Pravin U. Dugel, MD

The treatment of dry macular degeneration is currently the “holy grail” for the retinal specialist. There is increasing evidence that toxic by-products of the visual cycle may be a major reason for the development of macular degeneration. When a photon of light hits the photoreceptor cell, 11-cis-retinal is converted into all-trans-retinal. The rest of the visual cycle is designed simply to regenerate the 11-cis-retinal for another such cycle. During this process there is an accumulation of toxic by-products such as phosphatidylethanolamine (PE) A2E. This product is felt to enhance free radical formation, damage RPE cell membranes, inhibit RPE lysozymes, and activate complement factors. This understanding of the visual pathway, along with studies that show that alteration in complement activation may be a major rate-limiting genetic risk factor for macular degeneration, have led to study of complement inhibition in order to treat nonexudative macular degeneration. Soliris (eculizumab, Alexion Pharmaceuticals), a humanized antibody toward C5 delivered via systemic intravenous infusion, blocks the complement pathway in its early stages. Neither the efficacy of this strategy nor its safety is known. There is concern that blocking early in the complement pathway theoretically may result in reduced ability to combat infection.

Rosenfeld’s group in Miami has recently reported in a small study that eculizumab had no effect on drusen volume or drusen resolution. This is a preliminary result and there are various explanations that may be considered: The sample size may be too small, the measurement modality may not be sensitive or may not be appropriate, the follow-up may not be long enough, the disease itself may be too variable, and finally one must consider the possibility that this treatment strategy may simply not work. In other words, the inhibition of complement may simply be too far downstream to have any measurable clinical effect. If this is the case, then inhibition further upstream, for instance with visual cycle modulators, may be more appropriate. The bottom line is that the story has not yet been fully told and the book certainly is not closed. I applaud the investigators for their scientific rigor and transparency. I look forward to their undoubtedly important contributions that will be forthcoming.