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Background
Anecortave acetate (Retaane) (Alcon, Inc.) is an angiostatic steroid under investigation for the prevention and treatment of ocular diseases, in particular age-related macular degeneration (ARMD). It is administered with a blunt-tipped, curved cannula as a posterior juxtascleral depot. The curved cannula follows the surface of the sclera, without puncturing the globe. Once the cannula is in place, anecortave acetate is injected in the juxtascleral space (behind the eye) overlying the macula and the drug is slowly released to the choroid over a 6-month period. This novel method of drug delivery is intended to avoid the risk of intra-ocular infection and retinal detachment, the most common side effects associated with injecting therapeutic agents directly into the eye, and it requires less frequent dosing compared to other drugs.
In a multi-center randomized, placebo-controlled study, Schmidt-Erfurth et al (2005) reported no clinically relevant treatment-related safety issues of anecortave acetate depot suspension (3 mg, 15 mg, 30 mg) for subfoveal choroidal neovascularization (CNV) secondary to ARMD (128 eyes of 128 patients) over a period of 2 years. All eyes received a posterior juxtascleral depot application of anecortave acetate or a placebo, with re-treatment at 6-month intervals if the masked investigator believed the patient could benefit. Patients received periodic detailed ophthalmic examinations with both fluorescein and indocyanine green angiography, general physical examinations with electrocardiograms, and hematology/serum chemistry/urinalysis. Treatment with anecortave acetate (15 mg) trended toward significance over the placebo at month 12 for inhibition of total lesion growth and for inhibition of both the total CNV component and the classic CNV component in both the overall and subgroup analyses (102/128 with predominantly classic lesions at baseline). The investigators reported that anecortave acetate was statistically superior to placebo for stabilization of vision and for inhibition of neovascular lesion growth.
While anecortave acetate is a promising treatment for ARMD, randomized controlled studies are needed to determine its safety and effectiveness compared to other treatment options for ARMD.
In a prospective, masked, randomized, multi-center clinical trial, Slakter and associates (2006) compared 1-year safety and effectiveness of anecortave acetate (15 mg) with photo-dynamic therapy (PDT) with verteporfin in patients eligible for initial PDT treatment. A total of 530 patients with predominantly classic subfoveal CNV secondary to ARMD were randomized to treatment with either anecortave acetate 15 mg or PDT. In the anecortave acetate group, the drug was administered under the Tenon's capsule as a peri-ocular posterior juxtascleral depot (PJD) at the beginning of the study and at month 6. Before the 1st administration of anecortave acetate, patients in this treatment group received a sham PDT treatment, and sham PDT treatments were repeated every 3 months if there was evidence of leakage on fluorescein angiography (FA). Patients assigned to PDT received up to 4 PDT treatments at 3-month intervals, as needed based upon FA, and a sham PJD procedure at the beginning of the study and at month 6. Best-corrected visual acuity (BCVA) was determined at baseline and all follow-up visits. Safety data were regularly reviewed by an independent safety committee. The major outcome measure was percent responders (patients losing less than 3 lines of vision) at month 12. Percent responders in the anecortave acetate and PDT groups were 45 and 49 %, respectively (not statistically different, p = 0.43). The confidence interval (CI) for the difference ranged from -13.2 % favoring PDT to +5.6 % favoring anecortave acetate. The month 12 clinical outcome for anecortave acetate was improved in patients for whom reflux was controlled and who were treated within the 6-month treatment window (57 % versus 49 %; 95 % CI: -4.3 % favoring PDT to +21.7 % favoring anecortave acetate). No serious adverse events related to the study drug were reported in either treatment group. These researchers concluded that the safety and effectiveness outcomes in this study demonstrate that the benefits of anecortave acetate for the treatment of CNV outweigh the risks associated with either the drug or the PJD administration procedure.
The European Medicines Agency (EMEA) was notified by Alcon Laboratories (UK) Ltd in March 2006 of its decision to withdraw its application for marketing authorization of Retaane (anecortave acetate) 30 mg/ml suspension for depot injection (EMEA, 2006). Alcon Laboratories submitted an application for marketing authorization to the EMEA on November 29, 2004. At the time of the withdrawal, it was under review by the Agency's Committee for Medicinal Products for Human Use (CHMP) for the treatment of exudative ARMD. In their formal withdrawal letter, the company stated their research and development and marketing strategies as reasons for the withdrawal (EMEA, 2006).
