Abdhish R Bhavsar, MD
Clinical management of diabetic macular edema (DME) may change rapidly in the near future. The world looks positive for future treatments: there are at least 5 new agents in development that target underlying molecular mechanisms of the disease. The most popular molecular target is vascular endothelial growth factor (VEGF). Ranibizumab, VEGF trap, bevasiranib, and bevacizumab all target VEGF or VEGF receptors (VEGFRs) directly; ruboxistaurin targets protein kinase C (PKC) β, a substance activated by VEGF which also increases the activity of VEGF. Except for ruboxistaurin, all of these new treatments are intravitreal injections.
Ranibizumab, a nonselective VEGF inhibitor, has recently been approved for the treatment of age-related macular degeneration. In a pilot study of 10 patients with DME, it appears to be a safe and effective treatment, but requires redosing every 6 weeks. No systemic adverse events were noted in the pilot study, but there were 5 cases of mild to moderate ocular inflammation. Most patients’ visual acuity improved at 3 months, and 4 of the 10 gained at least 15 letters. Reductions in retinal thickness of the center subfield were also observed.
VEGF Trap, a fusion protein of key domains from human VEGFR-1 and -2 with human IgG, binds very tightly to all VEGF-A isoforms and penetrates all layers of the retina. Enrollment for a Phase I clinical trial for DME of VEGF Trap is complete. The Phase I trial is called Clinical Evaluation of Anti-angiogenesis in the Retina (CLEAR-DME).
Bevasiranib is a synthetic small interfering RNA (siRNA) which selectively silences the mRNA encoding for VEGF. Bevasiranib, also known as Cand5, may offer a more potent form of VEGF inhibition than a molecular antibody analog or aptamer. A Phase II trial of this drug has recently been completed (NCT00306904). The Phase II trial is called RNAi Assessment for Cand5 in patients with Diabetic Macular Edema (RACE).
Bevacizumab has changed the world for ophthalmologists: numerous case reports attest to its efficacy for a variety of retinal vascular disorders. Bevacizumab is currently approved as a systemic treatment for colorectal cancer, but no large prospective clinical trials of this nonselective VEGF inhibitor have been published in ophthalmology. The Diabetic Retinopathy Clinical Research network (DRCR.net) is currently evaluating the safety and efficacy of bevacizumab for the treatment of DME in a large multicenter clinical trial.
Ruboxistaurin, an oral drug, appears to be an ideal candidate for the treatment of DME and DR as its mode of action would be expected to reduce vascular permeability and neovascularization. In recent Phase III clinical trials of patients with nonproliferative diabetic retinopathy and DME, the drug reduced the progression of DME for patients with A1C ≤10%, although the pivotal retinopathy trials did not meet their primary endpoints. Adverse events noted in the trials did not reveal significant safety issues with systemic administration. The study sponsor is currently analyzing data subsets to determine whether greater benefits are found in selected patients.
Given the different modes of action, side effect profiles, and duration of effect of all of current and proposed treatments, there is an excellent chance that combination therapy will eventually be used for DME. Among the combinations Dr Bhavsar suggested as priorities for clinical trials are focal laser in combination with an anti-VEGF agent or bevasiranib, focal laser in combination with a steroid (to address inflammation), and focal laser in combination with a steroid and an anti-VEGF agent. DRCR.net is currently evaluating focal laser in combination with a sustained release steroid in a Phase III clinical trial. Pharmacological treatments could also be used in combination with each other, for example, a dispersant agent such as Vitrase (to clear hemorrhage) and an anti-VEGF agent.
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