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Sorting Out the Wet AMD Treatments
Lucentis is now approved. What next?
BY JERRY HELZNER, SENIOR EDITOR

With the FDA approval of ranibizumab (Lucentis, Genentech) on June 30 at a recommended monthly dose of 0.5 mg, retina specialists can now offer patients a clinically tested therapy that has been proven to reverse at least some of the vision-robbing effects of wet AMD. Two pivotal phase 3 studies of Lucentis that employed monthly treatment schedules resulted in gains in visual acuity averaging 15 letters after 1 year.

Lucentis now joins two other previously approved AMD treatments, verteporfin for injection (Visudyne, QLT/Novartis) and pegaptanib sodium (Macugen, [OSI] Eyetech). Both Visudyne and Macugen have been shown to slow or halt the progression of the disease but have not demonstrated Lucentis' ability to improve patients' vision.

Lucentis also joins off-label bevacizumab (Avastin), another Genentech drug with a similar molecular structure to Lucentis. Avastin was originally designed to be delivered intravenously to patients with colorectal cancer and was approved for that indication. However, studies initiated by Philip Rosenfeld, M.D., Ph.D., of Bascom Palmer Eye Center in Miami, showed that small amounts of intravitreally injected Avastin produced vision improvement comparable to the results achieved by Lucentis.

With the approval of Lucentis serving as a milestone, this article will explore the current wet AMD treatment environment and discuss other potential AMD treatments currently in clinical trials.

The approval of Lucentis marked a milestone in efforts to treat wet AMD.

Avastin Use Should Decline

In the past year, many retina specialists have begun using Avastin "off label" as either first-line therapy or as so-called salvage after other approved treatments have failed. Because of the small amount of the drug used for each injection and its low cost, Avastin has proven to be a relatively cost-effective therapy, even in those areas where it has not been reimbursed by the local Medicare Part B carrier.

The approval of Lucentis — with no major restrictions on its use and nationwide Medicare reimbursement — is expected to sharply curtail the use of Avastin for wet AMD. Physicians generally feel more comfortable and incur less potential liability when using a thoroughly tested, FDA-approved drug as opposed to an off-label therapy, especially when the two drugs produce comparable results.

With Lucentis now available and with its superior efficacy unquestioned, the developers of Visudyne and Macugen are now focusing more on treatments that employ a combination of therapies, with Lucentis used initially to treat the acute phase of the disease and Macugen or Visudyne then instituted as maintenance therapy.

Toward this end, (OSI) Eyetech recently initiated a new large-scale study called LEVEL whose goal is to demonstrate Macugen's effectiveness as maintenance therapy.

Dosing Regimens

Two of the key questions surrounding Lucentis are frequency of dosing and ideal dose. One-year results from Genentech's PIER study were recently announced at the Retinal Physician Symposium and indicated that quarterly injections of Lucentis, either at 0.3 mg or 0.5 mg, were not sufficient to sustain vision gains in most patients. In the PIER study, patients were given three monthly injections of Lucentis, followed by additional injections at the 6, 9 and 12 months. On average, the vision gains achieved in the first 3 months could not be sustained by the quarterly injections and patients tended to revert to their baseline vision by month 12. Patients receiving the 0.5 mg dose fared only slightly better than patients given the 0.3 mg dose in maintaining their vision gains.

"While the PIER regimen provided a 16-letter benefit compared to sham, the data suggest that treating patients on a quarterly basis may be less effective than monthly or individualized dosing," said Hal Barron, MD, Genentech senior vice president, Development and chief medical officer. "Data from ongoing phase 3b studies and emerging results from our Investigator Sponsored Trials should help us learn more about the optimal dosing regimen for patients."

One of those investigator-sponsored trials, PrONTO, conducted by Dr. Rosenfeld at Bascom Palmer, may hold the key to an individualized retreatment schedule for patients being treated with Lucentis. In PrONTO, the retreatment schedule for each patient was governed by periodic OCT measurements.

The average patient in the PrONTO Study received five or six injections over a 1-year period, with all patients receiving a monthly injection for the first 3 months. OCT was used to follow the patients and determine when retreatment was necessary. Overall, average vision improved in the treated eye almost two lines after 1 year. Additionally, 82% of patients had the same or better vision after 1 year and 35% of patients experienced a twofold improvement in vision as defined by gaining three lines of vision on a standardized visual acuity chart.

"By using OCT in this uncontrolled study, we were able to give fewer injections into the eye and observed vision improvement for most of our 40 patients," said Dr. Rosenfeld. "In addition to the improved vision, Lucentis appears to have caused a reduction in leakage from the abnormal blood vessels, and we observed a restoration of normal macular anatomy in this study."

Genentech is currently conducting a third study, SAILOR, that is designed to measure the effectiveness of two different doses (0.3 mg and 0.5 mg) of Lucentis in a broad AMD population. After three initial monthly injec

tions, investigators will use specific criteria, including OCT measurements, to determine when retreatment is necessary.

Therapies in Clinical Trials

The growing population of AMD patients and the aging of the baby-boomer generation has attracted a number of companies that either currently have drugs in clinical studies or that have announced their attention to pursue the development of AMD treatments. Among the investigative drugs whose progress is being closely followed are:

■ Anecortave acetate (Retaane 15 mg depot, Alcon). Retaane demonstrated promise in early trials but results of a pivotal phase 3 study were disappointing, possibly due to medication not reaching the back of the eye because of a (now corrected) flaw in the cannula-like delivery system.

Alcon says it will continue to pursue the use of Retaane as a treatment for wet AMD but further positive clinical studies will be required to achieve FDA approval.

■ Bevasiranib sodium (Acuity Pharmaceuticals). Acuity recently reported clinical evidence of efficacy in preliminary phase 2 trial results of its wet AMD treatment, bevasiranib sodium. Bevasiranib is a first-in-class small interfering RNA (siRNA) therapeutic designed to turn off or silence the gene that produces VEGF, the growth factor believed to be largely responsible for wet AMD.

■ VEGF Trap (Regeneron Pharmaceuticals). Regeneron recently reported encouraging results from a small phase 1 trial of VEGF Trap. VEGF Trap demonstrated positive preliminary efficacy over 6 weeks. Based on data that showed mean vision improvement of 4.8 letters after 6 weeks, the company has initiated a phase 2 trial.

Other wet AMD therapies in various stages of clinical studies include Genaera's Evizon, Miravant's Photrex, Sirna Therapeutics' Sirna-027 and Gen Vec's AdPEDF.

Looking Ahead

Retina specialists have been able to offer patients efficacious treatments for wet AMD since Visudyne was introduced in 2001. Clearly, the approval of Lucentis marks progress toward increasingly effective treatments. Given the significant commitment by numerous companies to develop new and better AMD therapies, it is safe to assume that both physicians and patients can look forward to even better AMD therapies in the years ahead.