Personalized Medicine's Bitter Pill

If it were not for the great variability among individuals,” 19th century physician William Osler observed, “medicine might as well be a science and not an art.” There will always be room for art in medicine, but the advent of diagnosis and treatment based on molecular knowledge of diseases is shifting the equation decidedly toward science. Almost from the moment the Human Genome Project completed its draft sequence in 2000, the intimate genetic knowledge it conferred has been accompanied by promises of a powerful, customized form of medicine. Visionaries talk of people carrying their entire genetic sequences on personalized CDs, of medicine artfully tailored to individual anatomies, and of diagnostic tests’ predicting who is likely to respond to a particular medicine, who is likely to react badly, and who is unlikely to benefit at all.

Armed with details of individual variation, biologists could parse patients  into subgroups and predict which is likely to have an aggressive or indolent form of a disease and which would respond to one drug rather than another. Allen D. Roses of GlaxoSmithKline and Duke University School of Medicine has predicted that this approach, called pharmacogenetics, “will change the practice and economics of medicine,” and the popular media have picked up and amplified that message. In 2001 BusinessWeek hailed personalized medicine as an idea that “has captured the imagination of biotech futurists,” and Newsweek suggested that “if pharmacogenetics works, the days of one-size-fits-all therapy could go the way of bleeding by leeches.”

But underneath those extravagantly rosy and somewhat wishful predictions lie important scientific, economic, and  societal questions, beginning with one of feasibility. David Altshuler, director of the Medical and Population Genetics program at MIT’s Whitehead Institute and an endocrinologist at Massachusetts General Hospital, points out that personalized medicine remains “a model, a hypothesis” of the way medical care will evolve. “The genome is going to empower all sorts of things, but it’s not going to happen for 20 years,” he says. Along the way, personalized medicine is likely to raise a number of prickly issues: foremost among them is the paradox that the more personalized the medicine, the less interesting the business. As numerous observers have pointed out, big pharmaceutical companies have become addicted to blockbuster drugs. Targeting a smaller subgroup of a patient population by definition focuses on a smaller market.

Theoretically, one economic advantage of personalized medicine is that clinical trials might be conducted more efficiently and with a greater chance of success when researchers can so specifically select patients for testing. But how small does the pie of potential patients have to shrink before it ceases to be economically viable? Furthermore, personalized medicine is not without social implications. A technology that identifies who will benefit from a new treatment automatically identifies who won’t benefit too.

Researchers, venture capitalists, and economists have been gnawing on these questions and wondering how the field of personalized medicine actually will evolve. Despite the compelling science, some investors find that the economics still leave a lot to be desired-at least in the short term. A venture capitalist who requested anonymity notes, “The vision of personalized medicine is that you’ll go to your doctor’s office, get your finger pricked, give a drop a blood, and it will be put in a machine-right there in the office-which will tell you what drug is going to work for you. But we haven’t seen very many companies that have a viable business model in this area.”

The view from the lab is different. “The treatments we currently use to treat most patients are grossly ineffective. In type 2 diabetes, many people don’t respond,” says Altshuler. “If it were true that you could identify five to 10 percent of the market, identify and treat them in a controlled and perfected way, I think it would be a wonderful thing, and I think you could make money on it too.”

Bumpy Road

Given the uncertainties, those starting down the road of personalized medicine could well learn from Genentech, the South San Francisco, CA, biotech pioneer, and its experience creating a cancer drug called Herceptin. Few people made the connection at the time, but Herceptin’s development-from the discovery of a surface marker on breast cancer cells in 1982 to the U.S. Food and Drug Administration’s approval of a drug targeting that marker in September 1998-is a useful study of the financial risks, clinical problems, social ramifications, and rich rewards of personalized medicine.

The defining characteristic of every form of personalized medicine is its biomarker, a kind of biological fingerprint that distinguishes a subset of the patient population. Herceptin is based on a marker protein that sits on the surface of malignant cells. Called neu when it was first discovered by Robert Weinberg’s group at MIT in 1982 and more popularly known as Her-2 following its independent isolation in 1985 by Genentech scientist Axel Ullrich, the molecule “listens” for signals that tell a cell to grow and multiply. Large numbers of these receptor molecules turn out to be present in certain aggressive breast cancers because the gene for the receptor is “overexpressed.”

As early as 1987 it had become clear that only 25 to 30 percent of women with breast cancer overexpressed the Her-2 gene and might benefit from a drug that blocked the growth signal. But by 1990 scientists at Genentech had developed a drug that would block the Her-2 protein and theoretically would block growth signals to a cancerous cell. “We weren’t really thinking of it in terms of individualized medicine back then,” says Debu Tripathy, an oncologist at the University of Texas Southwestern Medical Center who participated in the early testing of the drug at the University of California, San Francisco.

