BBI Contributing Editor

ORLANDO, Florida – The 1999 annual meeting of the American Academy of Ophthalmology (AAO; San Francisco, California), held here in late October, was heavily focused on the booming refractive surgery market. With an estimated 900,000 to 950,000 laser refractive procedures expected to be performed in the U.S. in 1999, at an average price of about $2,000 per eye, this sector of the ophthalmic industry has created unprecedented wealth for physicians and the industry alike. The excellent clinical outcomes for the vast majority of refractive surgery patients, along with the introduction of new technologies that will buoy clinical results and further raise patient satisfaction, bode extremely well for the laser vision correction industry.

In spite of the continuing huge interest, it is important to note that refractive surgery shared the limelight this year with another rapidly emerging new issue – the treatment of age-related macular degeneration (ARMD). Macular degeneration is a painless but devastating and degenerative eye condition that afflicts in excess of 10 million Americans and many millions more around the world. The annual incidence or new cases in the U.S. is generally accepted to be about 2 million per year. While there are several types of macular degeneration, by far the fastest-growing is age-related macular degeneration, which is the No. 1 cause of severe vision loss or legal blindness in adults over 60 in the U.S. Nearly 11% of the U.S. population aged 65 to 74 and 28% of those 75 years or older have the disease.

ARMD attacks the macula, the small, light-sensing area of the central retina which provides vision for fine work and reading and where the sharpest central vision and color perception occur. Although it rarely causes total blindness, ARMD reduces the clear, "straight ahead" central vision necessary for reading, driving, identifying faces, watching television, doing fine detailed work, safely navigating stairs and performing other daily tasks. Peripheral vision may not be affected, and while it is possible to see out of the corner of the eye, it is usually only in shades of black and white.

There are several well-recognized ARMD risk factors. Clearly, age is the single most important one; according to the Framingham Eye Study, the prevalence of ARMD increases from 1.6% of people between the ages of 52 and 64 to 27.9% in those over the age of 75. Other risk factors include gender (women tend to be at greater risk than men, perhaps suggesting that estrogen loss during menopause may play a role), race (whites are at greater risk than blacks), hereditary (those with immediate family members who have had it are at a higher risk of developing the disease) and smoking. Dietary factors may also play a role in ARMD. Certain green leafy vegetables like spinach and kale and brightly colored fruits and vegetables like mangoes, oranges and cantaloupes contain two carotenoids (lutein and zeaxanthin) that appear to support the health of the macular pigment. Johanna Seddon, MD, of the department of ophthalmology at Harvard Medical School (Boston, Massachusetts), has reported that those who consume the most carotenoids had a 43% lower risk for macular degeneration than those who ate the least.

Wet ARMD is less common, more severe

There are two main forms of age-related macular degeneration. The more common (estimated at about 90% of the total ARMD cases) but fortunately far less serious form is called dry ARMD, while the less common (the remaining 10%) but far more severe is the wet version. It is possible to experience both forms at the same time, in one or both eyes. In the case of the wet, typically later stage of the disease, it has been demonstrated that over a five-year period, the disease will develop in 26% of fellow eyes initially free of the disease.

The dry form of ARMD, also referred to as non-exudative ARMD, is characterized by the presence of drusen, which are tiny dots of yellow or white crystalline deposits that occur beneath the macular retina. Drusen under the macula can cause gradual thinning, or geographic atrophy, of the retinal pigment epithelial (RPE) cells in the macula. This atrophic process and the deterioration of the RPE cells can lead to a slow and progressive loss of vision in the central area, as well as a loss in color perception.

Clinical and epidemiological studies have demonstrated that the presence of drusen is a risk factor for the development of the more serious form of ARMD, known as wet, or exudative, ARMD. For patients with bilateral drusen, the three-year risk of developing wet ARMD is estimated at 13% overall and 18% for those aged 65 years or older. Although it afflicts only 10% of those who have the disease, wet ARMD accounts for an estimated 90% of the severe vision loss caused by ARMD. The process that occurs with wet ARMD involves the thickening and breaking of the membrane (known as Bruch's membrane) underlying the retina. As a result, the oxygen supply to the macula is disrupted and, in response, new, abnormal blood vessels begin to grow up from the choroid, the layer of the retina filled with blood vessels that nourish the retina. The growth of these new blood vessels, known as choroidal neovascularization (CNV), marks the beginning of the wet and most severe form of ARMD. These vessels often grow through the breaks of the membrane behind the retina towards the macula and can leak fluid or blood and sometimes cause shallow detachment of the retina. For patients who have already developed wet ARMD in one eye, the risk to the fellow eye approaches nearly 60% within five years.

