BBI Contributing Editor

NEW ORLEANS The annual meeting of the American Academy of Ophthalmology (AAO; San Francisco), the largest gathering of eye physicians in the world, took place here in late October at the Morial Convention Center. This meeting typically covers a broad rage of topics of interest to the ophthalmic community, including cataract and refractive surgery, glaucoma diagnosis and management and major retinal disorders such as diabetic retinopathy and age-related macular degeneration (AMD).

AMD is a chronic and progressive disease of the macula or central part of the retina and is the leading cause of severe vision loss and blindness in patients over the age of 50 in the developed world. According to an article in the April 2004 issue of Archives of Ophthalmology, the Eye Diseases Prevalence Research Group estimates that about 1.8 million Americans have AMD. Moreover, owing to the rapidly aging U.S. population, the number of persons having AMD is projected to increase by 50% to nearly 3 million by 2020.

Prior to 2000, there was only one AMD treatment option thermal laser photocoagulation, which has numerous clinical disadvantages and therefore has never been widely used. In April 2000, the FDA approval of the pharmaceutical agent Visudyne, developed by QLT (Vancouver, British Columbia) and marketed worldwide by Novartis Ophthalmics (Basel, Switzerland), sparked a surge in interest in AMD. This heightened interest has continued in the past four years, with promising new drugs and laser-based technologies fueling the upsurge in interest.

Visudyne was the first new pharmaceutical agent designed specifically for AMD therapy and also is the first drug using photodynamic therapy, an approach which uses light-activated drugs, called photosensitizers, to treat diseases that exhibit rapid tissue proliferation, e.g., the growth of tumors or abnormal blood vessels. Late-stage or wet AMD is characterized by rapidly growing blood vessels under the macula, which is called choroidal neovascularization or CNV.

Visudyne's revenue has grown rapidly since its debut and is expected to register worldwide sales in 2004 of about $430 million. This is testimony more to the desperate need for new treatment options rather than the efficacy of this drug, which typically does not improve the course of the disease, but rather prevents progressive vision loss in about half the patients. With the mediocre results of Visudyne, there is a huge vacuum existing, awaiting new therapies. However, both before and during the AAO, two companies reported disappointing clinical results that dampened enthusiasm in the ophthalmic community.

At the 2004 AAO Subspecialty Day titled "Everything You Ever Wanted to Know about Retina . . ." Elias Reichel, MD, associate professor of ophthalmology at the New England Eye Center of Tufts University School of Medicine (Boston) and study chairman of the Transpupillary Thermotherapy for Choroidal Neovascularization (TTT4CNV) trial, reported on the results of this multi-center randomized, prospective, double-masked 303-patient study. It was designed to look at eyes with wet AMD and randomized eyes with small (less than or equal to 3 mm diameter) subfoveal occult membranes and symptomatic vision issues.

In the TTT-treated eyes, laser energy was applied at 800 mW with a 3 mm spot size for 60 seconds with the Iridex (Mountain View, California) IRIS Medical OcuLight SLx 810 nm laser and large spot slit lamp adapter. The sham treatment consisted of the laser not being turned on. One re-treatment was permitted at three months during the follow-up period at the physician's discretion.

TTT, which was FDA-approved several years ago under a 510(k) designation, is a "kinder, gentler" laser therapy than thermal laser photocoagulation and numerous single arm studies over the past several years have reported solid safety and efficacy benefits. Iridex initiated the TTT4CNV trial about four years as a means to secure broader Medicare reimbursement coverage and further establish its clinical credibility. However, this trial, quite unexpectedly showed disappointing results, with patients in the TTT laser treatment showing results indicating that its treatment performed no better than a placebo treatment and, in one safety endpoint, somewhat worse.

Specifically, after two years 47% of eyes avoided modest or severe vision loss, compared to 43% of sham-treated eyes, data that was not statistically significant. Follow-up at 18 and 24 months showed an advantage of about four letters in TTT-treated eyes, though this trend also was not significant.

Safety results also were presented, also indicating less than satisfactory results for the TTT treatment. Some patients in both groups showed severe loss of vision at the one-month follow-up visit. Five percent of TTT-treated eyes showed severe loss of vision at the follow-up visit, compared to just 1% for sham eyes, though this finding was not statistically significant. Reichel did report that 11% of patients who were treated with TTT, compared to 3% in the control group, showed improvement (greater or equal to two lines increase) from baseline when evaluated at one year, a secondary outcome that was statistically significant.

In an interview with The BBI Newsletter following release of these results, Reichel said that while he was very disappointed with the TTT4CNV results, he remains a staunch believer in TTT. "I am very confident that TTT will prove to be an effective therapy for late-stage AMD."

He said that a careful subgroup analysis, which already is under way, would be necessary to determine its precise role in AMD therapy. Specifically, this subgroup of patients may have certain characteristics that would result in a high likelihood of improvement or stabilization over time. This subgroup data could be released at The Macula Society (Cleveland) annual meeting, which will take place in late February.