Regillo et al (2007) presented clinical safety profile of PJD administration of anecortave acetate 15 mg suspension as primary therapy or adjunctive therapy with PDT for the treatment of patients with wet ARMD (n = 358). Detailed ophthalmic examinations, physical examinations, and adverse event reporting were used to characterize the clinical safety of anecortave acetate 15 mg and were monitored by an Independent Safety Committee. Anecortave acetate 15 mg was safe and well-tolerated in the overall patient population. No serious, treatment-related deaths were reported. Ocular adverse events assessed as related to anecortave acetate 15 mg were non-serious with 1 exception (retinal detachment), mild-to-moderate in intensity with 1 exception, generally resolved with or without treatment, and did not interrupt patient participation in the studies with 2 exceptions. The authors concluded that anecortave acetate 15 mg is safe and well-tolerated when administered as a PJD at 6-month intervals for use as primary therapy or as adjunctive therapy with PDT.
Russell et al (2007) discussed the findings of 3 safety and effectiveness studies of anecortave acetate in patients with subfoveal CNV secondary to exudative ARMD. The Anecortave Acetate Monotherapy Trial enrolled 128 patients randomized to anecortave acetate (3 mg, 15 mg, or 30 mg) or vehicle administered as a sub-Tenon's PJD at 6-month intervals. The Anecortave Acetate and PDT with verteporfin Combination Trial enrolled 136 patients randomized to PDT with verteporfin followed by a single depot administration of anecortave acetate (15 mg or 30 mg) or vehicle. The Anecortave Acetate 15 mg versus PDT Comparison Trial enrolled 530 patients to receive either anecortave acetate 15 mg every 6 months plus sham PDT every 3 months or PDT with verteporfin every 3 months plus sham PJD administration every 6 months. Anecortave acetate 15 mg was statistically superior to vehicle in the monotherapy trial at both 12 and 24 months for maintenance of vision and inhibition of CNV lesion growth. In the combination trial, a trend favored adding either anecortave acetate 15 mg or 30 mg to PDT for these 2 measures of clinical effectiveness, but this short-duration study did not achieve statistical significance. Anecortave acetate 15 mg is comparable to PDT for maintaining vision over the 24-month period in the comparison trial. The authors concluded that anecortave acetate is safe and effective for the treatment of patients with exudative ARMD.
In September 2007, Alcon, Inc. received an approvable letter from the U.S. Food and Drug Administration (FDA) for Retaane, its anecortave acetate treatment for wet ARMD. However, the FDA will require an additional clinical trial before it grants final approval.
In a review on emerging therapies for neovascular ARMD, Donati (2007) noted that anecortave acetate was recently reported to have failed to meet the primary efficacy criterion in 2 large, placebo-controlled trials, and its clinical utility is uncertain. Furthermore, in a Cochrane review on the effects of steroids with anti-angiogenic properties in the treatment of neovascular ARMD, Geltzer and colleagues (2007) stated that anecortave acetate 15 mg may have a mild benefit in stabilizing vision, but further better quality evidence is needed.
An assessment by the Canadian Agency for Drugs and Technologies in Health (Brown et al, 2008) on the management of neovascular ARMD found only 1 randomized controlled trial that looked at the safety and effectiveness of anecortave acetate compared with PDT with verteporfin. The assessment stated that the trial failed comparing anecortave acetate to verteporfin PDT showed that both failed to improve VA in patients.
In an uncontrolled case series, Robin and colleagues (2009a) evaluated the intra-ocular pressure (IOP)-lowering potential of anecortave acetate (AA) in eyes with steroid-related ocular hypertension inadequately controlled with the maximal tolerated or appropriate medical therapy. A total of 8 eyes of 7 subjects with medically uncontrolled IOP following intra-vitreal or sub-Tenon injections of triamcinolone acetonide were included. All subjects received an 0.8-ml anterior juxta-scleral depot of 3 % AA solution (24 mg) under topical anesthesia. The IOP was assessed weekly for the first month, then monthly for a minimum of 1 year. The mean baseline IOP was 39.9 mm Hg. After 1 week, the mean IOP decreased 12 mm Hg (29 %; p = 0.005) and by 1 month, the mean IOP had decreased 14.1 mm Hg (34.5 %; p = 0.003) from baseline. Four eyes required surgical intervention despite a decrease in IOP because of markedly elevated initial IOP and the degree of pre-existing glaucomatous optic neuropathy. There were no adverse events. The authors concluded that an anterior juxta-scleral depot of AA markedly lowers IOP in some eyes with medically uncontrolled steroid-related ocular hypertension. They stated that further study is needed to clarify the role of AA in treating this condition as well as other forms of glaucoma.
