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Laser treatments for AMD show promise
Treatments for AMD, and even prevention, are on the horizon.
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As reported at the annual meeting of the American Academy of Ophthalmology (AAO) in Orlando, Fla., for the first time it appears that one or more methods for stopping the progress of age-related macular degeneration (AMD) and, perhaps even improving vision for those who suffer from AMD, are on the horizon. And in an even bigger leap of faith, additional clinical work is being undertaken on prophylactic treatment to determine if this disease can be stopped before it progresses to the final stages.
Most of the AMD news to date has been on the ongoing studies of photodynamic therapy (PDT) to stop the progression of wet AMD. QLT PhotoTherapeutics (Vancouver, British Columbia) and CIBA Vision (Duluth, Ga.) have been conducting studies, and Coherent (Santa Clara, Calif.) and Zeiss Humphrey (Dublin, Calif.) are conducting research with activating lasers.
QLT and CIBA Vision’s new drug application (NDA) for Visudyne therapy (verteporfin for injection) recently won recommendation for approval from the Food and Drug Administration’s (FDA) Ophthalmic Drug Advisory Panel. Following behind is the Miravant team (Santa Barbara, Calif.), with Pharmacia & Upjohn (Bridgewater, N.J.) as the marketer, and Iridex Corp. (Mountain View, Calif.) as the supplier of the Iris Medical activating laser, and then Pharmacyclics (Sunnyvale, Calif.), with marketing partner Alcon Laboratories (Fort Worth, Texas), and probably Diomed (U.K.) as the laser supplier. FDA final approval of Visudyne therapy might be in hand before this article reaches print but most likely will take place within first quarter of 2000. Miravant has completed enrollment of patients in its phase 3 clinical trial of Photopoint therapy, with a NDA expected to be filed sometime in 2000 or 2001. Pharmacyclics’ Optrin therapy is even further behind, with the company still running phase 1/2 clinical trials. Others in preclinical trials include Nippon Chemical and Toyo Kogyo, in association with Lederle Japan. (See table for a listing of manufacturers and the drugs/lasers involved.)
The PDT approach
In the PDT approach, a photosensitizer is administered intravenously, which selectively accumulates in the neovascularized tissue. A dose of carefully calculated laser light is administered directly to the lesions, which activates the photosensitizer, causing death to the cells and destroying the vessels. It is important to note that the effect of PDT treatment is photochemical, and there are no accompanying thermal reactions. Although the results are a stoppage of blood leakage from the disruption of the vessels, according to the results seen in the TAP study (Treatment of Age-Related Macular Degeneration with Photodynamic Therapy), as reported at the Vitreoretinal Update meeting held just prior to the AAO, the effect appears to be temporary, and as many as 3.4 treatments per year may be needed.
However, there are indications that the recurrence of bleeding should decrease with time. Visudyne is expected to be priced at about $1,200 per dose, and with the surgeon and facility fee added in, treatments could cost as much as $2,000 or $8,000 per year. But the results of the TAP study indicate that visual acuity, contrast sensitivity and angiographic outcomes are better in verteporfin-treated eyes than those receiving a placebo. Visudyne therapy can safely reduce the risk of vision loss in eyes with predominantly classic choroidal neovascularization (CNV) lesions. There appears to be less effect on lesions that are predominantly occult. CIBA Vision and QLT are currently studying these patients in a separate trial.
Based on phase 2 results, Miravant believes its competitive drug, SnET2, may have performance advantages over Visudyne in both vision improvement and/or longer lasting treatment effect.
However, there are several emerging new laser treatments for AMD currently undergoing clinical trials. A few are for the treatment of wet AMD, and at least two are for prophylactic treatment of patients with high risk drusen in the pre-neovascularization stage of dry AMD to prevent or delay the development of CNV.
TTT
One prospective, randomized, placebo controlled, multi-center clinical trial underway to treat AMD patients with subfoveal occult choroidal neovascular membranes (CNVM) with a low intensity laser is the Transpupillary Thermotherapy (TTT) for Choroidal Neovascularization Clinical Trial (TTT4CNV Clinical Trial), sponsored by Iridex Corp. The Iris Medical OcuLight SLx 810 nm infrared diode laser is used in its unique LongPulse mode to perform the TTT technique. The TTT technique has been validated in the treatment of choroidal melanomas and other ocular tumors to induce localized hyperthermia to close the CNVM without collateral damage to the overlying central retina.
In a recently published study “Transpupillary thermal therapy of occult subfoveal CNV in patients with AMD” (Ophthalmology. 1999;106[10]: 1908-1914), Elias Reichel, MD, of the New England Eye Center in Boston, noted that in a small sample of eyes treated with TTT (17 eyes of 16 patients), 75% experienced stabilization or improvement of visual acuity and 94% improvement of exudation. Another small study, presented at this year’s AAO meeting by Richard Newsome, MD, per formed at King’s College Hospital in London, showed that after an average of 6.5 months’ following the TTT treatment, CNV resolved in 71% of treated eyes, and visual acuity stabilized in 86% of treated eyes.