He also noted that there are "a number of questions for which analyses remain to be done. Specifically, careful inspection of baseline characteristics between groups and a per-protocol analysis that evaluates the subset of enrolled patients who met all key eligibility criteria needs to be done."

Reichel, who has performed TTT on many patients and may be its most visible spokesman, concluded his interview with BBI by saying, "It ain't over 'til it's over."

Echoing Reichel's comments, Ted Boutacoff, president and CEO of Iridex, said "We are very disappointed with these results but are very encouraged that a number of patients experienced a significant improvement in vision and look forward to the comprehensive analysis of the study data that may provide clarity into the patients who responded well to TTT." He added: "We remain optimistic about this therapy in light of the difficulties and inconsistencies in treating this devastating condition and the economic burden given the large numbers of newly affected patients."

Less-than-stellar results also were reported a week prior to the AAO meeting by Alcon Laboratories (Fort Worth, Texas), which announced disappointing clinical results for its flagship AMD agent Retaane. Initial analysis of the one-year data of Retaane, compared to Visudyne, showed that it did not meet its primary "non-inferiority" endpoint. Specifically, the percentage of patients who maintained vision, as defined by less than three lines of visual acuity, was 45% for Retaane vs. 49% for Visudyne.

At an analysts' meeting held prior to the AAO meeting, Alcon's management team reiterated statements made in its earlier press release that in analyzing the data, there were two controllable factors drug reflux and treatment timing that contributed to the poor results. Thus, the company indicated that these issues could be readily overcome and that it planned to submit a new drug application (NDA) before year-end.

Gerry Cagle, PhD, senior vice president, research and development, told the analysts that "we have looked very carefully at that data, have met with the FDA and have decided to move forward with an NDA filing." There was considerable skepticism by most of the analysts attending the meeting, with some noting that the results of the company's earlier Retaane trial had not been robust, due to a high patient dropout rate.

Several retinal specialists interviewed by BBI after the Alcon analysts' meeting indicated that failing to meet its primary endpoint could mean a rejection by the FDA, in spite of Alcon's ability to rationalize the clearly disappointing results.

The ongoing challenge in effectively treating AMD is to attack the disease earlier in its progression. To that end, Alcon is in the midst of a clinical study called the Risk Reduction Trial, which aims to assess the efficacy of treating patients with advanced dry (earlier stage) AMD who appear to be at risk of progressing to wet AMD. This trial uses a novel trans-scleral drug delivery device that implants a tablet behind the eye, enabling even longer-term delivery of Retaane.

Enrollment for this trial began early this year, and patient follow-up will occur over a period of four years. A total of some 2,500 patients ultimately 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.

According to Jason Slakter, MD, clinical professor of medicine at New York University School of Medicine (New York), who discussed Retaane at the Alcon analysts' gathering, "more than ever, we need to reduce the risk of getting full-blown AMD by treating it earlier." Slakter, well-known in the retinal world, also reminded the analysts that "AMD is a very nasty disease that thus far has not benefited [from] any magic bullets."

There was considerable interest at the AAO meeting in two other compounds Macugen, being developed by Eyetech Pharmaceuticals (New York), and Lucentis, being developed by Genentech (South San Francisco, California). Both work by inhibiting the effect of ocular vascular endothelial growth factor (VEGF), which the retinal community believes may thwart the development of choroidal neovascularization, or the formation of new blood vessels. Left untreated, CNV can cause bleeding and scarring in the macula, destroying central vision.

Just prior to the AAO meeting, Eyetech, which has partnered with the pharmaceutical giant Pfizer (New York) to market Macugen worldwide, reported that the treatment effect of Macugen extends for two years. This treatment benefit, which required an additional eight to nine injections in year two, was also seen for patients who received Macugen for two years compared to those only receiving one year of therapy.

Macugen was positively reviewed in late August by the FDA's Dermatologic and Ophthalmic Drugs Advisory Committee, and final approval is expected soon. Analysts have very high expectations for Macugen, with several Wall Street investment banks projecting peak global sales in excess of $1 billion.

While Macugen clearly has the best near-term revenue prospects, based on its likely near-term FDA approval and solid clinical results, Genentech's agent may be the most promising drug for late-stage, wet AMD therapy. Importantly, although Lucentis also is a VEGF inhibitor, it binds to all forms of VEGF, whereas Macugen binds to just one. Some retinal specialists believe that this is a very important distinction and will make a marked difference in clinical outcomes. Other retinal experts, such as Robert Bhisitkul, MD, PhD, assistant professor of ophthalmology at the University of California, San Francisco, are skeptical. Bhisitkul, who is a Lucentis investigator and is optimistic about its prospects, told BBI that this could be just "academic theory and irrelevant to clinical results."