In a prospective, interventional case series study, Robin et al (2009b) described the IOP-lowering effects in eyes with open-angle glaucoma (OAG) after treatment with an anterior juxta-scleral depot of AA. A total of 7 eyes of 6 subjects with OAG, with uncontrolled IOP while being administered one or more topical medications, received 24 mg AA delivered by anterior juxta-scleral depot. Intra-ocular pressure was assessed at baseline and regularly after treatment for up to 24 months. Mean IOP before AA treatment was 31.3 +/- 11.3 mm Hg and dropped by 9.5 +/- 4.5 mm Hg (32.7 % +/- 16.8 %) within 1 week after treatment. This IOP reduction was sustained through 6 months (8.4 +/- 5.4 mm Hg [29.6 % +/- 12.4 %]) and 12 months (9.5 +/- 5.7 mm Hg [34.0 % +/- 15.9 %]) after a single AA treatment. The injection process was well-tolerated, and no eyes experienced any injection-related or drug-related serious adverse events. The authors concluded that both the anterior juxta-scleral depot of a drug and AA may be promising candidates for IOP reduction in eyes with OAG. Moreover, they stated that additional studies are needed to establish better their safety and effectiveness, optimal dosing frequency, mechanism of action, and potential additivity to other IOP-lowering therapies.
In a prospective, interventional case series study, Prata et al (2010) evaluated the IOP-lowering effect of AA, delivered by anterior juxta-scleral depot injection, in eyes with various forms of glaucoma. A total of 28 uncontrolled glaucoma patients received a single injection of AA (24 to 30 mg) in 1 selected eye under topical anesthesia. Post-injection assessments were scheduled at week 1 and months 1, 2, and 3. Mean +/- SD age of patients was 58.2 +/- 18.6 years. Twelve patients had OAG and 16 had angle-closure glaucoma. Uveitic/steroid-induced glaucoma was the most frequent diagnosis (11 patients, 39.2 %). Mean baseline IOP was 30.7 +/- 9.3 mm Hg. Mean IOP at week 1 and months 1, 2, and 3 were 21.3 +/- 6.1, 19.8 +/- 6.3, 20.9 +/- 7.3, and 21.7 +/- 6.8 mm Hg, respectively. Significant mean IOP reductions were observed at week 1 and months 1, 2, and 3 (29.3 %, 33.8 %, 30.1 %, and 27.2 %, respectively; p < 0.001). The authors concluded that a single administration of AA by anterior juxta-scleral depot injection seems to result in a significant IOP reduction (compared with baseline) for at least 3 months in eyes with different types of glaucoma. No injection-related or drug-related serious adverse events were observed. They stated that additional studies are needed to better determine the safety, effectiveness, and mechanism of action of AA.
In a Cochrane review, Geltzer et al (2013) examined effects of steroids with anti-angiogenic properties in the treatment of neovascular ARMD. These investigators searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 11), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2012), EMBASE (January 1980 to November 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to November 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). They did not use any date or language restrictions in the electronic searches for trials. They last searched the electronic databases on November 21, 2012. These researchers included randomized controlled clinical trials of intra- and peri-ocular anti-angiogenic steroids in people diagnosed with neovascular AMD. Two authors independently screened abstracts and full-text articles, assessed risk of bias in the included trials, and extracted data. They did not conduct a meta-analysis. These researchers included 3 trials after screening a total of 1,503 abstracts and 21 full-text articles. The 3 trials included a total of 809 participants. One trial compared different doses of acetonide anecortave acetate with placebo, a 2nd trial compared triamcinolone acetonide versus placebo, and the 3rd trial compared anecortave acetate against PDT. They did not conduct a meta-analysis owing to heterogeneity of interventions and comparisons. The risk ratio for loss of 3 or more lines of vision at 12 months follow-up was 0.8 (95 % CI: 0.45 to 1.45) with 3-mg anecortave acetate, 0.45 (95 % CI: 0.21 to 0.97) with 15-mg anecortave acetate, 0.91 (0.52 to 1.58) with 30-mg anecortave acetate, 0.97 (95 % CI: 0.74 to 1.26) with triamcinolone acetonide, all compared to placebo and 1.08 (95 % CI: 0.91 to 1.29) with anecortave acetate compared with PDT. The authors concluded that based on the included trials, they found no evidence that anti-angiogenic steroids prevent visual loss in patients with neovascular AMD. With the emergence of anti-vascular endothelial growth factor modalities, based on evidence summarized in this review, it is unclear what role steroids have in treating patients with neovascular AMD.
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