Laser photocoagulation has drawbacks

There is currently only one proven mode of therapy for wet ARMD – laser photocoagulation. This therapy, which involves the use of a thermal laser, essentially cauterizes the leaking blood vessels and can halt the decrease in visual acuity. There are three notable drawbacks to this approach:

1) Only a fairly small percentage of wet ARMD patients can be treated with laser photocoagulation. Specifically, the results of the Macular Photocoagulation Study Group (based on 1991 data) showed that laser photocoagulation can only be applied to small, well-demarcated CNV lesions outside of the fovea (the most central zone of the retina), which are present in an estimated 13% to 26% of patients with neovascular (wet) ARMD.

2) Due to the indiscriminate, non-selective destruction of healthy adjacent retinal tissue caused by excessive heating of the treated area, laser photocoagulation typically causes an immediate and irreversible loss of visual acuity, typically three to four lines on an eye chart. Although their vision stabilizes thereafter, the immediate loss of vision represents a huge shortcoming for these already visually compromised patients.

3) The recurrence rate for these patients is very high, with the membrane reforming toward the fovea, the central part of the macula that provides the sharpest vision. Ultimately, laser photocoagulation is not successful in helping these patients.

In spite of its huge deficiencies, laser photocoagulation is still widely employed, mainly because it has been the only proven treatment option for wet ARMD sufferers. In a presentation at a pre-AAO Vitreoretinal Update 1999 symposium, Raymond Magherio, MD, et al., of the Beaumont Eye Institute (Royal Oak, Michigan), estimated that about 42,000 laser photocoagulation procedures (reimbursed by Medicare under CPT code 67220) were performed in the last year.

An important new therapy, which will benefit many wet ARMD sufferers, is expected to debut in the U.S. early this year. Photodynamic therapy (PDT) is a minimally-invasive procedure that uses light activated drugs (called photosensitizers) to treat a range of diseases that are associated with rapidly growing tissue, such as solid tumor cells, abnormal blood vessels and atherogenic plaque. PDT involves the administration, typically intravenously, of a photosensitizer agent. While circulating in the bloodstream, the drug attaches itself to molecules called lipoproteins. Because rapidly proliferating cells require a greater amount of lipoproteins, the photosensitizer accumulates more quickly and in higher concentrations in these cells than in normal cells. A pre-calculated dose of light, typically delivered by a laser, is then applied at a particular wavelength to the target site to activate the photosensitizer. The laser's impact is to precipitate cell death through the disruption of normal cellular functions. It is important to note that PDT's effects result from a photochemical effect and not from potentially harmful thermal or acoustic reactions.

PDT is a temporary, costly solution

There are several important advantages of PDT:

1) Relative to conventional surgery, PDT is a less-costly, minimally invasive procedure that can be performed in an outpatient setting.

2) It can access areas of the body that may be completely inaccessible or untreatable by conventional surgery.

3) Because it avoids the undesirable effects of systemic therapies but is highly selective in its impact, PDT is both safe and repeatable.

The first PDT approval in the U.S. occurred in December 1995, when the FDA cleared Photofrin (generically porfimer sodium) for the treatment of esophageal cancer. Photofrin, manufactured by QLT Phototherapeutics (Vancouver, British Columbia, Canada), was approved in January 1998 for the treatment of early non-small cell lung cancers.

There are three different PDT drugs targeted toward ARMD that are noteworthy at this juncture. By far the most significant agent is QLT's Visudyne (generically verteporfin), which in mid-November 1999 achieved a major landmark when the Ophthalmic Drugs Subcommittee of the FDA's Dermatologic and Ophthalmic Drugs Advisory Committee recommended that the new drug application (NDA) for Visudyne be made available for the treatment of predominantly classic lesions. Final FDA approval was expected by late January or early this month. U.S. marketing will be handled by CIBA Vision (Atlanta, Georgia), a unit of Novartis (Basel, Switzerland).

The findings of QLT's pivotal TAP (Treatment of Age-related macular degeneration with Photodynamic therapy) trial, a randomized, double-masked clinical study, were published in the October 1999 issue of the Archives of Ophthalmology. The trial, which involved 609 patients with a variety of CNV lesion characteristics, revealed that vision remained stable or improved (defined as a loss of less than 3 lines of vision on a standard eye chart) for 61% of patients treated with Visudyne therapy compared to 46% of patients administered placebo. In addition, although the goal of Visudyne therapy was to reduce the risk of vision loss, 16% of patients in the treatment group experienced an improvement in vision of one or more lines on a standard eye chart compared to 7% of patients on placebo. Also, severe vision loss (defined as a loss of at least 6 lines of vision on a standard eye chart) occurred in 14.7% of patients treated with Visudyne therapy as opposed to 23.7% of patients on placebo. Although PDT for the treatment of ARMD results in a stoppage of blood leakage and stabilization or improvement in visual acuity, it is both a temporary and costly solution. Patients in the TAP trial were treated an average of 3.4 times per year. Based on an anticipated cost for Visudyne of $1,200, plus the physician's fee and other expenses, BBI believes that each PDT session will cost about $2,000. In addition, PDT does not treat the underlying disease, but merely treats the symptoms. A careful analysis of the TAP trial data clearly demonstrates that Visudyne is the most effective in treating predominantly classic CNV, with a major drop-off in efficacy seen for those patients whose lesions are mainly occult.