Genentech is in the midst of its Phase III pivotal AMD trials and has completed patient enrollment in three of them. The first, called MARINA, compared two different doses of Lucentis to a placebo treatment and completed enrollment of about 716 patients at year-end 2003. The second trial, called ANCHOR, compared Lucentis and a sham Visudyne treatment to Visudyne and a sham injection and completed enrollment of 423 patients in September 2004. The third trial, called FOCUS, completed its 162-patient enrollment in early 2004 and compared Lucentis and a sham injection to Visudyne and a sham injection. Finally, the PIER trial, which is currently enrolling up to about 180 patients, is comparing two different doses of Lucentis to a sham injection.

Although Genentech has not released any pivotal Phase III data as yet, the positive buzz in the retinal community, based on the Phase I/II data and anecdotal reports, is enormous. For example, Philip Rosenfield, MD, from the Bascom Palmer Eye Institute, University of Miami School of Medicine (Miami), speaking at a Genentech-sponsored evening seminar, noted that there was a "dramatic" improvement in visual acuity (VA) patients treated with Lucentis in the Phase I/II trial. Moreover, this gain in VA was corroborated by optical coherence tomography imaging, a relatively new non-contact, non-invasive imaging technique used to obtain high-resolution, cross-sectional images of the retina. It increasingly is being relied on to assess the benefits of AMD drug therapy and may someday supplant the current gold standard, fluorescein angiography.

Rosenfield, one of the best-known retinal specialists in the U.S., said that he is "spectacularly impressed with the Lucentis results" and believes that enough patients have been treated with a known mechanism of action that the Phase III results should be equally impressive.

Peter Kaiser, MD, of the Cleveland Clinic Foundation (Cleveland), speaking at a symposium sponsored by Novartis Ophthalmics, expressed similar sentiments, telling BBI that "I think Lucentis is the real deal and if I were a betting man, that is where I'd put my money."

According to a Genentech spokesperson, the Phase III results for MARINA will be released in 2Q05, with a possible NDA filing several months later. Thus, final FDA approval for Lucentis could take up to 18 months to two years from now. However, it appears at this juncture that it will be the winner in this high-stakes market opportunity.

Another contender, albeit further behind, is Miravant Medical Technologies (Santa Barbara, California). At the AAO meeting, it unveiled additional results from analyses of the Photrex (rostaporfin, SnET2) Phase III clinical trials for the treatment of wet AMD. It is quite similar to the QLT/Novartis approach, using a light-activated drug and a laser to deliver photodynamic therapy.

The Phase III clinical trials of patients with CNV associated with wet AMD were conducted at 60 US centers. The primary efficacy endpoint for the two-year studies was the proportion of patients losing less than 15 letters (three lines) of vision on a standard eye chart.

Based on data from two randomized, placebo-controlled, two-year trials, investigators reported significant visual acuity benefits in Photrex-patients with occult CNV lesions. Angiographic evidence that Photrex treatments slowed the progression of both classic and occult CNV leakage and fluid accumulation; treatment benefit in Photrex patients regardless of visual acuities at commencement of treatment, with a greater benefit noted with higher baseline visual acuity; and Photrex clinical retreatment guidelines based on vessel leakage.

Edgar Thomas, MD, of Retina-Vitreous Associates (Los Angeles), presented favorable visual acuity results based on subgroup analyses of lesions with predominantly (greater than or equal to 50%) occult CNV, including pure occult lesions.

The occult VA outcomes were supported by secondary angiographic assessments reported by Ronald Danis, MD, of the Fundus Photograph Reading Center at the University of Wisconsin (Madison, Wisconsin). Photrex-treated lesions (both classic and occult CNV) had statistically significant reductions in vessel leakage and fluid accumulation, factors considered indicative of AMD disease activity.

Baruch Kuppermann, MD, PhD, of the University of California, Irvine, presented data on the effect of baseline visual acuity on efficacy at the study endpoint. Analysis of results showed a statistically significant treatment benefit for all baseline VA strata. The greatest relative gain over placebo was noted in patients at highest risk of vision loss that is, those with higher VA at the commencement of treatment. Irrespective of baseline VA, patients receiving placebo were about two times more likely to lose three or more lines of vision than treated patients.

Carl Regillo, MD, of Wills Eye Hospital (Philadelphia), provided data suggesting Photrex retreatment guidance. During the trials, patients were eligible for retreatment at three-month intervals. Primary efficacy was assessed in patients who received retreatment when there was evidence of ongoing or increased vessel leakage and compared to patients who did not receive re-treatment under those conditions. At two years, patients treated according to the leakage criteria had a statistically significant primary VA benefit.

On Sept. 30, 2004, Miravant reported that it had received an "approvable" letter from the FDA. The FDA also asked that a confirmatory clinical trial be completed before final approval could be granted. That was a setback to Miravant, which had been hoping for a final approval but now must conduct another costly, delaying Phase III trial.

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