Eyetech Pharmaceuticals Inc.'s CEO David Guyer typically is humble when he talks about the company's landmark potential $750 million deal in late 2002 with Pfizer Inc. for Macugen, the in-licensed aptamer for age-related macular degeneration.
And he doesn't blow Eyetech's horn too loudly over its wildly successful initial public offering earlier this year - which raised $136.5 million, with the firm's stock up more than 54 percent in the first day of trading and still performing well.
True to form, Guyer was fairly subdued over Eyetech's deal earlier this month with Archemix Inc., the aptamer-based company that licensed the rest of Gilead Sciences Inc.'s Systematic Evolution of Ligands of Exponential enrichment (SELEX), a combinatorial chemistry method that screens vast numbers of oligonucleotides for sequences with appropriate binding affinities and specificities toward any target. That was after Eyetech took its piece: Macugen (pegaptanib sodium), which the company is turning into a would-be AMD blockbuster.
So, Guyer probably would not boast of shrewdness or foresight with regard to the promise of aptamers, but for investors and scientists alike, their potential has become harder than ever to ignore.
Under the terms of the deal with Archemix - which has 170 issued aptamer patents and an equal number pending - Eyetech funds clinical development and gets the right to commercialize aptamers for ophthalmologic indications. Archemix gets an undisclosed up-front payment, plus fees for research and development, and potentially milestones, along with royalties.
Errol De Souza, president and CEO of Archemix, called the deal "a joint collaboration, from target to candidate."
Aptamers are single-stranded nucleic acids that form 3-dimensional shapes and bind target molecules in a manner similar to antibodies but more specifically and with more stability. Tony Adamis, chief scientific officer for Eyetech, seemed a bit more willing than Guyer to take credit for the aptamer "vision," as it were - though both had seen the possibilities early on.
"My laboratory had done work identifying [vascular endothelial growth factor] as a very attractive target for these back-of-the-eye diseases," said Adamis, former professor of ophthalmology at Harvard Medical School and director of residency training in ophthalmology at the Massachusetts Eye and Ear Infirmary, a teaching affiliate of Harvard.
VEGF has gotten plenty of attention all around. In humans, there are at least five subtypes, and Eyetech operates on the idea that two of those VEGF isoforms (isoforms 165 and 121) are present in the eye. Preclinical studies found that elevated levels of the animal counterpart of human isoform 165 are required for abnormal blood vessel growth in the retina. The unique shape of the Macugen aptamer apparently lets it bind to VEGF isoform 165 with high specificity through what Eyetech describes as a "lock-and-key type mechanism."
In various animal models, researchers found that the animal counterpart of VEGF isoform 165 was specifically increased in diseased creatures. What's more, Macugen's binding with the animal counterpart of isoform 165 proved highly effective in inhibiting abnormal blood vessel growth in the retina. In an animal study that directly compared a VEGF inhibitor that blocks all isoforms, Macugen came out just as effective at inhibiting abnormal blood vessel growth in the retina.
Adamis and Guyer had been consultants for NeXstar Pharmaceuticals Inc., the original owner of SELEX. "When Nexstar was acquired by Gilead [in April 2000], Gilead put the whole program up for sale," Adamis said. "We knew it was a unique opportunity, and that was really the catalyst for us to form [Eyetech]."
Another benefit: Macugen is a PEGylated molecule - that is, one with a molecule of polyethylene glycol attached to the strand of nucleic acid, in order to increase the half-life, making the drug available longer in the eye.
On the heels of Macugen, for which Eyetech and Pfizer expect to file a new drug application in the third quarter, are "a whole bunch of aptamers" going into clinical work, De Souza said. Adamis said initial selection of candidates can occur "in a matter of a few weeks," with optimization lasting only 12 months to 18 months. The lead for Macugen was identified around 1997, and Eyetech already was talking about Phase III data in 2003.
Due mid-year are more Macugen results: Phase II data in diabetic macular edema. "Glaucoma, which in spite of all the medications out there, remains the leading cause of blindness," could be another eventual aptamer target, Adamis told BioWorld Financial Watch.
The world is taking note of Eyetech. This month, analysts at Merrill Lynch initiated coverage with a "buy" rating. The 12-month price target is $45. Late last week, the company's shares were trading at around $35. The company's IPO was regarded as a bellwether of the open window, and Steven Burrill, CEO of Burrill & Co., said that although Eyetech's momentum has slowed since the big jump on the first trading day, the firm is still going strong.
In patients more than 50 years old in the developed world, AMD is the leading cause of severe vision loss and blindness. The Macula Vision Research Foundation estimates as many as 15 million people in the U.S. are afflicted by some form of AMD, with more than 1.6 million experiencing the active blood vessel growth and blood vessel leakage associated with what's called "wet" AMD. It's only going to get worse, as the Baby Boomers age.
So will other diseases of the back of the eye, most likely, and Eyetech is well positioned to combat them with an array of aptamers from the Archemix deal - led by the product that started it all.
Said Adamis: "Macugen obviously is the prototype."