Iridex also is involved in another infrared diode laser application for the indirect closure of subfoveal occult or classic CNVM through the laser photocoagulation of their extrafoveal feeder vessels. This very elegant treatment uses dynamic high-speed indocyanine green (ICG) angiography to identify and localize the tiny feeder vessels and the Iris Medical OcuLight SLx 810 nm diode laser to treat them extrafoveally with a train of repetitive infrared laser pulses. In an initial study, reported by Bert Glaser, MD, at the Vitreoretinal Update, the subspecialty meeting held just prior to the AAO, more than 80% of the feeder vessels treated were closed one day following treatment, with the patients noting a subjective improvement in vision and minimal side effects. The company is in the process of considering undertaking a multi-center study of this procedure.
Prevention?
But perhaps even more exciting than the studies underway to treat wet AMD are the two studies being undertaken by Iridex and the one by the National Eye Institute (NEI) to treat patients who have drusen secondary to dry AMD, to possibly prevent them from progressing to the exudative form. The first study is a therapeutic treatment to reduce drusen for vision improvement. An article in the November issue of Ophthalmology (1999;106[11]:2082-2090), entitled “Therapeutic benefits of infrared (810 nm) diode laser macular grid photocoagulation in prophylactic treatment of nonexudative age-related macular degeneration,” by Joseph Olk, MD, of the Retina Center of St. Louis, et al, describes that laser therapy resolved the drusen and improved vision. This study used both visible laser burns and subthreshold laser treatments to determine if the effects on the reduction/elimination of drusen would improve/stabilize visual acuity and reduce/delay the incidence of CNV.
Results of the pilot study showed reabsorption of the drusen in 68% of treated eyes and visual acuity improvement in 24% of a subset of treated eyes after a single treatment. One purpose of the pilot study was to determine the appropriate laser dose to be used in a follow-up prophylactic study. There is some evidence that the therapeutic approach is effective, while there is no evidence yet that the prophylactic approach is effective.
The second trial, the “Prophylactic Treatment of Age-Related Macular Degeneration” (PTAMD) trial, is a follow-on trial to more definitively evaluate the prophylactic treatment of high-risk drusen-evident patients using minimal, gentle, subthreshold micropulse laser treatments placed in a grid surrounding the drusen, to halt or delay progression from the dry form of AMD to the wet form, following up on the results obtained with the subthreshold treatments done previously. The PTAMD trial is currently in its second year, with more than 400 patients participating, of an anticipated 1,000 to 1,300 to be enrolled. Study results are anticipated in about 5 years.
The NEI-sponsored study, called the Complications of Age-Related Macular Degeneration Prevention Trial (CAPT), will attempt to determine if low-intensity argon laser treatment prophylactically decreases vision loss for patients at risk for severe AMD. Twenty-four selected sites across the country are participating in the CAPT trial. It is designed to assess the safety and effectiveness of low-intensity laser light to prevent disease progression and loss of vision in patients who are at risk for severe AMD. The CAPT study will enroll a total of 1,000 patients at the 24 clinical centers across the United States during an 18-month period. The trial is expected to last at least 5 years.
| Current participants in PDT AMD trials | |||||
|---|---|---|---|---|---|
| Company | Marketing partner | Drug name | Approval status | Laser partner(s) | Wavelength of activation |
| QLT Photo- Therapeutics | CIBA Vision Ophthalmics | Visudyne (verteporfin) | Recommended for approval | Coherent Opal Zeiss Humphrey Visulas 690 S | 689 nm |
| Miravant | Pharmacia & Upjohn | Photopoint (purlytin) | Phase 3 | Iridex | 664 nm |
| Pharmacyclics | Alcon Laboratories | Optrin (LuTex) | Phase 1/2 | Diomed | 732 nm |
| Nippon Chemical | Information unavailable | NPe6 (chlorin) | Preclinical | LaserScope | 664 nm |
| Toyo Kogyo | Lederle Japan | ATX-S10 (chlorin) | Preclinical | NA | 670 nm |
For Your Information:
- Looking for additional articles on research regarding treatments for age-related macular degeneration? . Some articles include: “Subthreshold treatment attacks AMD” (July 15, 1999, page 18); our Population at Risk series on AMD (October 1, 1999, page 37); “Less mortality/ocular morbidity shown with TTT for ocular tumors” (November 15, 1999, page 66); “After panel nod, Visudyne launch set for February/Visudyne gets FDA panel recommendation” (December 15, 1999, page 14); and “TTT may stabilize eyes with wet AMD” (January 1, 2000, page 42).