Age-related macular degeneration (AMD) is a demon of the elderly, snatching away their sight at a time in life when, for many, to watch the world is one of the great pleasures - a pleasure not afforded them in the busy, earlier years.
And the race is on for a better drug.
"It's a difficult disease, partly because there aren't any very effective therapies out there," said Douglas Miehm, analyst with RBC Capital Markets. "We're just learning about it."
The leading cause of blindness for people more than 50 years of age, AMD comes in two forms. The "wet," or neovascular, type is characterized by new blood vessels forming behind the eye as the body attempts to get more blood to retinal tissue. When the blood vessels break, the tissue around them is damaged. AMD's much more common and much more gradual "dry" form involves the forming of drusen - yellowish deposits - in the retina and a loss of pigment.
Although the wet form of AMD makes up only 10 percent to 15 percent of cases, it's responsible for most blindness caused by the condition, with vision loss starting about age 55. "Social blindness," or being blind enough for the condition to be a social hindrance, can result in two to three years.
There's a drug on the market for the dreaded wet form: Visudyne (verteporfin), developed by QLT Inc. and Novartis AG, but it's only effective in about 30 percent of patients. Right behind it is another treatment for the same type of AMD: Macugen, an aptamer designed to bind and neutralize vascular endothelial growth factor, which is in the late stage of development by Pfizer Inc. and Eyetech Pharmaceuticals Inc.
Others are in the AMD race. In September 2002, Alcon Research Ltd. began enrolling a 500-patient Phase III study comparing its modified steroid, anecortave acetate, to Visudyne. Genentech Inc. has Lucentis (ranibizumab), another anti-VEGF product, in Phase III trials for AMD, partnered with Novartis.
Regarding the dry form, fewer companies are pursuing treatments because, Miehm said, they believe blood vessels growing into the eye can be more easily targeted.
"With the dry form, eyesight may not even be that impacted," he said. "People might not even know they have it."
The dry form is a larger market, and it's well known that a certain percentage of dry-form AMD cases progress to wet, Miehm said. TLC Vision Corp. in 2002 formed a joint venture with Vascular Sciences Corp. creating OccuLogix LP, a partnership focused on the treating the dry form of AMD through rheopheresis, a blood-filtering process. Rheopheresis for dry AMD already is approved in Canada and Germany.
The wet form has gained more headlines, though. Based on strong Phase II data, hopes were high for Macugen, which was the subject of a potential $750 million deal for Eyetech with Pfizer. Investors came through with $108.5 million in a two-part financing based partly on enrolling the Phase II/III trials, and Eyetech still was riding high enough last week to set down the details of its proposed initial public offering. The price range is $18 to $20 and number of shares 6.5 million, which at the top end would raise $130 million. Eyetech filed for the IPO in September.
Things are looking less good now.
Limited Phase II/III data offered at the American Academy of Ophthalmology meeting last week in Anaheim, Calif., showed Macugen failed to achieve improvement over light-activated Visudyne. Neither Eyetech nor Pfizer issued a press release on the results - but QLT did.
Although the overall safety was deemed good, Leerink Swann & Co.'s MEDACorp group of physician consultants said the results were at "the low end of expectations," while possibly still satisfactory enough for a new drug application. Seventy percent of Macugen patients, compared to 55 percent on placebo, met the primary endpoint of limiting vision loss to no more than 15 letters (or three lines) when reading from a study eye chart. Eleven percent in the Macugen group had their vision improve, compared to 6 percent for placebo.
Those data fell below the consultants' expectations of 75 percent to 80 percent in the primary endpoint, and vision improvement in 15 percent to 20 percent of patients. MEDACorp experts said the pooled data - showing vision gain of two lines or more in 11 percent of Macugen patients as compared to 6 percent for placebo - just reached statistical significance.
Macugen, formerly EYE001, was in-licensed as NX 1838 from Gilead Sciences Inc. in April 2000 in a deal valued at at least $32 million. It's also being studied as a treatment for diabetic macular edema. But the AMD indication is getting the most attention.
Eyetech disclosed only top-line data from the Phase II/III trials. Those numbers, analysts noted, were pretty much in line with results from Visudyne's TAP (which stands for "treatment of AMD with photodynamic therapy") and VIP (verteporfin in photodynamic therapy), the studies that helped the compound win approval. But data from subgroups and from patients who got Macugen in combination with photodynamic therapy have yet to be revealed.
Results from the Macugen pivotal trials provided at the scientific meeting include data from 1,186 of the 1,190 patients who received at least one injection, based on an intent-to-treat analysis. Though the numbers came up positive - and can't be compared head to head with data from the Visudyne studies - improvement gained by treating with Macugen was not as great as the improvement gained in the Visudyne studies, when results are examined as percentage differences in treatment vs. placebo.
Another hitch: Macugen's data could seem better because the baseline visual acuity of patients was worse than those enrolled in Visudyne's TAP trial. Patients in the former had baselines of between 20/40 and 20/320, as compared to 20/40 to 20/200 in the TAP trials and 20/20 to 20/100 in the VIP trials. Wet AMD, as it advances, causes patients to lose fewer lines of visual acuity - so the Macugen subjects, in other words, may have appeared to fare better because they had less vision to lose in the first place, Miehm wrote in a research note.
"Obviously the subgroup analysis is going to be extremely important," he told BioWorld Financial Watch. "It really comes down to whether the FDA is willing to accept the data as a whole, or if they're going to choose to accept the subgroup data. And we don't even know [yet] if the subgroup data is positive, or if it's statistically significant."
More details may be revealed when Eyetech - in a quiet period because of the IPO filing - starts its road show, probably at the start of next year, Miehm said.