effect of anti-VEGF treatments is to decrease leakage, Dr. Kaiser said, radiation directly attacks growing vessels. It causes damage to the DNA in blood vessels, which eventually leads to their regression.
Hugo Quiroz-Mercado, MD, director of ophthalmology at the Denver Health Medical Center, conducted IRay’s phase 1 trial in Mexico City, where he is clinical research consultant at the Asociación para Evitar la Ceguera en México. Dr. Quiroz-Mercado said the proliferating endothelial cells are more susceptible to radiation, which inhibits their division and allows regression of new vessels. And he reiterated Dr. Moshfeghi’s comment that it slows inflammation and the development of fibrotic tissue.
The downside. In theory radiation makes sense, but in the past there have been problems. “We didn’t have the ability to deliver the radiation to the macula without the risk of collateral damage to the lens, optic nerve and even the brain,” said Robert L. Avery, MD, who is in private practice in Santa Barbara and who has treated such complications. Some radiation patients developed cataracts or, worse, radiation retinopathy, which can lead to permanent visual loss. It was a fairly infrequent side effect, said Dr. Avery. “But it was severe when we did see it.”
Quan Dong Nguyen, MD, MSc, associate professor of ophthalmology at Wilmer Eye Institute in Baltimore, said that physicians are understandably concerned about adverse events, which have been observed decades after treatment. “Management of radiation retinopathy and optic neuropathy is quite challenging,” he said.
Some delivery methods were clumsy, as well, said Dr. Moshfeghi. Brachytherapy, for example, entails placing highly radioactive material inside the body. Proton beam, he said, is impractical, given that there are only three or four facilities in the United Sates that offer this treatment. And external beam radiation, while more common, is difficult to deliver precisely without hitting other structures, he said.
Enter Lucentis
Still, those earlier experiments with radiation made sense when treatment options were limited. “Now, anti-VEGF therapy has raised the bar dramatically. We expect improvement in vision,” Dr. Avery said. “But it is at a cost of multiple injections.”
What if retina specialists could reduce the number of injections with some adjunctive therapy? The word “synergy” arises when describing the potential benefits of combining Lucentis with radiation. “There is a possibility,” said Dr. Kaiser, “that the sum of the combination may be more than just one plus one. There might be synergy of placing an anti-VEGF agent with the radiation, and that may allow us to get better visual results than either treatment alone.”
Dr. Avery shared that hope. “Lucentis should provide the initial ‘wow effect’ by drying up the macula, while radiation kicks in for the long term.”
Historically, external beam radiotherapy to treat a large lesion didn’t produce an immediate effect, Dr. Moshfeghi said, because the CNV-killing effect occurs three to six months out. “There was nothing to carry the patient from time zero to three to six months.” But fast-acting Lucentis buys time. “You don’t want someone to lose vision while radiation kicks in. Lucentis gets you through that.”
How IRay Works
The IRay borrows from the stereotactic radiotherapy technique used by neurosurgeons to precisely target brain tumors. And it borrows as well from the low voltage x-rays used by dental offices and airport scanners. The device delivers three convergent beams, 4 mm each in diameter, that overlap on a macular spot centered on the fovea. To avoid missing the mark, the patient’s gaze is immobilized by a vacuum-coupled scleral lens that is centered on the limbus. The slightest patient movement triggers a shutoff system.
Because the radiation beam enters through the inferior pars plana region, anterior segment structures, such as the lens and cornea, are out of harm’s way, said Dr. Moshfeghi, adding, “We’re physically holding the eye, and the computer is tracking the beam. We know where the beam is ending up.”
Clinical trials. Enrollment for the IRay phase 3 trial has begun at 10 European sites. A minimum of 150 patients will receive standard of care anti- VEGF therapy in conjunction with one of the following: sham radiation or radiation dosing of 16 or 24 Gy. Radiation is delivered one time only with Lucentis. Additional dosing of Lucentis will be considered monthly.
