The perhaps unreasonable power of preliminary data - especially when it's offered by an industry powerhouse - was proved once again late last month when mighty Genentech Inc. disclosed positive early figures from a Phase III trial with Lucentis against age-related macular degeneration (AMD).
Eyetech Pharmaceuticals Inc., which markets the approved aptamer Macugen for AMD (developed in partnership with Pfizer Inc.), took the news hard, losing 45 percent of its value.
In the first peek at one-year data, Lucentis (ranibizumab), made from a piece of the same antibody as Genentech's blockbuster Avastin (bevacizumab) for colorectal cancer, met its primary efficacy endpoint, maintaining vision in wet AMD patients. About 95 percent of those treated with the investigational drug maintained or improved vision (defined as a loss of less than 15 letters in visual acuity) at one year, compared to about 62 percent of those in the control arm (p<0.0001).
What's more, Lucentis patients averaged a significant improvement in visual acuity compared to visual acuity at study entry - one of the study's secondary endpoints - while the control group showed a substantial decrease in mean visual acuity from baseline.
Called the MARINA study, the trial included 716 patients with minimally classic or occult wet disease, randomized 2:1 to receive intravitreal Lucentis injections or a placebo injection as control. Lucentis patients were further randomized to get either a 0.3-mg or 0.5-mg dose of the drug once a month for two years. More complete one-year data will be unveiled in two months at the American Society of Retina Specialists meeting in Montreal.
Meanwhile, damage control was the name of the game for Eyetech.
The first and most obvious fact pointed out by Macugen defenders was that Genentech's trial was not a head-to-head study, and so punishing Eyetech for Lucentis data might seem unfair - even if investors view the matter differently. Specific problems with such comparisons lie in the population of patients enrolled by Genentech, i.e., those with minimally classic or occult AMD. Macugen has been tested and approved for all subtypes of the disease.
"We have the broadest possible label, and our trials were completely different in design" from Genentech's, noted Eyetech's CEO David Guyer. His firm conducted a "real-world trial, all comers," whereas Genentech "took more of a splitter approach, where they looked at different subtypes." In such a scenario, Guyer said, it's "really impossible to do a comparison, and especially in this disease, it's hazardous."
Another difference possibly brought about by trial design is that patients in the Lucentis control arm showed an impressive rate of maintained vision - 62 percent. No Lucentis patients previously had been given photodynamic therapy (PDT) by way of Visudyne (verteporfin) from QLT Inc. and Novartis AG, unlike some patients in Macugen's trial.
Christopher Raymond, analyst with Robert W. Baird & Co., said the Lucentis data could "ultimately position [the drug] well in the AMD space, since currently marketed therapy Macugen's label indicates only a slower rate of vision loss, not an improvement in vision, relative to control."
Guyer insists it's too early to tell. In a conference call following the release of interim data by Genentech, he remarked that a press release on the results "highlights patients who maintain or gain vision, [but] this group includes patients who lost up to three lines of vision. This is clearly not maintaining vision." He called the statement "misleading and inconsistent with our common understanding of how ophthalmologists measure vision loss and gain."
Lucentis, like Macugen (pegaptanib sodium), is designed to bind and inhibit vascular endothelial growth factor-A (VEGF-A), a protein involved in angiogenesis. But the Genentech drug binds to all five VEGF isoforms, whereas Eyetech's compound binds only to the 165 isoform, which Eyetech says is the key to AMD.
Safety is an issue, Guyer said. Lucentis is injected into the back of the eye once every four weeks, Macugen once every six.
"That's 50 percent less injections - important because Macugen has shown safety through two years, and the only safety events are through the injections," Guyer said, pointing out that AMD "is a chronic disease, and these are people that likely will need continuous anti-VEGF therapy," he told BioWorld Financial Watch.
"We know that Genentech is investigating the viability of less-frequent dosing in the PIER study," Guyer said during the conference call. "This approach is at odds with data from our Phase III trials and our preclinical studies that show that continuous VEGF inhibition is best for patients with neovascular AMD, just like constantly keeping cholesterol levels down is important for hypocholesteremia."
Eyetech and Pfizer also are investigating the possibility of fewer injections by way of using microsphere delivery. That effort has reached the proof-of-principle stage.
Of more concern is the broad anti-VEGF approach deployed by the Genentech drug, Guyer said. Elderly patients are particularly prone to systemic problems that could be brought about by the strategy. "Different VEGF isoforms were made for a reason," Guyer said.
The AMD space is hot, and Macugen's sovereignty has been questioned before. At the start of the year, Eyetech partner Pfizer's news of its plan to buy out Angiosyn Inc. for up to $527 million gave rise to undue suspicions that Pfizer had lost faith in Macugen. Angiosyn's product has been shown in preclinical models to be synergistic with Macugen.
That blew over, and now Macugen faces a different, apparently more formidable challenge - but one the size of which is still unclear.
"Our controls were different, and the most important differences [between the Lucentis and Macugen studies] we don't know," Guyer said. "We don't know the demographics, initial baseline vision, lesion size. But here's what we do know: We know we have first-mover advantage from [the partnership with] Pfizer, we have an advantage with dosing, and we don't see adverse events of inflammation in the eye."
Genentech noted an increased risk of uveitis in patients given Lucentis with PDT, which was serious enough to prompt an amendment to the study protocol while the trial was ongoing.
Guyer also nodded to Genentech's recent news regarding the successful Phase I/II trial with Lucentis combined with Visudyne, called FOCUS, which cited a frequency of cerebral vascular events that was slightly higher in those treated with Lucentis - "something we've not seen with Macugen," he said, noting that Avastin is "blackboxed" on its label with regard to the risk of thromboembolic trouble.
In top-line data from the Phase III MARINA study, though, "there appeared to be no imbalance in serious non-ocular adverse events," Genentech reported.
Guyer seemed confident that Macugen can hold its own, in a head-to-head trial if necessary. "The whole story will be won by first-mover advantage, by safety - which is so important - and by dosing," he said.