Splinter Groups

The Herceptin case offers multifold lessons for personalized medicine. But perhaps the most critical of those lessons concern what might be called the sociology of diagnostics. For all its power to help doctors target treatment, the precision of molecular genetics can easily generate a residue of medical frustration. “What do you say to someone who doesn’t qualify for the drug?” asks the National Breast Cancer Coalition’s Platner. In that sense, developers of personalized medicine can inadvertently dispossess subgroups of patients. And as its power to fractionate increases, personalized medicine could have the unintended effect of creating many slivers of groups too small to warrant the economics of further drug development. One patient advocate says, “The downside is: What about something that’s very effective, but only for one percent of the patient population? Is that going to be developed?”

Scientists at the National Human Genome Research Institute are exquisitely aware of the possibility of such problems. “The role of government is to work on the fragments of the patient populations that pharma isn’t going to pick up,” says one government researcher who has been participating in the development of the institute’s five-year plan. “Those discussions are still early, but that is already a concern, and it’s a real issue.”

Another collateral issue of personalized medicine is the accuracy of the diagnostic tests. Yet again, the Herceptin example offers a cautionary lesson. The first test that was developed to measure a woman’s Her-2 status typically identifies 10 to 20 percent of patients incorrectly, says Tripathy. In other words, the diagnostic was hardly definitive, and both false positives and false negatives caused a lot of frustration among breast cancer patients. Last August the FDA approved the use of an improved gene-based test for determining which patients qualify for Herceptin. The new test is “probably a little more accurate,” says Tripathy. But in that no man’s land between statistics and human emotion, the lives of many patients may be convulsed by inaccurate diagnoses. “I can foresee that happening with a lot of drugs, where the diagnostic doesn’t give a simple yes-or-no answer,” says Platner.

Promise and Peril

The Herceptin story offers an encouraging epilogue about the development of small-market drugs. Annual sales of the drug began modestly at $188 million in 1999. But sales have climbed steadily to about $346 million in 2001, and Genentech has deftly marketed the drug and expanded its possible uses. Originally approved for patients with the Her-2 marker who had developed metastatic breast cancer and had failed to respond to all other forms of chemotherapy, Herceptin is being tested as supplementary therapy following surgery for breast cancer and in cases of ovarian and lung cancer in which Her-2 is overexpressed.

Rituxan, an anticancer drug developed by IDEC Pharmaceuticals and marketed by Genentech, has followed a similar pattern. The FDA approved the drug in 1997 for non-Hodgkin’s lymphoma, a cancer that affects certain immune-system cells with a surface marker called CD-20. That marker allows for a targeted attack on malignant cells. Genomic analysis is identifying gene expression patterns that correlate with the disease’s progression; such analysis will ultimately affect treatment decisions. From initial sales of $162.6 million in 1998, its first full year on the market, Rituxan racked up sales of $818.7 million in 2001 and was well on its way to becoming a billion-dollar drug with expanded use by the end of 2002. The cells targeted in non-Hodgkin’s lymphoma may play a role in other diseases, such as chronic lymphocytic leukemia and rheumatoid arthritis, so the market may well extend even further.

So the pioneering drugs of personalized medicine convey messages of both caution and promise: Caution about the effect targeted biomarkers can have on a patient population, as well as the way the reaction of those patients can in turn influence the testing of drug candidates and the public’s perception of a company. Promise that a patient population can be identified and treated with a targeted drug that offers greater efficacy, as well as that nonresponders may be spared the ravages of toxic, ineffective treatments. And promise, too, that even a drug targeted to specific biomarkers can have economically bright prospects. The trick will be to capitalize on the promise without leaving too many disenfranchised patients behind.

As bumpy and fitful as was Herceptin’s journey to market, it serves as an inspiration to latter-day practitioners of personalized medicine. “I’m sure Genentech was having to wrestle with the decision of, If only 20 to 25 percent of the population responds, how are we going to compete?’” says Millennium’s Ginsburg. “But somebody had to be first, and I think it’s great that they did it.”

Despite the economic challenges and societal issues associated with personalized medicine, its role in the future of medical care seems all but assured. Not only is personalized medicine going to happen, argues Stephen Laderman, manager of the molecular diagnostics department at Agilent Labs’ Life Science Technologies Laboratory, in Palo Alto, CA, but it is going to happen soon, in part because more and more patients are learning to demand whatever knowledge will empower their decisions about disease treatment. As patients learn more about their options and researchers learn more about the molecular specifics of their patients’ diseases, personalized medicine may still be a bitter pill for many to swallow, but it will be one well worth taking as an antidote to the ravages of disease.