Light beam hits the blind spot

17 Jun 2002

Photodynamic therapy - in which a combination of drugs injected into the body are stimulated by laser light - is a common treatment for cancer. However, it now has an alternative use that could help millions of people around the world regain their sight. Douglas Clarkson investigates.

From Opto & Laser Europe January/February 2001

In the developed world, age-related macular degeneration is the principal cause of blindness in people who are over the age of 50. In Europe and the US, a new drug has recently been given approval for use in photodynamic therapy to treat this condition, opening up a large potential market for laser-system manufacturers.

The macula is the small portion of the retina that is responsible for the sharp, straight-ahead vision that is necessary for functions such as reading, driving a car and recognizing faces.

There are two types of age-related macular degeneration (ARMD). In the dry form, yellow deposits develop on the retina and reduce visual acuity.

Nearly one-third of all people over the age of 70 will exhibit the dry form to some extent. Principally, dry ARMD causes a mild blurring of vision, but in more severe cases significant loss of sight can occur.

In the less common wet form, a network of small blood vessels grows above the macula surface. This results in a loss of vision over a period of three months to two years.

While the wet form of the disease makes up only 15% of all ARMD cases, it is the cause of 90% of all severe vision loss. In the European Union approximately 200,000 individuals will suffer severely impaired sight each year due to wet ARMD. Conventional treatments for wet ARMD involve photocoagulation, but only 10% of cases recover their sight. This therapy is not without risk and it is only effective during the early stages of the condition.

Photocoagulation involves directing a beam of laser light at the abnormal blood vessels to destroy them and prevent them from leaking. Provided that the blood vessels have not grown under the macula, this treatment can be helpful in arresting the progress of the disease. If the blood vessels have already developed under the macula, the laser could cause scarring and result in a permanent loss of vision.

Until recently this technique was the only widely available treatment for the condition. Methods that are currently available in a more limited way include the use of ionizing radiation, such as proton beams that are derived from cyclotrons.

The recent emergence of photodynamic therapy (PDT) for wet ARMD permits treatment of the macula at levels that lie below optical-damage thresholds. However, it still involves injecting a chemical, which must then be absorbed by the macular tissues.

In PDT a drug is injected into the patient, who is then exposed to a non-thermal red light. This light activates the drug to close and seal off the abnormal blood vessels. The entire treatment only takes 30 minutes and no anaesthetic is required.

There are three drugs that are under development for the treatment of ARMD using PDT - Visudyne, Optrin and Photopoint. However, it is Visudyne, developed by Ciba Vision, that recently had approval from both the US Food and Drug Administration and the European Commission.

There are two laser systems - with the relevant European approval - for activating Visudyne. Carl Zeiss of Germany has produced the Visulas 690S system and Coherent has developed the Opal Photoactivator Unit that works at a wavelength of 689 nm.

In the UK, both of these systems are being offered by Ciba Vision on an extended free loan to hospitals and clinics that are planning the provision of a PDT/Visudyne service. During 2001 there will probably be an installed base of around 100 units in the UK alone. If, however, the range of PDT treatments are shown to have relevance to specific stages and sub-types of wet ARMD, then there could well be a market for multiple-wavelength delivery systems.

The critical requirement for accurate dosimetry has resulted in a range of refinements being incorporated into a new family of laser systems. The Opal Photoactivator, for example, includes a back-up output-power sensor, a homogenized laser-beam profile - for the uniform delivery of energy within the treatment area - and a sensor that detects the presence of a broken fibre.

This system also has an external power meter for the more reliable monitoring of the delivered output, bearing in mind that a vial of Visudyne has an anticipated cost of approximately USD 1200. An incorrect dose can be delivered by a portable unit that has a range of slit-lamp systems if the wrong power is delivered.

The scale of the clinical trials necessary in ophthalmology to give credibility to the eventual approval of PDT methodologies has required the initial product developers to team up with much larger partners.

QLT PhotoTherapeutics of Canada, the developer of verteporfin under the trademark Visudyne, has joined forces with Ciba Vision, the eye-care unit of Novartis of Switzerland, while Pharmacyclics, the developer of Optrin - which is based on motexafin lutetium - has teamed up with fellow US company Alcon Laboratories.

Also in the US, Miravant Medical Technologies, developers of Photopoint - which is based on tin ethyl etiopurpurin - has linked up with Pharmacia and Upjohn.

It is clear that Visudyne has a significant advantage by coming to market first after completing favourable 24-month clinical trials and with approval essentially granted at interim one-year reporting.

Visudyne is undergoing additional trials for the treatment of other ophthalmic conditions, including ocular histoplasmosis and macular oedema, which is associated with diabetic retinopathy.

With the clinical evaluation of Photopoint, which has an activation wavelength of 664 nm, and Optrin not yet complete, it is too early to determine which treatment ophthalmologists will ultimately select for their practice. It could even be the case that clinical studies will indicate that each PDT agent has specific advantages for specific phases and degrees of wet ARMD and that ophthalmologists will wish to maintain flexibility in their choice of treatment.

Interim results of the on-going multicentre clinical trials of Photopoint are likely to be reported early this year.

While one disadvantage of Photopoint is its relatively long period of photosensitivity - four weeks compared with only 48 hours for Visudyne - patients do not require as many treatments as they would need with Visudyne. ARMD sufferers treated with Photopoint, however, must observe strict precautions against exposure to light.

Optrin fluoresces on activation, allowing the identification of diseased tissue. This could be a significant advantage in the selective treatment of such areas. According to Jim Weiss of Pharmacyclics, Optrin is "1.5 years behind Visudyne in its phase of clinical evaluation". The drug is currently undergoing a second-phase trial that is designed to optimize drug delivery and light-treatment regimes.

The most recent clinical data, with respect to Optrin, relate to work reported at the Association for Research in Vision and Ophthalmology in May last year, where dose-ranging studies - involving a total of 54 patients - were undertaken, based on laser doses of 50, 65 or 95 J/cm² and drug doses of 2.0 mg/kg.

Laser treatment has become a cornerstone of ophthalmology. The extension of PDT to ARMD could be a boon to sufferers and laser companies alike.