Purely classic lesions represent the last stage of wet ARMD. They are well-defined, leak heavily and cause the most rapid deterioration of vision, whereas occult lesions are typically poorly defined, diffuse and are associated with less leakage and vision deterioration. Although the domestic annual incidence of wet ARMD is well-accepted at the 200,000-per-year level, the precise breakdown of wet ARMD lesions is far less certain. Estimates from various sources indicate that purely classic ARMD may account for only 5% to 10% of the total, with predominantly classic accounting for 20% to 50% of all wet cases. In part, this lack of consensus is indicative of the complex nature of ARMD as well as the mediocre diagnostic information generated by the most widely used diagnostic technique, fluorescein angiographic. A less-widely used diagnostic technique involves the use of another dye, called indocyanine green (ICG), which is marketed in the U.S. by Akorn (Buffalo Grove, Illinois). Dr. Jeffrey Marx of the Lahey Clinic (Burlington, Massachusetts) said ICG doubles the chances of being able to treat the blood vessels associated with macular degeneration and should become more important as ARMD becomes more treatable with PDT agents.

Whether PDT may have a broader application, specifically for the treatment of occult or predominantly occult CNV lesions, which account for well over half of all wet ARMD, will be known when the results of the Verteporfin In Photodynamic therapy (VIP) trial are released. The VIP trial involves 28 centers in Europe and North America and is investigating whether Visudyne reduces the risk of vision loss in patients that have subfoveal occult CNV lesions without the classic component. Enrollment was completed in September 1998, with the 12-month follow-up data expected to be available early this year. According to experts in this area, it is unlikely that the VIP trial will show that photodynamic therapy is as efficacious in occult lesions, primarily because the relatively low wavelength of the lasers being used may not adequately penetrate to treat these poorly defined, more deeply situated lesions.

Lasers await final FDA clearance

Two non-thermal diode lasers that have been used in conjunction with Visudyne PDT therapy in the clinical trial phase are expected to be granted final FDA approval when Visudyne attains its final marketing clearance. The Zeiss Humphrey Systems (Dublin, California) division of Carl Zeiss (Oberkochen, Germany) will market its Visulas 690s laser, while Coherent (Santa Clara, California) will market the Opal Photoactivator. Both lasers operate at 689 nanometers (nm), the relevant wavelength for activating Visudyne.

The second-closest drug to the U.S. market is Purlytin (generically SnET2 or porphyrin), which was developed by Miravant Medical Technologies (Santa Barbara, California) and will be marketed worldwide by Pharmacia & Upjohn (Peapack, New Jersey). The pivotal Phase III domestic clinical trial, which was conducted at 59 centers in the U.S., has now been completed, with 934 patients enrolled. An NDA filing with the FDA is likely to be filed sometime during the latter part of 2000 or 2001, with the exact timing dependent on how long of a follow-up period will be required by the FDA prior to submission of data. Iridex (Mountain View, California) will be the laser supplier for this combination therapy, which its developers have dubbed Photopoint Therapy. Its laser operates at 664 nm, the required wavelength to activate the drug.

The third PDT drug is Optrin (generically lutetium texaphyrin), which was developed by Pharmacyclics (Sunnyvale, California) and which will be ultimately marketed by Alcon Laboratories (Fort Worth, Texas), a wholly owned subsidiary of Nestle SA (Vevey, Switzerland). Favorable interim Phase I/II clinical results have been reported for its European trials and, based on this progress, clinicals have recently been initiated in the U.S. Optrin is activated at 732 nm, which may prove to be advantageous in treating the occult form of wet ARMD, which is generally accepted to account for well over half of all wet ARMD. In addition, early indications are that this compound may possess properties that will enable it to be used as a diagnostic agent as well.

In addition to PDT, several other interesting and promising clinical trials are now under way. For wet ARMD, the technique of transpupillary thermotherapy (TTT) is in the early stages of investigation for the treatment of the occult subfoveal CNV phase of ARMD. TTT is a technique to deliver hyperthermia (heat therapy) to ocular tissue using a near infrared diode laser photocoagulator, which operates at 810 nanometers. Local hyperthermia, with temperatures below the coagulative threshold but for a longer period of time, results in the closure of choroidal vessels without collateral damage to adjacent tissue. Within the past couple of months, favorable results of TTT have been released. The October 1999 issue of Ophthalmology, in an article titled "Transpupillary thermotherapy of occult subfoveal choroidal neovascularization in patients with age-related macular degeneration," authored by Elias Reichel, MD, et al., from the New England Eye Center (Boston, Massachusetts), noted that in a small (16 eyes, 15 patients), non-randomized study, 75% of TTT patients experienced improved or stable visual acuity post-therapy. Most importantly, 94% of the patients showed a reduction in their level of exudation.

