Retaane (Anecortave acetate) for wet macular degeneration

Background:

Retaane (Anecortave acetate) is an analog of cortisol acetate; among the modifications to the steroid are the removal of the 11ß hydroxyl OH group and an addition of a 21-acetate group. As a result of these modifications, anecortave acetate lacks the typical antiinflammatory and immunosuppressive properties of glucocorticoids. Anecortave acetate functions as an antiangiogenic agent, inhibiting blood vessel growth by decreasing extracellular protease expression and inhibiting endothelial cell migration. Its angiostatic activity does not seem to be mediated through any of the commonly known pharmacological receptors. (Ophthalmology 2004;111:2316-7) RETAANE blocks signals from multiple growth factors because it acts downstream and independent of the initiating angiogenic stimuli and inhibits angiogenesis subsequent to the angiogenic stimulation. Alcon Inc. is developing and marketing Retaane. In its May 24, 2005 press release Alcon, Inc. announced that the U.S. Food and Drug Administration (FDA) has issued an approvable letter for its New Drug Application (NDA) for Retaane.

In a March 2006 press release Alcon announced the withdrawal of its European marketing authorization application (MAA) for RETAANE(R) 30mg/ml (anecortave acetate suspension for depot injection) from The European Medicines Agency (EMEA) review process. The company chose to withdraw the application after being informed by EMEA that it would have to provide additional clinical data from existing and/or new clinical trials to support approval. The U.S. Food and Drug Administration (FDA) also recently advised the company that additional clinical data will be required for U.S. approval.

The company said it is revising its clinical strategy and plans to continue developing RETAANE(R) suspension for wet AMD in the United States, Europe and key markets around the world. The company said it would provide a timeframe for resubmission or amendment after it finalizes the revised clinical development strategy.

Since the results of clinical trials have not been published in peer reviewed journals, data on the clinical trials mentioned on this page is derived from the press reports hosted on the company website and presentations in scientific meetings. Even though this is likely the same data that is provided to the FDA, unpublished data in general is viewed as being less definitive and reliable as published data.

Retaane Clinical Trials

Phase II

In this study outcomes following Retaane injection were compared with outcomes without Retaane treatment. 73 percent of patients treated with Retaane 15 mg had stable or improved vision from baseline to 24 months after treatment, significantly more than the 47 percent of patients in the placebo group who did not receive Retaane (p=0.035).

Patients treated with Retaane 15 mg had no increase in growth of the classic component of the subfoveal choroidal neovascular membrane (CNV) between months 12 and 24, and the total lesion size remained stable over this period. Additionally, at 24 months, in the sub-group of patients with the more aggressive, predominantly classic CNV lesions, no patients treated with Retaane 15 mg had severe vision loss (> 6 lines loss) compared to a 23 percent rate in the placebo group, (p=0.023).

In this study outcomes following Retaane injection were compared with outcomes following Visudyne photodynamic therapy (PDT) treatment. In the study, the percentage of patients who maintained vision (defined as less than a three line loss in logMAR visual acuity) 1 year after Retaane treatment was 45 percent, compared to 49 percent after PDT treatment. Although Retaane did not meet the primary non-inferiority endpoint of the clinical study, these overall results indicate that the two therapies are not statistically different from each other.

After analyzing the data, Alcon believes there were controllable factors that negatively impacted the overall results of the study, including drug reflux and treatment interval. Reflux occurs when a portion of the medication leaks out through the small incision in the conjunctiva during or immediately after application of the drug. The treatment interval refers to the medically reasonable timeframe during which re-administration of the drug should occur. The recommended treatment interval for patients in the study was once every six months. Fifty percent of per protocol patients who did not have drug reflux during their second administration maintained vision compared to 39 percent for those who experienced such reflux (p=.105). As for treatment interval, 50 percent of per protocol patients who received their second dose of Retaane(R) Depot within 182 days maintained their vision compared to 33 percent for those who received it after 182 days (p=.021).

To control reflux during administration, Alcon has initiated changes in the procedure, expanded training measures and developed a simple counter pressure device (CPD). This device has been evaluated in pre-clinical models where it was determined to be effective in controlling reflux. Alcon has reported the results of a clinical pharmacokinetic (PK) study evaluating the effectiveness of a counter pressure device (CPD) it developed to control reflux during the administration of Retaane by posterior juxtascleral depot (PJD). The results of this PK study demonstrated that the CPD was effective in controlling drug reflux in 100 percent of the study participants.