As the first anti-VEGF drug to report Phase 3 clinical trial results, pegaptanib sodium (Macugen) represents the initial trickle from a pipeline of biologically engineered molecules aimed at blocking age-related macular degeneration. The response to the drug’s potential for clinical use might be expected to be jubilation.
But reactions since the initial Macugen results were presented have been more muted. Four years after photodynamic therapy transformed ophthalmologists’ approach to AMD, visual results that are “only” roughly equivalent to those from verteporfin (Visudyne) may not seem like enough.
For the clinician, however, the limited one-year Macugen data that have been released do suggest a widening of the therapeutic possibilities for AMD, say ophthalmologists familiar with the research results.
“The disappointment is that Macugen appeared to be only modestly effective at preserving visual acuity,” said John I. Loewenstein, MD, assistant professor of ophthalmology at Harvard University and residency program director at the Massachusetts Eye and Ear Infirmary. Until recently, Dr. Loewenstein oversaw the MEEI portion of the Macugen trial.
“Still, the good news is that Macugen appears to be effective for all AMD lesion subtypes,” Dr. Loewenstein said. “Macugen would give us a modality to use for patients for whom PDT is not appropriate.”
David R. Guyer, MD, Eyetech’s CEO, said the company designed its trial to mimic the real world of treating AMD. All types of AMD were treated, and there was a broad range of lesion size and visual acuity among the patients. All that makes the results uniquely applicable in clinical practice, Dr. Guyer said.
“We didn’t have just a sliver of the types of AMD patients, and our controls were ‘usual care’ controls,” he said. “So, in a real-world situation, the Macugen response was above and beyond what PDT demonstrated in clinical trials where control patients received no treatment at all.”
Dr. Guyer added, “Not only is this the first treatment to target the underlying cause of the disease, but we have the first positive efficacy results for minimally classic and occult disease at one year—and that’s three-quarters of the people with AMD.”
Interpreting the Data
Macugen results. Last fall, Carmen A. Puliafito, MD, MBA, professor and chairman of ophthalmology at the University of Miami, presented results in 1,186 patients who received intravitreal injections of Macugen.
At one year, visual acuity stabilized or improved in 33 percent of the treated patients, vs. 23 percent of the placebo group, he reported. In addition, 70 percent of the treated patients had lost less than three lines of visual acuity at one year, compared with 55 percent for placebo patients.1
Moreover, 11 percent of the Macugen group gained 2 or more lines of vision, compared with 6 percent of those who received placebo. Visual acuity either remained stable or improved in 33 percent of patients with any type of AMD lesion.
Comparison with PDT. In the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) trial that tested Visudyne, 67 percent of the overall patient group lost less than 3 lines of vision.
In addition, 10 percent of the overall TAP group gained 2 or more lines, but that was not statistically significant. The 10 percent TAP figure was statistically significant only in patients with predominantly classic lesions, defined as those with classic CNV involving more than 50 percent of the entire lesion.
However, comparisons between the Macugen and Visudyne trials must be done with great caution because the patient groups and study designs differed, said Andrew P. Schachat, MD, a retinal specialist at Johns Hopkins University and editor-in-chief of Ophthalmology. For instance, TAP only enrolled patients whose initial visual acuity measured no worse than 20/200, compared with 20/320 for the Phase 2/3 Macugen patients.
“I don’t think that you can compare the overall Macugen patients to the overall Visudyne patients,” Dr. Schachat said. “But in part you can compare patients in one study who might have been eligible for the other—for example, predominantly classic patients. It was my impression that the predominantly classic patients had a result that was fairly similar to those in the TAP study.”
Potential patient selection. Dr. Schachat agreed with Dr. Loewenstein that the primary potential benefit Macugen offers is for patients who don’t have predominantly classic lesions. “Based on the information that I heard, I think that as of now my main interest in considering Macugen would be for patients for whom there is no FDA-approved therapy—that is, all-occult and minimally classic patients,” he said.
Issues of Drug Delivery
Macugen is an RNA-based oligonucleotide ligand (aptamer) that binds to vascular endothelial growth factor (VEGF), an angiogenic molecule known to be involved in pathological blood vessel growth. It is being developed by New York–based Eyetech Pharmaceuticals, in cooperation with drug-industry giant Pfizer.
VEGF also is the target of a VEGF-binding fragment of a recombinant, humanized monoclonal antibody that Genentech has in Phase 3 trials both alone and in combination with PDT. Formerly known as rhuFAB, the drug
is now called Lucentis (ranibizumab).
Injections vs. implants. One factor that may be dampening initial enthusiasm for Macugen is the need to deliver it through a series of intravitreal injections. This raises the chances for complications such as endophthalmitis and retinal detachment. In the Macugen trial, there was a 0.16 percent rate of endophthalmitis (12 cases in more than 7,500 injections); four retinal detachments, for a risk of 0.05 percent; and five cases of lens damage or cataract, for a rate of 0.07 percent.
For that reason, Drs. Loewenstein and Schachat said they are eager to see if the sustained-delivery implant devices that Eyetech is testing might eventually be used with Macugen. Last year, Eyetech principal Anthony P. Adamis, MD, and colleagues at MEEI reported success in vitro of transcleral delivery of Macugen, which had been sequestered in microspheres that were packed into a polypropylene implant and allowed to diffuse through the sclera.2
“If Macugen could be given by transscleral means, that would be ideal,” Dr. Loewenstein said. “Probably a continuous slow release would be ideal against CNV, because the vessels are continually growing.”
“If the efficacy were similar, the safety would almost certainly be better,” Dr. Schachat agreed.
Drug development. Many involved in the field believe that therapy for AMD eventually will involve multiple modalities, depending on disease type and stage. Researchers involved in trials of corticosteroid injections and implants against the inflammatory component of AMD see it as an adjunct to whatever other therapies come along.
As Pfizer is seeking to change the AMD treatment paradigm with Macugen, other drug makers also are looking to the future. Alcon is testing scleral “depot” delivery of its Retaane (anecortave acetate) against AMD inflammation, and Novartis is looking to a post-Visudyne future by licensing the international marketing rights for Lucentis from Genentech.
Macugen approval. It’s too early to speculate about whether Macugen or Visudyne will be better, Dr. Schachat said. “Trying to decide if you would use Macugen or Visudyne is a nonissue at this point because Macugen is not FDA-approved. Presumably Eyetech is going to file for approval, and if they do maybe it’ll be approved in 2005, or perhaps in late 2004. But when and if it does get approved there’ll be other data to see, and there’ll be more data on PDT, and I’m sure there’ll be a role for both.”
Dr. Guyer said that Eyetech plans to file for FDA fast-track approval in the third quarter of 2004 and hopes to be marketing Macugen in the first half of 2005.
1 Academy Retina Subspecialty Day, Sat., Nov. 15, Anaheim, Calif.
2 Carrasquillo, K. G. et al. Invest Ophthalmol Vis Sci 2003;44(1):290–299.
Dr. Guyer is an employee of Eyetech. Dr. Loewenstein has no related financial interests. Dr. Schachat has consulted for Eyetech and Genentech, and his university receives research grant support from Novartis and Alcon.