Another small study (42 eyes in 39 consecutive patients), presented at this year's AAO meeting by Richard Newsom, MD, et al., from the King's College Hospital (London), indicated that its initial TTT results demonstrated maintenance of visual acuity in both classic and occult membranes. Specifically, results were impressive in the group of patients with occult subfoveal CNV, which represents an estimated 70% of wet ARMD. In this group, 16 out of 22 eyes showed CNV resolution. Clearly, further randomized, double-masked trials will be required to substantiate these early results, but at this juncture TTT represents a very promising approach for the vast majority of patients with the occult form of ARMD. Indeed, under the auspices of Iridex and using its Iris Medical OcuLight SLx laser, a 24-center, 336-patient, fully randomized, double-masked trial called the TTT4CNV trial will commence shortly.

Another interesting approach to treating an earlier stage of wet ARMD was discussed at the AAO gathering by Dr. Robert Murphy and Dr. Bert Glaser of the Glaser Murphy Retinal Treatment Centers (Baltimore, Maryland). High-speed ICG dye-enhanced angiography is first employed as a tool for the precise identification and location of very tiny feeder vessels, which manifest early in wet ARMD and may not be clearly demonstrated with conventional fluorescein angiography. Then, the Iridex 810 nm OcuLight SLx laser photocoagulator, which is pulsed rapidly and penetrates deeply, coagulates these embryonic feeder vessels before they progress to a more serious form. Although these results are anecdotal, lacking in a randomized, masked format, initial results are very promising, with excellent clinical success (more than 80% of the feeder vessels were successfully coagulated), improved visual acuity (78% showed a one-line vision gain, while 43% achieved two lines of improvement) with minimal side effects. Further clinical trials are being conducted at the Glaser Murphy Retinal Treatment Centers and by Dr. Giovanni Staurenghi at the University of Milan (Milan, Italy).

Trials study treatment of dry form

While the prospects for thousands of patients deriving benefit from TTT and PDT are exciting, perhaps the greatest potential lies in two Iridex-sponsored trials for the treatment of the earliest stage of ARMD, the dry, or non-exudative, form. As previously noted, dry ARMD often is the precursor to wet ARMD and accounts for the lion's share of the total cases. In this regard, Iridex is sponsoring two separate clinical trials using the 810 nm OcuLight SLx laser photocoagulator to substantiate both safety and efficacy. The first study, known as the Prophylactic Diode Laser Photocoagulation for the Prevention of Choroidal Neovascularization in Age-Related Macular Degeneration trial, has enrolled more than 150 patients and 200 eyes to date. The trial has demonstrated that 67.6% of treated eyes show significant drusen reduction as compared to the 3.3% for the observation (non-treated) group and, more importantly, there was a two or more line improvement in visual acuity for the 11.4% of the treated eye cohort relative to no improvement for observed patients. An article in the November 1999 issue of Ophthalmology, titled "Therapeutic benefits of infrared (810 nm) diode laser macular grid photocoagulation in prophylactic treatment of nonexudative age-related macular degeneration," authored by R. Joseph Olk of the Retina Center of St. Louis (St. Louis, Missouri), et al., discussed in detail this clinical trial. These findings were consistent with the results of other studies that show evidence of laser therapy fostering the resolution of foveal drusen and improving vision. Data from this first trial have been incorporated in the design of the larger, multicenter, randomized, prospective follow-on study, called the Prophylactic Treatment of Age-related Macular Degeneration (PTAMD) trial. The premise of the PTAMD study is to examine whether sub-threshold diode laser photocoagulation that reduces drusen can result in a decreased risk of visual loss from CNV. Successful results from this trial would be an extremely important development for patients with early-stage ARMD. To date, 400 patients have been enrolled, with 25 centers up and running. A total of 1,000 to 1,300 patients are expected to be enrolled, with the study slated to be completed by early 2003.

Longer term, three other approaches may afford even more important progress for ARMD patients. First, the development of anti-angiogenic steroid compounds, which potentially could arrest the function of vascular endothelial factor, which has been implicated in ocular neovascularization, offers great promise. However, these agents are several years away from commercial reality. Second, genetic research may enable physicians to identify the new gene or new gene locus that causes macular degeneration. It has been suggested that there may be 10 or more genes contributing to the disease. Once the gene is identified, a study can be done to determine in what way this gene mutation interferes with the normal functioning of the retina to cause macular degeneration. Third, transplantation of diseased cells, notably the photoreceptor cells and the retinal pigment epithelial cells, with new cells may provide a solution to macular degeneration.