BBI Contributing Editor

ANAHEIM, California The annual meeting of the American Academy of Ophthalmology (AAO; San Francisco, California), which took place at the Anaheim Convention Center in mid-November, covered a broad rage of topics of interest to the ophthalmic community. Prior to the meeting, there had been a tremendous build-up of excitement and anticipation, as retinal specialists and the financial community eagerly awaited the clinical results of several new drugs for the treatment of age-related macular degeneration (AMD).

AMD is a chronic, progressive disease of the macula or central part of the retina, causing irreversible loss of central vision. It is the leading cause of severe vision loss and blindness in patients over the age of 50 in the developed world. The most common symptoms of AMD are a central blurred or blank spot, distortion of objects or simply blurred vision. The disease typically affects patients initially in one eye, with a high likelihood of it occurring in the second eye over time.

As its name implies, age-related macular degeneration is strongly associated with aging, afflicting 18% of people between 70 and 74 years of age, surging to 47% among people 85 years of age and older. The most important treatable risk factor for AMD is smoking, which leads to a three-fold increased risk of disease and may cause as much as 15% of AMD. An estimated 15 million to 20 million people in the U.S. suffer from some form of AMD, with more than 10% of these individuals experiencing the "wet" form of AMD, which occurs when new blood vessels from the tissue layer in the eye just beneath the retina, called the choroid, invade into the retinal layers. This abnormal blood vessel growth generally is known as angiogenesis and, in the context of wet AMD, is called choroidal neovascularization (CNV). These new blood vessels tend to be fragile and often bleed and leak fluid into the macula, resulting in loss of vision. Untreated, this blood vessel growth and leakage can lead to scarring and, eventually, to the destruction of the macula. The typical wet AMD patient suffers from severe vision loss in the affected eye within about two years after diagnosis of the disease. Although wet AMD represents only 10% of all cases of AMD, it is responsible for 90% of the severe vision loss associated with the disease.

There are two primary forms of treatment approved in the U.S. and available to wet AMD patients. The first is thermal laser photocoagulation, which essentially cauterizes the leaking blood vessels and can halt the decrease in visual acuity. There are several significant drawbacks to this approach. These include its applicability to less than 25% of wet AMD sufferers, a very high recurrence rate and, last, 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.

Photodynamic therapy

In April 2000, an important new AMD therapy, called photodynamic therapy (PDT), received FDA approval and immediately made a major impact on the market, racking up estimated worldwide revenue of approximately $350 million this year. Photodynamic therapy uses light-activated drugs, called photosensitizers, to treat diseases which exhibit rapid tissue proliferation, e.g., the growth of tumors or abnormal blood vessels. Patients receive a photosensitizing drug via an intravenous infusion. Once in the bloodstream, these photosensitizers attach themselves to lipoproteins and are transported to sites of rapid tissue proliferation. Based upon the hypothesis that rapidly dividing cells need lipoproteins more quickly and in higher concentrations than normal cells, it is expected that photosensitizers accumulate more quickly in the rapidly dividing cells. Applying a specific dose of non-thermal laser light with a specific wavelength at the target site activates the photosensitizer. The light interacts with the photosensitizer to convert cellular oxygen into singlet oxygen, a highly energized form of oxygen that causes cell death by disrupting normal cellular function. Since the photosensitizer and the light must be combined for cell death to take place, PDT is a safe and selective therapy, which can be used multiple times.

At present, the only FDA-approved compound for PDT is Visudyne, which was developed by QLT (Vancouver, British Columbia) and is marketed worldwide by Novartis Ophthalmics (Basel, Switzerland). Visudyne's impressive market acceptance has occurred despite the fact that it basically does not reverse the course of this devastating disease but merely slows its progression. Its performance has also been hindered by important therapeutic indication restrictions in the U.S. that have confined the treatment only to certain types of wet AMD (predominantly classic) and in the European Union only for the treatment of the predominantly classic and occult subtypes of wet AMD. Visudyne therapy also has another critical shortcoming it lacks durability. The vast majority of the patients who received Visudyne have experienced a recurrence of the condition within three months of treatment, necessitating re-treatment. Furthermore, the method of administering this therapy requires the physician to invest in expensive laser equipment, retain paramedical personnel to assist in the intravenous infusion of the photosensitizer and, due to Medicare drug reimbursement coverage issues, stock the drug in inventory. PDT also is very expensive therapy, with each drug dose, which is administered every three months, costing more than $1,500.

