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Macugen reviewed by advisory panel; questions raised, answered
In the FDA review meeting, topics of discussion included endophthalmitis and the long-term effects of the drug.
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ROCKVILLE, Md. – A drug being developed for the treatment of wet age-related macular degeneration seems to slow vision loss but may not improve vision, according to testimony before an advisory panel to the Food and Drug Administration in late August.
The FDA panel reviewed studies assessing the safety and efficacy of Macugen (pegaptanib sodium injection, Eyetech).
The advisory panel did not formally vote on whether Macugen should be approved. The FDA presented the panel with questions regarding the data, and it will consider the panel’s opinions as the agency moves forward in its expedited approval process for the drug.
“The FDA had a clinical submission from Eyetech. … We did not think it was beneficial to vote, so we simply asked questions to help review the data,” said Wiley Chambers, MD, deputy director of the Ophthalmic Division of Anti-Inflammatory, Analgesic and Ophthalmic Drug Products for the FDA, briefing reporters after the meeting. He said the meeting had no impact on how soon the drug would be approved.
Dr. Chambers said the Macugen data submission is part of a “rolling” application, an FDA pilot program that allows companies to submit an application in several parts as the data become available. The process is designed to speed drug approval times, he said.
The data under consideration included 54-week follow-up. Eyetech has said it will submit additional information once 2-year data are available.
Macugen safe and effective
David R. Guyer, MD, chief executive officer of Eyetech, and Anthony Adamis, MD, the company’s chief scientific officer and vice president of research, presented data on two clinical trials assessing three dosing regimens of Macugen vs. placebo. Total enrollment in the two trials was 1,186 patients.
The researchers monitored four groups of patients. The groups received one of three doses of Macugen (0.3 mg, 1 mg, 3 mg) or a sham injection that served as a placebo. Patients received a series of nine intravitreous injections. The primary endpoint of the study was loss of less than 15 letters on the Early Treatment for Diabetic Retinopathy Study (ETDRS) chart.
Macugen slowed the progression of vision loss at all three dosing levels, compared to placebo, according to the presenters. At 54 weeks, 70% of patients given the lowest dose of Macugen lost less than 15 letters of Snellen acuity, compared with 55% of patients receiving placebo.
Given its efficacy and safety profile, the 0.3 mg dosage of Macugen was found to be the most appropriate dosage, the Eyetech representatives said.
Questions posed
The agenda for the panel meeting listed a series of questions to be answered by investigators and discussed by the panel.
One of the questions addressed at the meeting was the incidence of endophthalmitis reported in the eyes receiving Macugen, which over the first year of the trial was 0.16% per injection, or 1.3% per patient. Eyetech representatives said in information provided after the meeting that during the Macugen development program, trial investigators were contacted and reminded to pay strict attention to the protocol, including the use of an eyelid speculum. The company also amended the injection protocol to incorporate the use of either pre-injection topical antibiotic drops for 3 days prior to the injection, or a 10 cc povidone iodine flush just prior to the injection.
According to officials at Eyetech, these changes were accompanied by a reduction in the rate of endophthalmitis to approximately 0.05% per injection, which company officials said perhaps reflects both greater attention to the aseptic technique and an overall increased comfort with the intravitreous injection technique itself.
Another question concerned the validity of the visual acuity testing in the trial. Investigators used the ETDRS VA chart at 2 m rather than the standard 4 m at which the chart’s validity was established. Eyetech representatives responded that investigators had taken precautions to avoid variations in VA measurement that can occur at 2 m.
The day’s questioning also addressed potential cardiovascular concerns in association with Macugen. Macugen works by inhibiting a protein needed in blood vessel formation, according to Eyetech. The FDA recently mandated the manufacturer of another VEGF inhibitor approved for colon cancer to warn physicians that patients on the drug have a higher chance of developing blood clots.
Eyetech representatives pointed out at the meeting that no evidence for cardiovascular toxicity was observed in their trials. They emphasized further that Macugen is given locally and so it is associated with minimal systemic exposure, and that Macugen is a selective inhibitor of VEGF 165, the VEGF isoform associated pathologic ocular neovascularization. The panel suggested long-term post-marketing surveillance and follow-up.
FDA presentation
To ensure objectivity, the FDA conducts its own analysis of the data as part of its standard review. Jennifer D. Harris, MD, a medical officer in the FDA’s Division of Anti-Inflammatory, Analgesic and Ophthalmic Drug Products, made the FDA presentation.
Overall, Dr. Harris said, Eyetech’s results on Macugen’s safety and efficacy were well balanced among the study population in both the international and North American trials. Vision loss was reduced with the recommended 0.3 mg dosage, she said.
“All patients continued to lose vision, including in the sham group. Sham patients lost vision at a higher rate,” she said.
Lesion size also increased, but it “appeared to increase to a lesser degree in the 0.3 mg group than in the sham group for both studies,” Dr. Harris said.
During the panel discussion, the issue of the duration of the regimen and the long-term effects of the drug were raised. Members of the committee recommended studying the effects of the drug for an additional 2 years.
Jeffrey Lehmer, MD, one of the panel members, asked whether an implantable drug delivery system for Macugen was feasible.
“We are already working on it,” Dr. Guyer replied.
For Your Information:
- David R. Guyer, MD, and Anthony Adamis, MD, can be reached at Eyetech Pharmaceuticals Inc., 3 Times Square, 12th Floor, New York, NY 10036; 212-824-3100; fax: 212-824-3101; Web site: www.eyetk.com.
- Wiley Chambers, MD, and Jennifer D. Harris, MD, can be reached at the Food and Drug Administration, Division of Anti-Inflammatory, Analgesic and Ophthalmic Drug Products, HFD-550, Office of Drug Evaluation V, Center for Drug Evaluation and Research, 5600 Fishers Lane, Rockville, MD 20857; 301-827-2040; fax: 301-827-2531.
- Jeffrey Lehmer, MD, can be reached at 5329 Office Center Court, Suite 120, Bakersfield, CA 93309; 661-322-8400; fax: 6641-322-8489.
- OSN Staff Writer Jeanne Michelle Gonzalez specializes in practice management, regulatory and legislative topics, in addition to cataract and refractive surgery.