Two-year ANCHOR results favor ranibizumab over PDT
KOLOA, Hawaii — Two-year results of a phase 3 trial have shown that ranibizumab helps maintain vision — with few adverse effects — better than photodynamic therapy in patients with wet age-related macular degeneration.
The results of the ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD) trial were announced here by Peter K. Kaiser, MD, at Retina 2007, held in conjunction with Hawaiian Eye 2007.
“The safety in the ANCHOR study is consistent with that of the MARINA [trial] 2-year results and other ranibizumab trials,” said Dr. Kaiser, an OSN Retina/Vitreous Section Member. “More importantly, there was a statistically significant benefit over PDT in predominantly classic CNV maintained from month 12 to month 24.”
The study included 423 patients randomized to receive 0.3 mg or 0.5 mg of ranibizumab along with sham verteporfin PDT or sham injections plus active verteporfin PDT. Treatments were performed monthly over 2 years.
Patients included in the study had predominantly classic choroidal neovascularization secondary to age-related macular degeneration and had not received any prior PDT treatments.
Dr. Kaiser said 90% of patients in both ranibizumab (Lucentis, Novartis/QLT) groups lost less than 15 letters of visual acuity, compared with 65.7% of patients in the PDT group.
Visual acuity improved a mean of 11 letters compared with baseline in the ranibizumab groups; 34% to 41% of patients improved more than 15 letters and 9% to 14% of patients improved more than 30 letters.
Nearly 78% of patients in the ranibizumab groups maintained baseline visual acuity or gained some letters, compared to 28.7% in the PDT group, Dr. Kaiser said.
In the group that received 0.5 mg of ranibizumab, 93% of patients achieved 20/20 or better compared with 4.3% in the group that received 0.3 mg and 0.7% in the PDT group.
Dr. Kaiser said there “was a low rate of serious adverse events.” He said there was approximately a 2% incidence of endophthalmitis, which he said is not surprising, considering the injections are intravitreous.
Seven patients experienced non-ocular hemorrhage, six of whom took anticoagulants. Dr. Kaiser said this could have been related.
“The study was not designed to find small safety issues. We need to continue to follow these patients,” he said.
He and other faculty members encouraged audience members to report their findings to MedWatch. ANCHOR concludes with these data, but all patients are enrolled in the extension trial, HORIZON.
Following are highlights from the Retina 2007 meeting held in conjunction with the Hawaiian Eye 2007 meeting. Most of these items appeared first as daily coverage of the meeting on OSNSuperSite.com and in the onsite daily publication, Hawaiian Eye Daily News.
Image: Wolkoff L, OSN
Preferential hyperacuity may improve early AMD detection
Using preferential hyperacuity perimetry may lead to earlier diagnosis of AMD compared with current diagnostic methods. Earlier diagnosis could result in earlier treatment and improved visual outcomes, according to Allen C. Ho, MD, an OSN Retina/Vitreous Section Member.
Dr. Ho said that although significant advancements in treatment therapies for AMD have been made, “without early detection of the progression to CNV, even the best therapy will result in significantly impaired vision.”
“Earlier detection is needed to take advantage of the new therapies. CNV often grows rapidly, so monitoring patients more frequently may result in better visual outcomes,” he said.
Dr. Ho cited a study that showed eight out of 10 patients who develop CNV would be diagnosed earlier with PHP than they would with current diagnostics.
“Monitoring patients with hyperacuity perimetry may result in earlier detection of wet AMD and may permit better visual outcomes,” he said. “I think that’s a reasonable assumption.”
With PHP, Dr. Ho said it is necessary to change patients’ examination schedule in order to catch the early progression of CNV.
“For patients diagnosed with intermediate-stage dry AMD, schedule a PHP test every 3 months and look for progression to CNV,” he said.
Dr. Ho referenced clinical studies with the Preferential Hyperacuity Perimeter manufactured by Notal Vision. The latest version of this device, called Foresee PHP, is manufactured by Notal Vision and distributed by MSS.
