Upfront: From the Editor-in-Chief

Changing vessels


Changing Vessels

“In a chronically leaking boat, energy devoted to changing vessels is more productive than energy devoted to patching leaks.”
—Warren Buffett

Peter K. Kaiser, MD

Anything Warren Buffett says I listen to with great interest. Who wouldn't? Over the last 50 or so years, Berkshire Hathaway's stock has grown at a rate of ~20% compounded annually, and reading his shareholders' letters is fascinating and required reading for any investor. Had you been lucky enough to purchase a Class A share for $19 in 1965, it would be worth $132,800 today. Unfortunately, I have none.

Truly one of the greatest investors of our time, Buffett never worried about short-term market movements but instead invested for the long term. He only invested in things he understood, so I know for a fact that he was not talking about angiogenesis when he made this quote, but I think it's funny how it applies to what appears to be some of the most exciting clinical trial results in recent memory. (Note: I am a consultant for Ophthotech and so grossly conflicted.)

For the past seven to 10 years, we have focused our attention and clinical trial dollars on blocking VEGF in the extracellular space to fix the “chronically leaking boat.” At first, we believed this led to blockade of VEGF-induced angiogenesis, as was shown in the preclinical animal models. But as more and more data appeared, it seemed that anti-VEGF agents largely work by reducing vascular leakage and drying the retina, not by eliminating choroidal neovascularization. Therefore, we are just patching leaks, not fixing the problem.

Looking closer, however, the vessels are definitely different. We rarely see disciform scarring; instead, there is often a flat, fibrotic scar. That anti-VEGF does not cause CNV regression is likely related to these vessels maturing over time and other factors being involved in the process. It is time to “change vessels,” or in this case change the vessels.

One line of thought holds that CNV membranes mature over time, possibly even due to the presence of anti-VEGF therapy, such that pericytes are attracted to the naïve endothelial network. Pericytes envelop the vessel, presumably protecting the endothelial cells from anti-VEGF therapy and even producing more VEGF. Thus, the vessels become more resistant to continued anti-VEGF therapy, and they “chronically leak.”

Platelet-derived growth factor (PDGF) is a key cytokine involved in this recruitment. In this issue, the results are discussed from a new class of drugs that blocks PDGF. Because this type of blockade only blocks pericytes, it is not going to be successful as monotherapy but instead will need to be combined with anti-VEGF agents.

Combination therapy faces a tough regulatory hurdle in that the two drugs together need to be superior to either alone. Thus, whether this class of drugs will help us “change vessels” remains to be seen, but like Mr. Buffett, we'll have a longer time line to find out. RP