The clinical results of three new compounds that have received significant publicity in the retinal community were released at the AAO's Subspecialty Day, "The Retina Debates 2003." In a packed room, noted retinal specialist Carmen Puliafito, MD, of the Bascom Palmer Eye Institute (Miami, Florida), told attendees that the clinical trial for Macugen had demonstrated excellent safety and solid efficacy across all major types of wet AMD. The trial, which was the largest AMD trial ever conducted, was sponsored by privately owned Eyetech Pharmaceuticals (New York), which has indicated it intends to have an initial public offering early this year. Macugen appears to inhibit the effect of ocular vascular endothelial growth factor (VEGF) and is the closest to FDA approval, having completed its Phase III clinical trial. The rationale for VEGF inhibition in the retina is that it may thwart the development of neovascularization, which ultimately can result in scarring and/or bleeding in the macula. In the words of Mark Blumenkranz, MD, chairman of the department of ophthalmology at Stanford University School of Medicine (Stanford, California), Macugen "specifically targets the disease mechanism."

This trial, called the VEGF Inhibition Study in Ocular Neovascularization (VISION), showed that 70% of Macugen patients (statistically significant) vs. 55% of those on placebo met the primary endpoint, which was a change in best corrected visual acuity (BCVA) after one year, with success being defined as losing less than three lines of vision (or 15 letters in the ETDRS chart) in the one year treatment In addition, 33% of patients on Macugen showed stabilization improvement in vision vs. 23% for those on placebo. Eleven percent of the Macugen group experienced vision improvement, compared to 6% for placebo cohort. Relative to the results of Visudyne, these data were certainly encouraging. However, relative to the much-hyped, pre-AAO meeting expectations, most physicians were disappointed. According to Blumenkranz, "this is clearly not a miracle drug; people are not going to jump up and down over this data."

Nevertheless, he noted that there are several advantages that appear to make Macugen an important new agent in the fight against AMD. First, it is a safe drug. Second, it will likely be less costly than PDT therapy, which requires an expensive laser and extra personnel in the ophthalmologist's office. Third, it works across all types of wet AMD. Fourth, by targeting the process of angiogenesis, it attacks the disease head-on.

A new drug application for Macugen is expected to be submitted sometime this year, with a possible FDA approval several months later. In December 2002, Eyetech entered into a wide-ranging collaboration with Pfizer (New York) to develop, manufacture and commercialize Macugen for AMD and related eye conditions. Under the terms of the agreements, Pfizer paid Eyetech $100 million, consisting of a $75 million initial license fee and a $25 million equity investment with an obligation to purchase up to an additional $25 million of Eyetech common stock in specified circumstances. Pfizer will co-promote Macugen in the U.S. and will share in the profits and losses of Macugen for up to 15 years. Outside the U.S., Pfizer will have an exclusive license to sell Macugen and will pay Eyetech a royalty on net sales. Finally, Pfizer is potentially obligated to pay up to $195 million in milestone payments based on the achievement of worldwide regulatory submissions and approvals, and up to an additional $450 million in milestone payments based upon achieving agreed-upon Macugen sales levels.

There was considerable interest at the AAO meeting in two other compounds, Retaane, under development by Alcon (Fort Worth, Texas) and Lucentis, being developed by Genentech (South San Francisco, California). The former is an angiostatic cortisene compound that is administered every six months onto the outer surface of the back of the eye using a specially designed, curved, blunt-tipped cannula that does not pierce the eyeball. It delivers the drug onto the outer surface of the back of the eye, adjacent to the macula. This approach, called posterior juxtascleral deposition, avoids the risk of intraocular infection and retinal detachment. Competing treatments require intravitreal (direct) injections into the eye up to nine to 12 times annually, while PDT is generally administered intravenously every three months.

As a long-term alternative to twice annual posterior juxtascleral placement of Retaane using a cannula, Alcon has begun investigating a novel transscleral drug delivery device that implants a tablet behind the eye, enabling even longer term delivery of Retaane. According to Jason Slakter, MD, clinical professor of ophthalmology at New York University School of Medicine (New York), who presented the latest Retaane clinical results at the AAO, the possibility of delivering an AMD agent over many months makes this approach "ideally suited" to the treatment of wet age-related macular degeneration.

