Washington Editor

ROCKVILLE, Md. - An FDA advisory panel Friday leaned toward favoring Macugen, a proposed treatment for age-related macular degeneration expected to have an impact on the aging Baby Boomer population.

The Dermatologic and Ophthalmic Drugs Advisory Committee met in a public forum with sponsors Eyetech Pharmaceuticals Inc. and Pfizer Inc. to go over the rolling new drug application submitted June 17 under fast-track and priority-review guidelines. Priority review suggests FDA action could come six months after the application is submitted, meaning Macugen could be approved as early as mid-December. (See BioWorld Today, June 18, 2004.)

The panel did not take a formal vote. In a press conference with reporters after the meeting, Wiley Chambers, an FDA official, said the hearing was held so that reviewers could get outside expert advice on the application. Since the NDA remains under review, the agency did not ask for a vote.

Officials with Eyetech and Pfizer, both New York-based companies, were not available following the meeting. However, within an hour of adjournment, the companies released a statement simply saying the panel "met today to review the clinical submission for the investigational drug Macugen."

Eyetech's stock (NASDAQ:EYET) was held most of the day, but began trading after the panel. It fell $1.74 to close at $37.46, after rising to $39.20 Thursday in advance of the meeting.

Proposed for the neovascular or wet form of age-related macular degeneration, Macugen, an intravitreous injection, is expected to be a blockbuster. Its chief competition will be Visudyne, a treatment for the predominately classic form of wet AMD, made by Vancouver, British Columbia-based QLT Inc. and Novartis AG, of Basel, Switzerland. (For the first two quarters ended June 30, global sales for Visudyne reached $210 million.)

Macugen (pegaptanib sodium) is a pegylated anti-VEGF aptamer, which binds to and thus inhibits the activity of vascular endothelial growth factor (VEGF). VEGF plays a role in angiogenesis and increased blood vessel leakage, two of the primary processes responsible for the vision loss associated with neovascular age-related macular degeneration (AMD).

The proposed dose is a 0.3 mg injection every six weeks, a point that concerned some panel members.

"I'm not an ophthalmologist, but can't we find another way to deliver this drug?" said Elaine King Miller, a panel member and patient representative from Amarillo, Texas.

Indeed, Peter Kresel, a panel member and senior vice president of global regulatory affairs at Allergan Inc., of Irvine, Calif., echoed Miller's concern, asking how many injections a patient could endure over a period of time. "I guess patients tend to vote with their feet," he said.

During the hearing, a Macugen patient said she'd had six successful eye injections without any pain. She said the injection was a small price to pay for the drug's results.

The firms presented two-year data, another concern for some panel members. Among them, Paula Knudson, executive coordinator of IRM Research and Academic Affairs at the University of Texas in Houston, recommended that the companies be required to follow patients beyond two years in order to compile long-term data.

The NDA is based on two Phase II/III trials that included a total of about 1,200 patients, with a primary efficacy endpoint being the portion of responders, defined as patients avoiding 15-letter loss of visual acuity, a clinically meaningful benefit for a patient.

According to the analysis, the 0.3-mg dose achieved statistical significance for a clinically meaningful primary efficacy endpoint in the two trials.

Macugen 1 mg also achieved a statistically significant treatment benefit in study EOP1003 and was near to significance in EOP1004.

Jennifer Harris, FDA medical officer, told the panel that the 0.3-mg dose of Macugen reduces the risk of vision loss in patients with neovascular AMD, and demonstrated a 15 percent treatment effect over the placebo. However, Harris said the trials demonstrated no clinically meaningful increase in vision.

Overall, she said, similar adverse events were seen in all treatment groups, and most were likely to be related to the intraocular injection such as eye pain, floaters, iritis, endophthalmitis and systemic VEGF inhibition.

Anthony Adamis, a physician who presented data on behalf of the companies, said two-thirds of the patients participating in the trials never reported pain associated with the injection or the drug. The companies believe most pain is associated with the preparation work associated with injection, he said.

Other drugs in Phase III development for AMD indications include Lucentis, an anti-angiogenesis product made by South San Francisco-based Genentech Inc., and a modified steroid called Anecortave Acetate from Fort Worth, Texas-based Alcon Research Ltd.

Pfizer in late 2002 signed on as Eyetech's development partner in a deal worth more than $750 million (including a $100 million up-front fee) for Eyetech. The two would co-market Macugen in the U.S. and share profits. Pfizer has exclusive rights to develop and commercialize Macugen overseas. (See BioWorld Today, Dec. 19, 2002.)

AMD, a progressive degenerative disease of the macula, is classified as either neovascular or non-neovascular. The non-neovascular (dry) form is more common and leads to a slow deterioration of the macula with a gradual loss of vision over a period of years. The neovascular (wet) form is responsible for a majority of cases of severe vision loss and is due to the proliferation of abnormal blood vessels behind the retina.

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