Anecortave acetate holds promise for halting AMD

Preclinical models show this modified steroid markedly inhibits blood vessel growth without toxicity. Phase 2 studies are underway.

NEW YORK — Sub-Tenon’s injections of anecortave acetate, a modified angiostatic steroid, hold great promise for suppressing abnormal blood vessel growth in patients with exudative age-related macular degeneration, according to a presentation here at a New York Academy of Medicine meeting, Current Thoughts on Macular Degeneration.

“Anecortave acetate inhibits extracellular matrix breakdown and endothelial cell proliferation, essentially providing a ‘double hit’ against early stages of neovascularization,” said Jason Slakter, MD, assistant clinical professor of ophthalmology at the Columbia University College of Physicians and Surgeons.

“The theoretical scientific basis for this — the preclinical models and the clinical trials of pterygium — is very exciting, and we look forward to getting data from the ongoing AMD phase 2 studies,” he said.

Dr. Slakter, director of the Digital Angiography Reading Center that analyzes fluorescein images for the phase 2 studies, was referring to eight pre-clinical models in which anecortave acetate has been tested. In all of the models, anecortave acetate was shown to have striking inhibitory activity.

“This is the only compound I know of that has been able to totally shut down neovascularization in the cornea, as well as inhibit neovascularization in a wide variety of animal models with different angiogenic stimuli,” said Abbot F. Clark, PhD, senior director of therapeutic target research at Alcon Research Ltd.

“Other agents can inhibit but not totally shut down neovascularization like anecortave acetate did in Prof. BenEzra’s rabbit corneal neovascularization model,” Dr. Clark said. In two models of pre-retinal neovascularization, anecortave acetate showed significant inhibition, 67% in John Penn’s rat pup model and 50% in Dale Phelps’ kitten model.

“In Dr. Penn’s rat ROP model we showed that among other things, anecortave acetate regulates an inhibitor that shuts down the enzyme cascade involved in allowing vascular endothelial cells to break through the basement membrane and proliferate. Therefore, anecortave acetate inhibits an important step in the very early course of the angiogenesis, which is independent of the inciting cause of angiogenesis,” he said.

Phase 2 studies now enrolling

Alcon Laboratories (Fort Worth, Texas) specifically designed the compound anecortave acetate (AL-3789) to retain the positive attributes of angiostatic steroids while eliminating the glucocorticoid ocular side effects, namely ocular hypertension and subcapsular cataracts. In addition to angiostatic activity in a variety of pre-clinical models, a recent clinical study indicates that topical ocular administration anecortave acetate can inhibit the growth of recurrent pterygium. Phase 3 study data for pterygium are expected mid-year.

There are currently two double-masked, placebo-controlled phase 2 trials underway for determining the compound’s effect on exudative AMD, Dr. Slakter said. The first began in 1999, for patients with predominantly classic vessels or subretinal vessels that show classic lesions larger than 1.6 mm². Patients are treated with a sub-Tenon’s injection of placebo or one of three anecortave acetate doses, then followed for 6 months for changes in visual acuity and lesion size by fluorescein angiography.

At that time, if the investigator thinks the injection has been helpful and well-tolerated, the patient is offered reinjection for another 6-month period.

“Enrollment of 120 patients is almost complete, and more than 35 patients have been reinjected, seven have received more than three injections,” said Dr. Slakter, an attending surgeon in the vitreoretinal service of Manhattan Eye, Ear and Throat Hospital.

The second AMD trial involves a combination of photodynamic therapy (PDT) with Visudyne (verteporfin for injection QLT PhotoTherapeutics/Novartis Ophthalmics), followed by placebo or sub-Tenon’s injections of anecortave acetate. The idea is to see if the drug can delay the onset of re-treatment with PDT. Enrollment is more than 50%.

Corneal neovascularization was induced by mid-stromal implantation of pellets containing LPS, a potent angiogenic stimulus. The rabbit eyes were treated topically twice a day with vehicle (left) or anecortave acetate 1% suspension (right) for 8 days. The florid neovascularization seen in the placebo treated eyes was almost totally inhibited by anecortave acetate treatment.

Excellent safety profile

“Anecortave acetate has an extraordinary safety profile,” Dr. Slakter said. “We are very encouraged by the fact that no safety concerns and no protocol modifications have arisen since the inception of the studies. In fact, no toxicity has been registered at all, which ironically delayed the onset of the trials because the FDA insisted on having us pinpoint the levels at which toxicity would set in. We couldn’t report toxicity levels because there were none,” he said.

Dr. Clark, who has worked on anecortave acetate at Alcon for the past 12 years, concurs with the level of safety. “All the preclinical data suggest there are no safety issues. In addition, we have an independent panel of physicians that meets to determine the safety of this compound, delivered by sub-Tenon’s injection. In the pterygium trials, more than 600 patients have been treated topically for over a year with no problems at all,” he said.

First entirely digital study

One unique feature of these phase 2 studies is that they are the first entirely digital ocular studies to be conducted in this country (see sidebar on page 76). Trial sites transmit their digital fluorescein angiograms by computer to the Digital Angiography Reading Center in New York, where they are read within 24 hours — sooner if necessary. This enables quick decisions on whether a patient qualifies for enrollment in the anecortave acetate and the PDT/anecortave acetate studies or whether the patient is eligible for re-treatment in the first study.

Promising drug

“I think the anecortave acetate is just a remarkable drug,” Dr. Slakter concluded. “That’s my initial impression. We obviously have to wait until the study is completed and unmasked, but we’re looking at a drug that theoretically has some great promise. When I see the data I’ll be happy to know if it really does anything or not. But it certainly has wonderful promise.”

For Your Information:

• Jason S. Slakter, MD, can be reached at 519 E. 72nd St., Ste. 203, New York, NY 10021; (212) 861-9797; fax: (212) 628-0698. Dr. Slakter is a paid consultant for Alcon and his reading center is compensated by the companies using its service.
• Abbot F. Clark, PhD, can be reached at 6201 South Freeway; Ft. Worth, Texas 76134; (817) 551-4909; fax: (817) 568-7645.

References:

• BenEzra D, et al. Invest Ophthalmol Vis Sci. 1997;38:1954-1962.
• Penn J, et al. Invest Ophthalmol Vis Sci. 2001; Jan;42(1):283-90.
• Santos CI, Zeiter JH, et al. Efficacy and safety of topical 1.0% anecortave acetate (AL-3789) as anti-neovascular therapy for recurrent pterygium. Invest Ophthalmol Vis Sci. 1999;40(4):S1778.