Pfizer/Eyetech's Macugen Safety To Be Discussed By FDA Advisory Cmte.
This article was originally published in The Pink Sheet Daily
Executive Summary
The agency will ask the committee to discuss the potential impact of VEGF inhibition on cardiovascular events. FDA also will seek input on whether Macugen's efficacy was adequately demonstrated; only one of three tested doses of the macular degeneration drug showed a statistically significant effect in both clinical trials.
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FDA's Dermatologic and Ophthalmic Drugs Advisory Committee will discuss safety issues related to Pfizer/Eyetech's Macugen . "Are there adverse experiences that are of particular concern for this product?" 1 FDA briefing documents for the Aug. 27 meeting ask. [Editor's Note: To 2 watch a webcast or order a video/DVD of this meeting, visit FDAAdvisoryCommittee.com.] Pfizer/Eyetech are seeking approval of Macugen (pegaptanib) for treatment of neovascular (or "wet") age-related macular degeneration. The committee will be asked to discuss the potential impact of the vascular endothelial growth factor antagonist on the development of collateral vessels in ischemic heart disease. "Inhibition of VEGF in the systemic circulation could present a theoretical increased risk of symptomatic cardiovascular disease in the target population of elderly patients with AMD," FDA states. "Has the adverse event profile of the two randomized Phase III trials raised any concern over the possible systemic effects of this therapy?" The agency also will ask the committee to consider the increased incidence of endophthalmitis associated with Macugen in clinical trials. "Endophthalmitis (approximately 2%) was observed in these studies. What is the optimal follow-up needed to minimize the impact of potential endophthalmitis cases?" FDA asks. Pfizer/Eyetech believe that the increased incidence could be related to improper administration of Macugen, rather than the drug itself. "In 11/16 or approximately 70% of the cases of endophthalmitis, there was at least one violation of the original injection procedure (for instance, no eyelid speculum used) identified in audits," 3 Pfizer/Eyetech briefing documents state. The committee will also discuss whether the clinical program adequately demonstrated Macugen's efficacy. The two double blind, placebo-controlled clinical trials examined Macugen's efficacy in preventing a 15-letter loss of visual acuity after 54 weeks of treatment. Macugen 0.3 mg was the only dose to show a statistical significance in both trials (p=.0031 and p=.0105; significance threshold =.025 using the Hochberg procedure), according to the companies' briefing documents. One of the two trials for the 1 mg dose demonstrated statistical significance (p=.0273 and p=.0035), while neither trial of the 3 mg dose (p=.1294 and p value not applicable) resulted in a statistically significant difference. The design of the studies' visual acuity evaluation will also be discussed by the committee. Eyetech/Pfizer took measurements using the Early Treatment of Diabetic Retinopathy Study scale placed at two meters. "The validity of the ETDRS scale was established based on readings at four meters," FDA briefing documents state. "Are the visual acuity findings sufficiently robust to overcome the potential bias introduced by visual acuity measurements at two meters?" The committee also will consider the impact of concomitant use of Novartis' Visudyne (verteporfin) on the efficacy results (see 4 (Also see "Macugen Advisory Committee To Discuss Concomitant Use With Visudyne" - Pink Sheet, 25 Aug, 2004.)). - John Rancourt |