Photo Dynamic Therapy For Macular Degeneration
Irving J. Arons
In an announcement made earlier this year, Ciba Vision Ophthalmics (Atlanta, GA) and Quadra Logic Technologies (Vancouver, BC), have agreed to join forces in the joint development of the use of photodynamic therapy (PDT) as a potential treatment for certain eye diseases, including age-related macular degeneration.
Under the terms of the agreement, Ciba Vision will fund 60% of the development costs and QLT the remainder. Profits from all product sales will be equally shared after deductions for marketing and manufacturing costs and third party royalties.
The initial development efforts will be with QLT's proprietary light activated drug, benzoporphyrin derivative (BPD), a photosensitive dye currently in Phase I trials for treating a variety of diseases including cancer and psoriasis.
In photodynamic therapy, a photoactive dye is injected intravenously, becomes absorbed selectively in the target tissue, and is released by normal tissue. Laser light of the correct wavelength (at the absorbance maximum of the dye) is used to "activate" the dye, which in the activated state interacts with oxygen and other compounds to form reactive intermediates, such as singlet oxygen. This can disrupt or destroy cellular structures such as blood vessels, and in the case of cancers, destroy the host cells.
One of the drawbacks of early photoactive dyes was the short wavelength of activation (630 nm with Photofrin, the most widely used photoactive dye). This results in shallow penetration of the initiating laser light source and, characteristic of this particular compound, made the host patient extremely light sensitive for long periods of time. BPD, and other "second generation" photoactive dyes, operate at longer wavelengths (692 nm, in the case of BPD), allowing deeper penetration of the activating laser light (useful for deeper-seated tumors), and cause much less light sensitivity for the patient.
In treating age-related macular degeneration (ARMD), the approach is to selectively destroy the abnormal blood vessels associated with the neovascularization within the choroid, characteristic of ARMD and other retinal and ophthalmic diseases, including disc neovascularization in diabetic retinopathy and iris neovascularization in neovascular glaucoma. According to QLT and a recent review in the MGH Laser Center Newsletter (Massachusetts General Hospital, Boston), ARMD is the leading cause of legal blindness in people over the age of 50, with an estimated 7 million afflicted in North America alone, and approximately 400,000 new cases diagnosed annually. About 80% of the ARMD cases with severe visual loss have choroidal neovascularization. Current treatment relies on laser photocoagulation of the vessels, which although effective, also destroys normal tissue along with the abnormal blood vessels.
It is expected that the use of PDT will selectively treat the pathological new vessels without damaging surrounding tissue and without systemic toxicity. QLT's BPD is in pre-clinical trials at MGH, and has been shown effective in treating choroidal neovascularization in animal models, in a study under the direction of Drs. Joan Miller and Evangelos Gragoudas. (The same drug is in Phase I clinical trials at MGH for the treatment of metastatic skin lesions and psoriasis.)
Fluorescein angiography 24 hours after PDT using BPD demonstrated large areas without significant fluorescence, where PDT had effectively closed the neovascular vessels in the animal models treated. Optimal dosimetry, including dye dosage, light radiant exposure, and irradiance have been determined for the animal models and will be applied to human testing. Chronic effects on tissue and the process of tissue repair are also being investigated. Based on these preliminary results, PDT with BPD appears to be an effective modality for choroidal neovascularization. If the data are confirmed in the human studies, PDT could have a major clinical impact on the management of many blinding eye diseases.
The agreement between Ciba Vision and QLT also covers the study of other potential applications of PDT in ophthalmology, including corneal revascularization, intraocular tumors and diabetic retinopathy.