The primary outcome measure will be improved visual acuity in both naïve and previously treated patients with wet AMD. Investigators also will consider whether treatment reduces the need for repeat injections.
In the phase 1 trial, conducted in Mexico City with 60 patients, the mean number of injections in 27 patients who reached 12 months was much lower than with Lucentis alone. The study also found:
- No apparent difference in outcomes between naïve and previously treated patients;
- Vision data that were the same or better than in patients treated monthly with ranibizumab;
- Most study patients who received radiation experienced superficial keratopathy related to application of the fixation device, which resolved without treatment;
- Fundus photos and fluorescein angiography revealed no effects on the retina or optic nerve related to radiation. There was no effect, after one year, on the lens and zonules, nor were cataracts or optic neuropathy observed.
“What was interesting was seeing a large improvement we didn’t expect in several patients,” said Dr. Quiroz-Mercado. Fundus photos of patients with large choroidal neovascularizations showed a decrease in CNV size, something that wouldn’t be seen with Lucentis or Avastin alone, he said.
How Vidion Works
The Vidion handheld device delivers strontium-90 beta ionizing radiation. Surgeons thread a probe into the eye until it reaches the abnormal area in the retina, then they give a precisely-timed dose of radiation directly to the lesion in a beam 5.4 mm wide.
Clinical trials. King’s College in London is enrolling 363 patients at 25 U.K. hospitals in a phase 3 trial to test the Vidion system for delivering epimacular brachytherapy concomitantly with Lucentis, and comparing the results with Lucentis administered alone. The two endpoints are visual acuity gain and reduction in the number of injections.
In an earlier Vidion trial in Mexico and Brazil, 91 percent of patients did not need a repeat injection of Lucentis by one year. Seventy-nine percent remained re-treatment free after two years. After three years, 58 percent still needed no further treatment.
A Long View
Dr. Avery, who has been following the radiation trials, regards them as good news. “There are so many phase 1 or 2 trials that look great but then the phase 3 data don’t pan out,” he said. “But to have another company with a similar treatment using a different delivery modality and achieving similar results—visual improvement and reduction in the need for injections—is confirming that this probably works.”
Bracing for unpleasant surprises. While he’s excited about the possibility that radiation may reduce the injection burden, Dr. Avery noted that the potential adverse effect of radiation retinopathy often doesn’t develop for a year or more. The lower doses of radiation used in these trials may preclude the delayed adverse effects, and the anti-VEGF therapy may even have a protective effect, he added. “It’s still a concern to me that we may see radiation retinopathy. It could show up late. Fortunately, we have not seen it yet.”
Dr. Nguyen, who shares that concern, also worries about the risks and benefits. “What additional benefits will the patient have at the end of everything we do?” he said. “Will they gain more vision, or will they only have the number of injections decrease?” While he said he applauds the innovators, he needs more data to decide whether the risks are acceptable.
Dr. Moshfeghi said the phase 3 trials will provide more answers. In the meantime, he said, “Radiation seems to have an effect. If you take a patient who presents with wet AMD and don’t treat with anything, on average this patient loses two lines of vision within the first 12 months. That hasn’t happened in the phase 1 IRay trial. Radiation has demonstrated an independent additive effect. We’re not talking about a cure,” Dr. Moshfeghi said. “But if you can get a patient down from an average of six injections a year, everybody’s happy.”
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1 Gertner, M. et al. Med Phys 2010;37(2):600–606.
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Drs. Avery and Nguyen report no related financial interests. Dr. Kaiser is a consultant to Genentech, Novartis and Oraya and holds equity in the form of stock options in Oraya that have been approved by the conflict of interest committee of the Cleveland Clinic. Dr. Moshfeghi is a consultant to Oraya and holds equity in the form of stock options. Dr. Quiroz-Mercado received financial support to conduct the phase 1 trial but is not a consultant to Oraya.