More than just laser may contribute to ROP ischemia
A study that examined the incidence of ischemia in infants with ROP following laser photoablation found that the laser treatment was not the only contributing factor for its development.
Nina Berrocal, MD, presented results from a retrospective review of 1,440 premature infants with ROP treated between January 1, 2006, and June 1, 2006.
Confluent, dense laser therapy does not induce ischemia. All infants who developed ischemia were treated with intermittent dense laser patterns with a diode laser.
Dr. Berrocal said 10 eyes of seven patients developed signs of anterior segment ischemia secondary to laser photoablation with diode laser. No patients showed evidence of inadvertent treatment of anterior structures or retinal detachment.
Although studies by Kaiser and colleagues, and Lambert and colleagues, suggested that ischemia is caused by confluent laser treatment, Dr. Berrocal said, “I don’t use intermittent laser and I have never had a case of ischemia.”
Dr. Berrocal said there were other contributing factors to the development of ischemia. For instance, she said, “anterior segment ischemia primarily affects premature infants with low birth weights.” She said the mean birth weight of patients developing anterior segment ischemia was 855 g with a range of 620 g to 1,075 g.
“The mean gestational age of patients developing anterior segment ischemia after laser therapy was 26.1 weeks with a range of 24 to 28 weeks,” she said. “Patients developed cataracts approximately 4.5 weeks after laser treatment.”
“Excluding referrals, only three eyes in two patients developed signs of anterior segment ischemia secondary to laser photoablation.”
Additionally, out of seven referrals, Dr. Berrocal found experienced surgeons treated four eyes, and inexperienced surgeons (those with less than 1 year of experience) treated three eyes. Of the three eyes to develop ischemia in her clinic, fellows treated them all. Other reasons for anterior segment ischemia are direct laser-induced injury to immature long posterior ciliary vessels, subclinical damage to anterior segment structures, scleral depression-induced ischemia and VEGF decline following laser therapy causing anterior segment or ciliary vasculature dysgenesis.
Investigational DR treatments could improve vision
Treatments under investigation for diabetic retinopathy have shown promise in targeting the underlying pathophysiology of the disease and could potentially improve vision, according Andrew P. Schachat, MD.
Dr. Schachat said he hopes investigational treatments — both intravitreal and systemic — will address some of the deficiencies of current treatments. “Current treatments are less than ideal,” he said. “Even patients with good metabolic control may develop DR.”
The current standard of care for diabetes is intensive glycemic control, according to guidelines established by the Diabetes Complications and Control Trial and the U.K. Prospective Diabetes Study.
Existing pharmacological treatments for diabetic retinopathy (DR) are focused on controlling glucose levels and blood pressure, Dr. Schachat said.
There is also some evidence that lipid control and angiotensin converting enzyme (ACE) inhibition could offer additional benefits; however, studies that have demonstrated this effect did not have DR as the primary endpoint, he said.
Surgical treatments include laser photocoagulation and vitrectomy, but these are unlikely to improve vision, according to Dr. Schachat.
A handful of intravitreal treatments for DR are currently in phase 2 or 3 clinical trials, including dexamethasone, fluocinolone acetonide, hyaluronidase, pegaptanib and triamcinolone.
Data on these seem to indicate that these injections improve visual acuity in diffuse macular edema, but the risk of ocular side effects is higher than the risk of systemic side effects with some of the investigational systemic treatments.
Systemic treatments for DR that are under investigation include new therapies as well as new indications of approved drugs.
One of the treatments in the latter category, ruboxistaurin mesylate, was investigated by Eli Lilly for moderate to severe nonproliferative DR. In October, the U.S. Food and Drug Administration requested an additional 3-year phase 3 trial after the drug had already received an “approvable” letter.
According to Dr. Schachat, this occurred because Lilly changed the primary endpoint in the middle of its trial, which caused the regulatory body to question the results and request an additional trial.
Dr. Schachat said the once-daily oral therapy appeared to be safe and well tolerated in the first trial, providing a 45% reduction in sustained visual loss among treated patients with few adverse effects.
