Anecortave acetate effective for CNV, 12-month data show

No patients with predominantly classic lesions receiving 15 mg of anecortave acetate experienced severe vision loss after 12 months.

SAN FRANCISCO — Twelve-month data from the phase 2/phase 3 trial of anecortave acetate show a 15-mg dose to be superior to placebo and safe and effective for maintaining vision in patients with exudative age-related macular degeneration.

Jason S. Slakter, MD, a retinal surgeon with Vitreous Retina Macula Consultants of New York and director of the reading center for the study, announced the results at the Retina Congress here. The trial, which is still following patients, evaluates the effectiveness of anecortave acetate on visual acuity change and progression of choroidal neovascularization. The main goal of treatment is preservation of vision.

In addition to demonstrating the drug’s efficacy, Dr. Slakter said, the trial showed juxtascleral injection to be a safe and effective procedure for delivery of the drug to the choroid and retina. The drug is injected through a small incision in the conjunctiva and Tenon’s capsule that is made under local anesthesia. A curved, blunt-tipped cannula delivers the drug behind the eye to the region overlying the macula.

“The unique aspect of the drug is that it is delivered outside of the eye, and its duration of action is 6 months,” Dr. Slakter said.

Alcon is currently enrolling patients for a phase 3 trial comparing the drug to photodynamic therapy, a standard treatment for AMD patients with predominantly classic lesions. The trial is taking place at 50 sites in the United States, Australia and Europe. Patients with predominantly classic subfoveal neovascularization are eligible for enrollment and will be randomized to two treatment regimens: 15 mg of anecortave acetate and a sham application of PDT without active drug, or a sham anecortave acetate dose and active PDT as indicated by manufacturer labeling protocol.

12-month data

According to Dr. Slakter, the 12-month results were from the phase 2/phase 3 monotherapy trial evaluating the drug alone vs. placebo. One hundred twenty-eight patients were enrolled and randomized to receive either 30 mg, 15 mg or 3 mg of the drug or a placebo injection.

According to Dr. Slakter, the original design of the study allowed optional re-treatment at 6 months follow-up if the investigator believed there was a beneficial effect for the patient.

To date, 62 patients have received at least three applications of the drug, Dr. Slakter said.

Patients randomized into one of the three treatment groups or the placebo group all had essentially equal visual acuities at baseline (approximately 20/125).

Total area of the lesion (including choroidal neovascularization, blood and surrounding elevated fluid), total neovascularization (including classic and occult forms) and total area of classic neovascularization were all evenly distributed between the groups.

Dr. Slakter said there was a statistically significant difference in the mean change in vision between the 15 mg anecortave acetate group compared to the placebo group, with roughly twice as much vision loss in the placebo group (79% vs. 53%).

Researchers found more patients in the 15-mg treatment group had at least 2 lines of visual improvement at 1 year compared to 3% of the placebo group, Dr. Slakter said. This difference was not statistically significant, which he attributed to the group’s small sample size.

Statistically significant differences between these two groups were seen when the percentages of patients losing 6 or more lines of vision were compared.

Predominantly classic CNV

Patients with predominantly classic CNV, who accounted for approximately 80% of the patients in the trial, were further divided into a subgroup during the data analysis.

“We see in this group — which represents a more aggressive type of neovascularization — that anecortave acetate actually performs better,” Dr. Slakter said.

There was a statistically significant difference in mean change from baseline logMAR vision score for the 15-mg group vs. the placebo group, with a 2.5-line difference in visual acuity at 1 year.

“When we look at those who lost less than 3 lines at 1 year, we see a better effect,” Dr. Slakter said.

For reference purposes only, Dr. Slakter said the results compared favorably with results for similar patients treated with PDT as part of the Treatment of AMD with Photodynamic Therapy (TAP) study.

According to Dr. Slakter, 12% of patients with predominantly classic lesions who were treated with 15 mg of anecortave acetate experienced an improvement of 2 lines or more while no patients in the placebo group experienced an improvement. Dr. Slakter said the difference was not statistically significant and again attributed it to the study’s small sample size.

No patients with predominantly classic lesions receiving 15 mg of anecortave acetate lost 6 or more lines of vision compared with the placebo group, which was a statistically significant difference, he said.

“This means at 1 year, in this particular study, no patients with predominantly classic lesions receiving 15 mg of anecortave acetate had severe vision loss,” he said.

The anatomic response of the lesion paralleled the visual response exhibited by the patients, Dr. Slakter said. Both the group as a whole and those patients with predominantly classic CNV experienced a 50% growth in classic CNV lesion size at 12 months, while patients receiving placebo experienced growth roughly three times that amount (150%), he said.

Safety profile

The trial safety committee reviewed all unmasked data in September and found no clinically relevant application- or drug-related adverse events following single or multiple applications of the drug, Dr. Slakter said.

Previous preclinical and animal studies of anecortave acetate have also shown it to be safe, he noted.

While the drug is a steroid derivative, it does not have any conventional steroid activity.

“It is not an anti-inflammatory. It does not cause cataract development, nor does it result in [intraocular pressure] elevation as do conventional steroids. In addition, it has no apparent safety issues whatsoever in either preclinical or clinical development,” Dr. Slakter said.

According to Dr. Slakter, adverse events were mild and transient and equally distributed between the anecortave acetate group and the placebo group. No patients in the study discontinued treatment due to ocular or systemic treatment-related adverse events. Additionally, no systemic adverse events were attributed to the drug delivery method or the drug itself during the course of the trial.

Transient visual changes were experienced in the treatment groups. However, Dr. Slakter said more than 50% of these visual changes were in the fellow eye as well as the treatment eye, which was not clinically relevant.

Stella Robertson, PhD, vice president of pharmaceutical products research and development for Alcon, said in a conference call that 52 patients dropped out of the study. Most of these patients dropped out after the 6-month follow-up, which she attributed to the design of the study.

Dr. Slakter said that the timing of the study affected the drop-out rate. At the time the study began, there were no approved treatments for AMD. Visudyne (verteporfin for injection, Novartis Ophthalmics) PDT received approval during the course of the study, and some participating investigators withdrew their patients to go with the approved therapy.

“It would have been nice to mandate retreatment, but it would not have been ethical at the time. I think if the investigators knew then what we know now, they probably would have kept the patients in the trial,” Dr. Slakter said.

Only three patients in the 15-mg treatment group were withdrawn because the treating investigator believed the disease was progressing, Dr. Slakter said.

For Your Information:

• Jason S. Slakter, MD, can be reached at 519 E. 72nd St., Suite 203, New York, NY 10021; (212) 861-9797; fax: (212) 628-0698.

• Alcon Laboratories Inc., manufacturer of anecortave acetate, can be reached at 6201 South Freeway, Fort Worth, TX 76134; (817) 293-0450; fax: (817) 568-6142.