Alcon reported 24-month results from the Phase II/III trial, which randomized patients into either a Retaane or placebo treatment arm. These results were similar to the 12-month follow-up results that were reported earlier in 2003. This Phase II/III trial data will be part of its premarket approval application filing, which is expected to occur about a year from now. This trial has shown that Retaane preserves vision, prevents severe vision loss, and inhibits lesion growth. Seventy-three percent of treated patients had stable or improved vision, vs. 47% in the placebo group. In the subgroup with more aggressive, predominantly classic lesions, no patients had severe vision loss (less than six lines), vs. 23% in the placebo group.

Another Retaane trial compares it to PDT using Visudyne. In July 2003, Alcon completed the enrollment of 533 patients in the multi-center Phase III clinical trial. These patients will be followed for one year prior to filing, and 12-month data should be available in the fall of 2004. This data will be packaged together with the Retaane vs. placebo results and is expected to be submitted in 4Q04. FDA approval is expected in mid-2005 following a priority review. A dropout rate approaching 40% had been an issue in the Phase II/III study, although this was likely due to the fact that Visudyne was approved as a treatment for AMD during the enrollment period of that study. The number of dropouts to follow-up seemed to increase once again when the company recently reported 24-month results. The company maintains that it is not concerned about this issue and that it will not affect the FDA's position on final approval.

Perhaps the most significant news emanating from Alcon during the AAO was that the company will initiate a Retaane risk reduction study. This trial addresses patients who already have wet AMD in one eye and dry AMD in the other. The purpose of this study is to evaluate whether treating the dry AMD can prevent its progression to the more dangerous wet form. Enrollment for this trial is scheduled to begin this month and patient follow-up will occur over a period of four years. A total of about 2,500 patients will be enrolled at 100 sites worldwide. The FDA has given a fast-track designation to this trial, because it represents a significant unmet medical need for a serious condition.

There are currently no FDA-approved medical treatments for dry AMD, although there are other non-pharmaceutical treatment modalities, such as rheopheresis and diode laser therapy now under active clinical investigation. Alcon's trial represents the most significant medical management trial for dry AMD.

Genentech's anti-VEGF compound, called Lucentis, also has shown promise for wet AMD therapy. The company is conducting two Phase III trials, one which compares the safety and efficacy of Lucentis to PDT and the second which compares Lucentis to a placebo treatment. A total of 426 patients who have predominantly classic AMD category are being enrolled in the former trial, which is expected to be completed in the first half of this year. The latter trial, which is enrolling 700 patients in the minimally classic and occult category, was scheduled to be completed by the end of 2003. Twelve-month follow-up will be required before a new drug application filing. Lucentis is administered with monthly intravitreal injections.

Although wet AMD is far more serious than the earlier stage dry AMD, there is considerable interest in treating the dry form of the disease with device modalities. Perhaps the most intriguing is rheopheresis (RHEO), an advanced application of an established method of plasma therapy called membrane differential filtration (MDF), which was originally developed by Japanese scientists almost 20 years ago. MDF works by removing excess amounts of certain macro-proteins and fatty components that have been associated with certain diseases and may be harmful when circulating in a person's blood. Rheopheresis treatment is based on the theory that age-related disorders such as AMD are diseases of the microcirculation and that the removal of certain macromolecules may improve the flow of blood through small vessels in the body, including those beneath the retina.

The initial results of the first 43 patients treated in the Multi-center Investigation of Rheopheresis for Age-Related Macular Degeneration (MIRA-1) trial were released at the AAO's 2002 annual meeting and subsequently were published in Clinical and Experimenal Ophthalmology. In those patients with a best corrected visual acuity (BCVA) worse than 20/40, there was a 1.1-line (ETDRS) improvement of BCVA over the year vs. a 1.9 line decrease for the control group. This was highly statistically significant. In addition, a significantly higher percentage of patients gained three or more lines of BCVA compared to the placebo group.

At this point, a total of about 90 patients have been enrolled in the MIRA-1 trial, with another 90 patients expected to be enrolled by mid-2004. The trial design includes a 2:1 entry of patients into rheopheresis vs. "sham." Thus, 120 patients will receive therapy and 60 patients will be the control group. Patients are treated eight times over a 10-week period and then are followed for a full-year. The trial is double-masked and placebo-controlled and is being conducted in the U.S. at six trial sites. The lead investigator is Dr. David Boyer of Los Angeles, California. Assuming that enrollment is complete by mid-2004, then patient follow-up for a one-year period, PMA submission of the data to the FDA could occur by the latter part of 2005. Thus, a possible final FDA approval is conceivable by mid-to-late 2006.

