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The rationale and design of ongoing maintenance trials with anti-VEGF agents
New AMD treatments are revolutionizing patient care. The advent of antivascular endothelial growth factor (VEGF) agents brought about an overall improvement in how patients are managed. Currently, ongoing trials are evaluating various anti-VEGF-based regimens to find an optimal regimen that will benefit patients in terms of efficacy, safety and convenience. This article discusses the designs of these trials, the rationale behind the regimens and how anti-VEGF therapy has affected the study of AMD and the future direction of AMD research.
The LEVEL trial
LEVEL (Evaluation of Efficacy and Safety in Maintaining Visual Acuity with Sequential Treatment of Neovascular AMD) is a phase 4 trial in which 1,000 patients with AMD who met the inclusion criteria of receiving active treatment for AMD (providing there is evidence of improvement based on clinical and anatomic findings) are being enrolled. Previous treatments can include ranibizumab (Lucentis, Genentech), bevacizumab (Avastin, Genentech) or any regimen deemed effective by the investigator. Patients then receive intravitreal pegaptanib sodium (Macugen, [OSI] Eyetech) every 6 weeks for 48 weeks.1 If for any reason a patient’s condition deteriorates during the trial, treatment with ranibizumab or bevacizumab can be re-instituted. The goal of the trial is to determine if pegaptanib can maintain the treatment benefits of the nonselective anti-VEGF agents.
The regimen used in this trial includes induction with a nonselective anti-VEGF inhibitor (ranibizumab or bevacizumab) followed by maintenance therapy with the selective anti-VEGF agent pegaptanib sodium. The nonselective agent is used for induction because it achieves a relatively faster and more effective reduction in leakage associated with AMD compared with the selective inhibitor pegaptanib, which selectively blocks VEGF isoform 165. The question then becomes: “If a nonselective anti-VEGF agent is more effective, then why switch to maintenance therapy with a selective anti-VEGF agent?”
One answer is convenience. According to the product labels, ranibizumab should be injected every 4 weeks compared with pegaptanib, which is dosed every 6 weeks.2,3 The PIER study (Phase 3b, Multicenter, Randomized, Double-masked, Sham Injection-controlled Study of the Efficacy and Safety of Ranibizumab in Subjects with Subfoveal Choroidal Neovascularization with or without CNV Secondary to AMD) evaluated the use of quarterly doses of ranibizumab following three consecutive monthly injections in patients with AMD. In the trial, the initial visual acuity improvement that occurred in the first few months was lost, with the visual acuity returning to baseline during the period of quarterly dosing. Although the ideal long-term dosing schedule has not been determined for either agent, if ranibizumab has to be dosed monthly to sustain the visual gains and pegaptanib is found to be effective in doing so with injections every 6 weeks, then pegaptanib use after an induction period would be advantageous. Less frequent dosing correlates with a possible lower cumulative rate of injection-related complications.
The second and more important answer is safety. A potential benefit of pegaptanib maintenance is the established safety profile.5 Although ranibizumab trials have not yielded any significant ocular or systemic safety signals over 1 to 2 years of follow-up in phase 3 clinical trial testing,2 theoretically, safety concerns exist with ongoing, long-term nonselective VEGF blockade. These concerns are especially relevant in the wet AMD population where patients are more likely to have cardiovascular comorbidities than patients without the condition.6
| Table: Induction Phase
Characteristics of induction phase of an induction-maintenance regimen. Table courtesy of Carl D. Regillo, MD |
The BRIDGE study
The protocol for the BRIDGE study (Bridging Industry and NEI) is not yet finalized but will include a baseline treatment with ranibizumab 0.5 mg. Patients will then be randomized to receive anecortave acetate (Retaane, Alcon) every 3 or 6 months or sham injection. All patients will receive ranibizumab 0.5 mg on an as-needed basis, although a monthly ranibizumab 0.5-mg arm may be added to the study. One of the major goals of the study is to determine whether the addition of anecortave acetate, given at regular intervals, to ranibizumab will augment efficacy and result in improved visual outcomes compared with ranibizumab monotherapy. A second goal is to determine if the addition of anecortave acetate will reduce the ranibizumab dosing frequency while maintaining an equivalent or enhanced efficacy level.
