With a new drug selling and a potential blockbuster looming on the horizon, the wet age-related macular degeneration (AMD) market has been anything but boring.
Genentech Inc.'s Lucentis turned up the heat last month after preliminary results of a Phase III trial demonstrated that 95 percent of patients with minimally classic or occult wet AMD who were treated with the drug maintained or improved vision at one year, compared to about 62 percent of those in the control arm. Lucentis (ranibizumab) is a humanized therapeutic antibody fragment designed to bind to vascular endothelial growth factor.
Last week, Genentech and partner, Basel, Switzerland-based Novartis Pharma AG, reported positive results from a Phase I/II trial of Lucentis in combination with Visudyne, developed by QLT Inc. In that study, Lucentis again met is primary endpoint of maintaining or improving vision in about 90 percent of patients who received both products vs. about 68 percent who received Visudyne alone.
Those data - besides negatively impacting the stock of Eyetech Inc., which sells Macugen in the AMD space - have left some wondering how the AMD landscape will be shaped years from now, and in particular, where the data leave Visudyne.
As the first to arrive on the scene, photodynamic therapy Visudyne (verteporfin), developed by Vancouver, British Columbia-based QLT, received FDA approval in 2000, primarily for predominately classic lesions, and the drug's availability "brought a lot of exposure and brought more patients in for earlier treatment," said QLT spokeswoman Tamara Hicks.
Visudyne's sole position in AMD ended late last year when the FDA approved Macugen (pegaptanib sodium injection), a VEGF inhibitor that demonstrated efficacy in clinical trials against all types of wet AMD, regardless of lesion subtype or size.
There was much early enthusiasm on Wall Street, but analysts said Macugen's hold on the AMD market might be short lived, if Lucentis continues to pick up steam.
"Macugen will be dominant until Lucentis comes out," said Yaron Werber, of New York-based Smith Barney Citigroup, which recently released a physician survey that suggests Lucentis will "become the front-runner in this market," particularly in the minimally classic and occult lesion segments that make up about three-fourths of the AMD patient population.
What's The Future Of Visudyne?
The photodynamic therapy is technically approved for only the predominantly classic lesions, making up the remaining quarter of the AMD market, Werber said, and the product has managed to hang on to those patients despite the hype surrounding Macugen's January launch.
QLT said it hasn't changed its 2005 guidance for Visudyne sales, estimated to total between $500 million and $530 million. As the company's top-selling product, Visudyne pulled in first-quarter worldwide sales of $124 million, with $50 million in revenue going to QLT. Partner Novartis Pharma holds marketing and commercialization rights.
"Combination therapy is probably going to be the way of the future," Hicks told BioWorld Today, which might ensure Visudyne's role in the AMD field, in tandem with other products like Lucentis. "It doesn't look like there's going to be any one agent that's going to cure the disease, so we believe retinal specialists will continue to combine these agents to try to get better outcomes."
But Werber warned that combination studies might become unnecessary if Lucentis proves to be just as efficacious by itself. There is an ongoing head-to-head ANCHOR study comparing Lucentis vs. Visudyne, with data to be released during the next year.
QLT also has ongoing studies of Visudyne in combination with intravitreal steroid injections. That combination therapy would have to be administered every six months, as opposed to dosing every three months with Visudyne alone. Data from those trials are expected next year, and "could potentially cement Visudyne in predominantly classic patients," Werber said. "If Visudyne with steroids shows robust results with less-frequent dosing than needed with [Macugen or Lucentis], then it might remain entrenched in that corner of the market."
Visudyne also is approved for choroidal neovascularization caused by pathologic myopia and histoplasmosis syndrome. In addition to ongoing trials of its eye disease drug, QLT also plans to move into late-stage clinical development as early as next year with investigational drugs to treat benign prostatic hyperplasia, rosacea and carcinoid tumors.
The company posted a net income of $15.3 million for the three months ending March 31, and had cash and short-term investments totaling $408 million.
Lucentis Vs. Macugen
Ten weeks after Macugen hit the U.S. market, the VEGF inhibitor pulled in revenues of $25.4 million for New York-based Eyetech, which anticipates in its 2005 guidance that net sales of Macugen will total between $135 million and $150 million for the year, while Smith Barney Citigroup has estimated 2005 sales of $178 million. Macugen is co-promoted with New York-based Pfizer Inc.
Though Genentech's drug is about two years away from marketing, the data surrounding Lucentis are encouraging, said analyst Ian Somaiya, of Thomas Weisel Partners in New York, adding that, if Lucentis holds up to further clinical scrutiny, it could easily "take a bigger share of the market, over time."
It is the possibility of vision improvement that has industry observers intrigued.
"We don't know the rate of vision improvement yet," Werber said, "but we believe it may be north of 15 percent, and those would be landmark results."
Because it works using the same mechanism of action, Macugen stands at risk to lose the biggest share if Lucentis is approved, he added. Lucentis "binds to all five isoforms of VEGF, while Macugen binds only to one. The data now suggest that pan-VEGF inhibition is important."
Analyst Howard Liang, of AG Edwards & Sons, agreed, and said, "The head-to-head competition will be those angiogenesis inhibitors."
Wall Street is leaning toward Lucentis. The day Genentech released its Phase III data, Eyetech's stock (NASDAQ:EYET) took a nosedive, losing $11.02, or 45 percent, to close at $12.95. Eyetech's CEO David Guyer defended his company's product, and called into question the trial design for Lucentis, which he said evaluated patients with less severe forms of AMD than were tested in pivotal trials of Macugen. (See BioWorld Today, May 25, 2005.)
Additional analyses from the Phase III study and the Lucentis/Visudyne combination trial are expected to be released later, and analysts said those data likely will determine Lucentis' future.
"We still need to be wary as we await some of the further details," Somaiya told BioWorld Today, "namely, the percentage of patient improvement, which would give it an edge over Macugen, and also the side effect profile of the drug."
While QLT and Eyetech look over their shoulders at Lucentis, several other products are in development for wet AMD that could enter the market during the next several years. Regeneron Pharmaceuticals Inc., of Tarrytown, N.Y., has completed a Phase I trial of its VEGF Trap, while Genaera Corp., of Plymouth Meeting, Pa., is in Phase II studies with squalamine for the treatment of choroidal neovascularization associated with AMD.
Two companies are in Phase I studies in AMD: Philadelphia-based Acuity Pharmaceuticals Inc. is developing an RNAi-based drug Cand5, and Visient Therapeutics Inc., of Seattle, is testing Litx (Light Infusion Technology), a combination product comprising a photo-reactive agent, LS11, activated by non-coherent light infusion devices. In preclinical development is Cambridge, Mass.-based Alnylam Pharmaceuticals Inc.'s RNAi candidate.