“The side effects parallel the side effects in the placebo group. This is basically a safe drug as far as they could detect,” he said.
While ruboxistaurin’s fate is uncertain, Dr. Schachat said he is optimistic that some of the other investigational treatments “might hopefully lead to improved vision.”
Spectral-domain OCT for evaluating AMD
The advent of spectral-domain optical coherence tomography could signify a better standard of care for patients with age-related macular degeneration and other retinal diseases, Philip J. Rosenfeld, MD, PhD, said.
The newest generation of optical coherence tomography (OCT) offers better image quality, segmentation of the macula, fundus reconstruction, image registration and other features that will enable specialists to become more familiar with the disease and its clinical manifestations, he said.
“We’re going to have a better understanding of the disease so we can provide better care for our patients,” he said, adding that the technology provides “beautiful anatomy.”
“We’re going to get a great appreciation of how patients respond to therapy using this technology,” he said. “Everything I’m telling you of spectral-domain is true for all the devices out there. It’s how the information is processed that is going to distinguish the different companies.”
Image: Wolkoff L, OSN
One of the virtues of spectral domain is that you can combine all scans and to reconstruct a virtual image of the fundus, he said.
“You know exactly where you’re cutting. It’s remarkable that you can register exactly where the cuts are on the fundus image,” he said.
He added that spectral-domain OCT also provides a clear resolution of epiretinal membrane and the ability to view drusen topographically on the level of retinal pigment epithelium.
“I’m looking forward to doing some longitudinal studies using this technology,” Dr. Rosenfeld said.
In a separate presentation, Jay S. Duker, MD, OSN Retina/Vitreous Section Member, discussed another advancement to OCT technology, the ultra-high resolution OCT. While this is not commercially available because of the high cost of building it, he said for research purposes the advancements in imaging represent a “promising research tool.”
He also said he is “a little less optimistic than [Dr. Rosenfeld]” that spectral-domain OCT and ultra-high resolution OCT will be a “revolution in our field.”
“There is no evidence that it is improving our ability to treat disease, although it is helping us visualize better,” he said.
Although the three-dimensional images are dramatic, he said he is not sure how clinically relevant they will be when it comes to treating a patient from visit to visit.
Bevacizumab for myopic CNV results encouraging
A retrospective case series of intravitreal bevacizumab injections for the treatment of myopic choroidal neovascularization shows improved visual results and good safety, according to a speaker.
Image: Mullin D, OSN
Elias Reichel, MD, presented updated results from a study published in the British Journal of Ophthalmology on Avastin (bevacizumab, Genentech) intravitreal injections. The updated results included data for 15 eyes of 13 patients at a mean of 10 months follow-up.
According to Dr. Reichel, about 10% of eyes with degenerative myopia develop CNV and, if left untreated, more than 90% of eyes deteriorate to 20/200 or worse after 10 years.
In the study, baseline visual acuity was 20/20 to 20/40 in one eye, 20/50 to 20/100 in eight eyes and 20/200 or worse in six eyes. At the last follow-up exam, six eyes were 20/20 to 20/40, seven eyes were 20/50 to 20/100, and only two eyes were 20/200 or worse. There was a mean improvement of three lines.
Baseline central foveal thickness was 324 µm and, at 10 months, central foveal thickness was 229 µm, for an average reduction of 93 µm, Dr. Reichel said.
For the treatment, one eye received five injections, one eye received three injections, two eyes received two injections, and 11 eyes received one injection.
“There were no complications in this small case series,” Dr. Reichel said. “There were no retinal tears or retinal detachments and no endophthalmitis.”
In the future, Dr. Reichel added, “I think something important is that because we aren’t going to have clinical trials for these oddball cases, we really have to pull our safety data from other case series and see if we are inducing retinal tears or detachment.”
Dr. Reichel also added one cautionary note: “Most of the subjects were women, and it’s very important to take a good history. Personally, I won’t treat a pregnant woman.”