The Future

Macugen is the second anti-VEGF therapy to enter the marketplace, but is the first aptamer approved in the United States for human therapeutics. In the clinical trials performed to date, Macugen has demonstrated significant efficacy in preserving vision in eyes with neovascular AMD, and has also exhibited a very favorable safety profile.

But the Macugen story is far from complete. These clinical trials showed that the most significant safety issues associated with Macugen arise from the method of drug delivery. Efforts are now aimed at making the delivery of the drug safer. To this end, the study protocol by which the drug is injected into the vitreous cavity has been revamped, and so far, this has significantly reduced the rate of en-dophthalmitis. Molecular modifications to extend the drug's half-life and reduce the frequency of injections are also being pursued. Aptamers, by virtue of their relative chemical stability, are well suited to this type of reformulation. These post-market refinements in both the molecule and its delivery protocol will continue to improve the safety of an already very well-tolerated drug.

Optimal timing of treatment for AMD may also require further elucidation. If VEGF inhibition merely suppresses neovascularization, then the drug should optimally be applied before a subretinal neovascular membrane forms - perhaps as prophylaxis in high-risk eyes. But VEGF inhibition may also be capable of inducing regression of neovessels (as was seen in the study by Inai et al., 2004, discussed above). Emerging data suggest that newly formed vessels are amenable to regression if exposed to anti-VEGF therapy early, but if they are allowed to mature and gain their supportive pericyte layer (typically within 10-14 days of forming), these older vessels become less responsive to anti-VEGF treatment (Ishida et al., 2003a; Bergers et al., 2003).

In addition, Macugen may find applications beyond AMD. Emerging science supports that diabetic retinopathy and macular edema are both VEGF-mediated disease states, and may respond to Macugen therapy. Also, its efficacy in cancer therapy has not been tested, and may prove to be an extra-ocular application for this unique drug.

The marketplace will soon have a plethora of angiogenesis-inhibiting agents -at least 30 are currently under development around the world. The impact of this new therapeutic modality on long-term morbidity and mortality will be evident in the coming years.

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