Something Old, Something New: Biotech’s Enormous Potential
Friday, April 30, 2010
Medical breakthroughs from using existing drugs in new ways await discovery—if manufacturers have an incentive to pursue them.
A story in the health section of this week’s New York Times was a classic example of an item whose importance can be appreciated only by someone who has followed several trends in the endlessly fascinating biotechnology industry. The story was prompted when the medical journal Ophthalmology posted the results of a clinical trial of Lucentis, a biotech drug from Genentech, a southern San Francisco firm that after many years of independent operation recently became a fully owned (rather than partly owned) subsidiary of Roche, headquartered in Basel, Switzerland. Lucentis is a monoclonal antibody fragment, an extraordinarily complex kind of product created through a combination of diverse biotechnology tools (Wikipedia does a pretty good job on mabs).
Lucentis works by suppressing a process called angiogenesis, in which cells essentially create new arteries so they can grow quickly and sometimes (as in cancer cells) beyond normal limits. Lucentis was developed to treat the wet form of age-related macular degeneration (ARMD), in which cells in the eye suddenly flood the retina with blood, sometimes causing blindness in a matter of weeks. Lucentis proved extraordinarily effective, a true miracle drug that prevents ARMD from progressing to blindness more than 90 percent of the time and goes far toward restoring vision in victims when caught early. Nothing else is remotely as effective for this condition.
The incentive to perform this kind of research might vanish if the manufacturer knows that if it succeeds, a government agency will then spend taxpayer money to demonstrate that a tiny amount of the original drug works just as well.
The new study in Ophthalmology addressed diabetic macular edema, which is caused by diabetic retinopathy. Diabetic retinopathy is the leading cause of blindness in working-age Americans—just as age-related macular degeneration is the leading cause of blindness in the elderly. The results weren’t as spectacular as for age-related macular degeneration, but Dr. Frederick L. Ferris III, the clinical director of the National Eye Institute (part of the National Institutes of Health, NIH), was quoted as saying, “This is the first new treatment for people with diabetic macular edema in a quarter of a century.”
This episode is full of interesting connections. Because Lucentis was approved nearly four years ago, the new results are an example of a breakthrough new drug treatment that does not involve a new drug, but a new use of an old drug. This kind of thing has been happening for decades, but it seems to be happening faster than ever in the modern biotechnology-driven age of drug discovery. The Lucentis trial, like the development of Lucentis itself, was motivated by basic scientific reasoning. Lucentis is an angiogenesis-inhibitor that works by suppressing a vascular endothelial growth factor (VEGF). VEGF was discovered a couple of decades ago by a Genentech research team headed by Napoleone Ferrara. This discovery eventually led to the first practical use of the seminal work of the late Judah Folkman, a Harvard researcher who proposed back in the 1970s that a good way to attack cancer could be to inhibit cancer-cell angiogenesis. Folkman and others demonstrated through a long series of elegant laboratory experiments that angiogenesis lay at the heart of cancer cell growth (and other important biological processes as well). But it was Ferrara’s team that isolated VEGF and then developed two closely related monoclonal antibodies to inhibit it.
‘This is the first new treatment for people with diabetic macular edema in a quarter of a century.’
After quite a few years of clinical trials that included near-devastating setbacks as well as encouraging results, one of these angiogenesis-inhibitors, Avastin, was approved by the FDA in 2004 to treat colorectal cancer. It has since been approved for other cancers as it has been put through literally hundreds of clinical trials. This long research stream is typical of biotechnology drugs as researchers pursue new leads inspired by what they know about the biological processes addressed by these drugs (as described in detail in an article Elizabeth DuPre and I wrote a few years ago).
Because the Genentech researchers knew that age-related macular degeneration was caused by angiogenesis, they also developed a variant of Avastin—with one leg of the Y-shaped monoclonal antibody chopped off—which was designed for the very different environment of a drug that is injected directly into the eye rather than being infused into the entire body (as when treating cancer). That research led to Lucentis, arguably one of the half-dozen or so greatest triumphs of the still-young biotechnology industry.
Diabetic retinopathy is the leading cause of blindness in working-age Americans—just as age-related macular degeneration is the leading cause of blindness in the elderly.
Even more stories can be conjured from the Times story, and they lie at the intersection of science and economics. The Lucentis diabetic retinopathy trial was run by NIH, not Genentech, although Genentech provided $9 million-plus in free drugs. NIH was criticized by at least one academic, however, who said NIH should have run the trial with low-dose Avastin instead of Lucentis. The academic was Philip Rosenfeld of the University of Miami, who has researched and advocated the use of small doses of Avastin instead of Lucentis to treat age-related macular degeneration. Because Avastin is sold in quantities sufficient for infusion into cancer patients, the tiny amount necessary to inject into the eye to treat age-related macular degeneration costs less than 5 percent of the price of Lucentis. Although the Times story does not mention it, the National Eye Institute is in the middle of a large trial to demonstrate that low-dose Avastin works about as well as Lucentis for age-related macular degeneration. The results remain in doubt, because certain properties of Lucentis, especially its smaller molecular size, make it much better suited for retinal use.
If the campaign to replace Lucentis with low-dose Avastin succeeds, it will have two effects. One is that most cases of the wet form of age-related macular degeneration will be treated at an astonishingly low cost. The second implication, however, is that there will be little money to be made in developing new uses that require only very small amounts of an innovative drug. Genentech’s demonstration of a practical way to defeat age-related macular degeneration through angiogenesis inhibition was a major scientific achievement that required considerable expenditure and was far from certain of success. No doubt, similar breakthroughs with different drugs and conditions await discovery—if manufacturers have an incentive to pursue them. Genentech attacked angiogenesis in age-related macular degeneration by developing a different drug (although it is very similar structurally to Avastin), but sometimes it may make more sense simply to rebrand a drug for sales in a different dose and form at a very different price. But the incentive to perform this kind of research might vanish if the manufacturer knows that if it succeeds, a government agency will then spend taxpayer money to demonstrate that a tiny amount of the original drug works just as well.
In the meantime, as the Times story indicates, Lucentis is a billion-dollar-a-year drug even though sales have been cannibalized by low-dose Avastin. What the Times does not mention is that other angiogenesis-inhibitors are in development by competing firms and some of them may also prove effective for age-related macular degeneration.
But that is enough for today’s lesson in why biotechnology is the source of small stories about big events.
John E. Calfee is a resident scholar at the American Enterprise Institute.
FURTHER READING: Calfee recently wrote “Reform through Reconciliation—Worse than Imagined” describing the healthcare overhaul’s ill effects, and “We Already Know Why Healthcare Overhaul Will Fail.” Calfee also reviewed drug importation provisions circulating within the healthcare debate in "Drug Development in the Balance," and outlined "The Dangers of Fannie Mae Healthcare." “Tough Challenges at the FDA” argued that President Obama’s Food and Drug Administration commissioner should avoid making the drug development process more costly and inefficient, and “A Troubling Supreme Judgment” covered the Supreme Court’s decision in Wyeth v. Levine.
Image by Rob Green/Bergman Group.