Alcon stops FDA approval for wet AMD treatment

November 15, 2007

Alcon Laboratories received an approvable letter from the FDA for 15 mg anecortave acetate depot suspension (Retaane) for the treatment of wet age-related macular degeneration (AMD). The letter advised Alcon that approval will require an additional clinical study. The company said it has no immediate plans to conduct a new study of anecortave acetate depot suspension for the treatment of wet AMD, due to the difficulty of recruiting patients for such a study in light of other treatments currently available.

Key Points

Fort Worth, TX-Alcon Laboratories said it will no longer pursue FDA approval for its anecortave acetate depot suspension (Retaane) 15 mg as a treatment for wet age-related macular degeneration (AMD) and will refocus its efforts on other applications.

Doug MacHatton, the company's vice president of investor relations and strategic corporate communications, said the company would not conduct the additional study the FDA called for in a recent approvable letter. Instead, it will investigate its active ingredient for applications in glaucoma and halting the progression of dry AMD to the wet form.

It would be too difficult to recruit patients for a new study, because they would be eligible for other wet AMD treatments, including ranibizumab and bevacizumab, which are yielding impressive results, he said.

Anecortave acetate depot suspension held great promise when it was presented to the FDA for approval in 2003. The "fast-track" designated product was accepted as part of the FDA's new Pilot 1 Continuous Marketing Application program because of its potential as a treatment for a significant unmet medical need in patients with a serious condition.

The program allowed for a "rolling" new drug application that allowed each portion to be submitted as it was completed.

Alcon first submitted its Chemistry, Manufacturing and Controls unit in 2003, and the pre-clinical review portion was submitted in March 2004. The third, clinical portion was submitted in December 2004.

Alcon, however, faced intense competition from other VEGF inhibitors-just 4 days after Alcon announced that it had submitted its third portion to the FDA, the FDA announced its approval of pegaptanib sodium injection (Macugen, OSI Eyetech/Pfizer) for the treatment of wet AMD. And within 5 months, spectacular results of initial studies were emerging on ranibizumab (Lucentis, Genentech) for the treatment of wet AMD, sending retinal specialists scurrying to its parent drug, bevacizumab (Avastin, Genentech), which already enjoyed FDA approval for cancer and was being used off-label with equally dramatic results.

Faced with such competition, and coupled with studies that failed to show anecortave acetate depot suspension was superior to photodynamic therapy, retina specialists began to look elsewhere. A May 2005 approvable letter from the FDA showed that the agency was generally favorable toward anecortave acetate depot suspension but outlined further requirements. Meanwhile, October 2005 comparative study results showed no clinically relevant safety issues, and mean visual acuity remained stable from month 12 to 24.

Although Australian drug regulators approved the use of anecortave acetate in December 2005, Alcon withdrew its European marketing authorization application in March 2006 after it learned that agency would also require new clinical data.

The advent of ranibizumab and bevacizumab in wet AMD treatment has presented the same kind of paradigm shift as timolol once did in the treatment of glaucoma, MacHatton said. With ranibizumab able to preserve and, for some, even improve vision for patients with wet AMD, the bar has been raised.

"This is a very difficult and different standard," he said. "Historically . . . less than 3 lines lost of vision was considered a successful endpoint. That is no longer the endgame."

Now, new medications must be able to perform at or above the level of ranibizumab, with some additional benefit-such as less frequent administration. The day will come when, just as prostaglandin analogues proved far more efficacious than timolol for glaucoma treatment, researchers will improve on ranibizumab, he said.

"Raising the bar is a challenge for us and others as we develop medications," Mac-Hatton said. "[Ranibizumab] is dramatically better than what we had before, but what we had before was basically ineffective. Now the challenge is, how do we get a product that is equal to or better than [ranibizumab]?"

Meanwhile, Alcon is hoping that anecortave acetate will help to reduce IOP associated with glaucoma. In that application, the drug is administered via an interior juxtascleral injection; it is injected into the scleral cavity, then it circles the iris and diffuses through the trabecular meshwork, MacHatton said.

Three-month clinical data released in July demonstrated potential for prolonged reduction of IOP, even 3 months after a single injection. Two studies are ongoing and 6-month results may be revealed at the American Glaucoma Society meeting in the spring.