It is important to note there is currently a high degree of skepticism among retinal specialists regarding RHEO, and even physicians that acknowledge the encouraging initial data express concerns over the underlying science. It is not surprising that retinal specialists would express caution with regard to rheopheresis, as the pivotal trial has not yet been completed, and the blood filtration procedure is very different from treatments currently provided by these physicians. It is worth noting that RHEO is a treatment that may never become the domain of retinal specialists but could be prescribed by general ophthalmologists that treat these earlier stage AMD patients.

In mid-2003, TLC Vision (Mississauga, Ontario) and Diamed Medizintechnik GmbH (Cologne, Germany) announced a 50/50 investment totaling up to $12 million in Vascular Sciences (Tampa, Florida), which owns the rights to the RHEO technology. TLC Vision now holds 26% and Diamed holds 24% of Vascular Sciences. Diamed is the exclusive RHEO distributor in Germany, Austria, Switzerland and Luxembourg. TLC Vision already has a 50% interest in OccuLogix (Tampa, Florida), its joint venture with Vascular Sciences, designed to commercialize treatment for dry AMD. The companies said they made the investment to fund and speed the completion of the pivotal U.S. trial.

Another device-based modality is being employed in the Prophylactic Treatment of Age-Related Macular Degeneration (PTAMD) trial. This study, supported by Iridex (Mountain View, California), was designed to determine whether prophylactic laser treatment for patients with dry age-related macular degeneration could preserve visual acuity and/or reduce the risk of disease progression from dry to wet AMD. It is a multi-center, prospective, placebo-controlled randomized trial conducted at 20 centers in the U.S. and one in Mexico. The bilateral arm of the trial was designed to look at the eyes of patients 50 years of age or older with nonexudative or dry AMD, with at least five large soft drusen in both eyes and visual acuity of 20/63 or better on the ETDRS chart.

The PTAMD clinical trial utilizes a gentle "sub-threshold" 810-nanometer infrared diode laser treatment that minimizes damage to the retina and is not perceptible to the patient or to the clinician. The rationale for a prophylactic laser treatment of dry AMD is based on the fact that laser treatment in patients with dry AMD has been shown to cause a reduction in size or actual disappearance of drusen, and this may benefit the natural course of the disease. Drusen resorption promoted by laser treatment occurs also in drusen not directly addressed by and distant from the laser treatment spots (e.g. beneath the fovea, the center of vision) and the ophthalmic literature has reported some evidence that disappearance of drusen can, in some cases, lead to improvement of vision as well as alter the natural rate of CNV occurrence.

In late 2001, the executive committee of the PTAMD trial advised study investigators that current enrollment was sufficient to detect a clinically relevant difference in the clinical outcomes of the study and that further enrollment be stopped. At that point, a total of 1,276 eyes had been enrolled, half in the treatment arm and half in the placebo arm. According to an Iridex spokesman, the release date for the final study results was not certain as of early December.

It is clear to all involved in AMD therapy that this is a very challenging disease that will require novel approaches to achieve a better outcome. In this regard, an early stage project worth noting is being developed by Daniel Schwartz, MD, associate professor and director of the retina division at the University of California, San Francisco (San Francisco, California). In collaboration with scientists at the California Institute of Technology (Caltech; Pasadena, California), Schwartz has developed a research plan to better diagnose and treat the early stages of AMD, before significant visual loss occurs.

Specifically, in early stage AMD, there is progressive accumulation of lipids in Bruch's membrane, a thin tissue layer that lies between the retina and its blood supply. As these fats accumulate and block transport across Bruch's membrane, retinal nutrition is impaired. Inadequate delivery of oxygen and nutrients to the retina eventually causes neovascularization, which in turn leads to bleeding and results in severe visual loss. At present, there is no means to either detect or treat the lipid accumulation in Bruch's membrane that develops in early AMD.

Utilizing technology developed at Caltech, the project aims to diagnose early-stage lipid accumulation and reduced transport across Bruch's membrane. As a byproduct of this effort, the project will aim to develop better means to image the retina and underlying vasculature clinically. In addition, the effort will strive to develop novel methods to remove lipid from Bruch's membrane using a light source. If this approach is successful, earlier diagnosis of AMD will be possible. Furthermore, if this therapeutic strategy is effective, patients with AMD will be treated once or twice per year with light in an outpatient setting to avoid development of neovascularization and ensuing irreversible visual loss.

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