By combining two agents with complementary mechanisms of action, it is hoped that a synergistic or additive effect will be achieved. Ranibizumab acts extracellularly by inhibiting the effects of freely diffusible VEGF on endothelial cells and other cells involved with the neovascular process. Anecortave acetate, on the other hand, is a modified steroid that works intracellularly to decrease neovascular growth and development. Both of these agents have good safety profiles, and there are no predictable drug interactions. These drugs have separate routes of administration, with ranibizumab administered intravitreally and anecortave acetate administered juxtasclerally.
The overall goals of designing the combination regimen with ranibizumab and anecortave acetate include decreasing the incidence of adverse events, improving compliance and increasing cost-effectiveness. Complication rates from intravitreal injections may be minimized if the addition of anecortave to the regimen succeeds in lengthening the dosing interval for ranibizumab. This increased dosing interval may increase the convenience and, therefore, compliance to the regimen.
Anti-VEGF therapy and its effect on AMD research
Nearly all types of progressive neovascular AMD benefit from anti-VEGF treatment; therefore, it has become unethical to design clinical trials with placebo arms. All study groups in AMD trials must receive active treatment, and future trials will likely be designed as head-to-head comparisons, especially at the phase 3 level of testing. An alternative is to introduce a new treatment but offer rescue therapy if treatment fails. For example, if patients in the LEVEL study deteriorate while receiving pegaptanib in the maintenance phase, they will be given rescue therapy with a nonselective anti-VEGF agent (ranibizumab or bevacizumab). Yet another approach to clinical trial design in AMD is to offer a new drug as an adjunct to an existing treatment. The BRIDGE study provides a good example of this design because the study protocol includes anecortave acetate plus ranibizumab.
Use of anti-VEGF agents in the treatment of AMD has also advanced the clinical end points in trials. The former standard in wet AMD studies involved slowing the progression of neovascularization and decreasing the rates of vision loss over 1 to 2 years. However, current endpoints evaluate the ability of anti-VEGF agents not only to stop the progression of the neovascular process and associated exudation, but also to improve vision.
As discussed above, the future of AMD research includes anti-VEGF-based combination and induction-based regimens. Alternative therapeutic strategies targeting VEGF include blocking the production of VEGF (ie, via the small interfering RNA approach) or directly inhibiting the VEGF receptor. Researchers are also investigating other growth factors that may be involved in the pathogenesis of neovascular AMD, including platelet-derived growth factor-B. Another target may be the endogenous growth-inhibiting factor pigment epithelium-derived factor. Upregulating this natural inhibitor of neovascularization may have therapeutic implications.
References
- (OSI) Eyetech Pharmaceuticals Pressroom resources page. (OSI) Eyetech Pharmaceuticals Web site. Available at: http://phx.corporate-ir.net/phoenix.zhtml?c=70584&p=irol-newsArticle&ID=782521&highlight=. Accessed September 2, 2006.
- Lucentis [package insert]. San Francisco, Calif.: Genentech, Inc; 2006.
- Macugen [package insert]. New York, N.Y.: Eyetech & Pfizer; 2004.
- Brown D. PIER Study Presentation [Retinal Physician Web site]. July 2006. Available at: http://www.healthcareconferencegroup.com/conferences/63/pier.htm. Accessed September 18, 2006.
- D’Amico DJ, VEGF Inhibition Study in Ocular Neovascularization (VISION) Clinical Trial Group, Patel M, et al. Pegaptanib sodium for neovascular age-related macular degeneration: Two-year safety results of the two prospective, multicenter, controlled clinical trials. Ophthalmology. 2006;113:992-1001.
- Shah S, Zlateva G, Zhou S, Javitt JC. Comparison of comorbid conditions between wet AMD patient and a control cohort in the Medicare population. Presented at the annual meeting of the Association for Research in Vision and Ophthalmology; May 2, 2006; Fort Lauderdale, Fla.