WHAT'S HOT IN... MEDICINE, Jan./Feb. 2008

The eye has not featured much among the highly cited clinical papers tracked by ScienceWatch.com, but at #4 this time there is something from an ophthalmological journal. Macular degeneration is an important cause of blindness; being age-related, the disease is likely to increase in importance over the years. In the "wet" form, which is the more serious variety, new growth of vessels behind the retina adversely affects vision, so one approach to treatment might be to try and stop this neovascularization.

Inhibitors of vascular endothelial growth factors (VEGF) have been attracting much interest across the spectrum of medical research, most obviously perhaps in cancer treatment—indeed, this column has recently covered one of these agents, the monoclonal antibody bevacizumab (Avastin), in the context of colon cancer (see ScienceWatch.com, 16[6]: 5, November/December 2005).

Ranibizumab (Lucentis) is related to bevacizumab but is about two-thirds smaller in molecular size. Unlike its companion, ranibizumab is licensed for the treatment of age-related macular degeneration, but ophthalmologists have been using bevacizumab "off label," which involves pharmacists making up bevacizumab in a form suitable for direct injection into the eye.

Last October Genentech, which has developed both drugs, said that from January 1, 2008, it would no longer allow compounding pharmacies to purchase bevacizumab from wholesalers. In reaching this decision ("not made lightly") the company cited concerns over the safety for ophthalmic use of a product designed for intravenous injection.

Genentech said that it had had to destroy $200 million worth of the drug that would have met the standards for systemic use, but added that it would be willing to reverse its policy if the Food and Drug Administration authorized such action. This development can only have heated up an already lively debate about the intravitreal use of bevacizumab—see, for example, the review by Tien Wong and colleagues (Lancet, 370 [9583]: 204-06, 2007) and subsequent correspondence (Lancet, 370 [9597]:1479-81, 2007).

Because ranibizumab is much more expensive than the other drug, some critics see the company’s unwillingness to seek a license for the intravitreal use of bevacizumab as profit-driven, which Genentech strongly denies. On the other hand, unwanted cardiovascular effects of anti-VEGF agents are a concern, and there is uncertainty about how much of the drug injected into the eye reaches the general circulation.

Head-to-head clinical trials of the two Genentech drugs should help to resolve issues of safety and efficacy, and two such studies are in the pipeline. In the U.K. the National Institute for Health Research is recruiting 600 patients for a randomized trial of bevacizumab and ranibizumab, and the U.S. National Eye Institute has announced that it will fund a similar study.

From 2005 the interest of both the ophthalmological community and patients in bevacizumab has been fuelled by non-randomized evidence such as that in the paper by Dr. Robert L. Avery and his colleagues (#4). Avery et al. studied 79 patients (81 eyes) given monthly intravitreal injections of bevacizumab 1.25 mg, and recorded, among other variables, changes in retinal thickness and visual acuity. Both improved. No significant systemic or ocular adverse effects were seen.

In a much larger study of 716 patients, with sham injection as the control, Dr. Philip J. Rosenfeld and coworkers used ranibizumab doses of 0.3 and 0.5 mg (P.J. Rosenfeld, et al., New Engl. J. Med., 355[14]: 1419-31, 2006). Visual acuity improved with both doses of ranibizumab while it deteriorated in the sham-injected patients.

Six months separate these two papers, and Rosenfeld’s randomized trial of the other drug has not yet made it to the Top Ten (with 50 total cites and 17 in the latest counting period). Has bevacizumab been given intravenously to patients with neovascular macular degeneration? Yes. For example, Rosenfeld’s group (A.A. Moshfeghi, et al., Ophthalmology, 113[11]: 2002-11, 2006) gave 5 mg/kg injections to 18 such patients with "impressive results." However, they think it unlikely that a large trial of this approach will be done because of the "potential risks associated with systemic anti-VEGF therapy."

A former deputy editor of The Lancet, David W. Sharp, M.A. (Cambridge), is a freelance writer living in Minchinhampton, Gloucestershire, U.K.