Julia Barchitta's main physical complaint these days is blisters on her feet. That's pretty remarkable, considering she has been living for three years with metastatic kidney cancer -- a notoriously hard-to-treat disease. Until May, 2004, the 61-year-old dean of the Center for Career Development & Experiential Learning at Wagner College in New York was lucky enough to respond to interferon, a drug that works for only 10% to 20% of patients. But she grew resistant, and the tumors spread throughout her body.
Barchitta knew how tough it can be to beat cancer. Shortly after her own tumor was discovered, her husband was diagnosed with lung cancer and died four months later. So in June, 2004, Barchitta agreed to enter a clinical trial at Memorial Sloan-Kettering Cancer Center for an experimental therapy named Sutent, one of a new class of multitargeted cancer drugs. Sutent was originally discovered by Sugen Inc., an innovative biotech firm that was absorbed into giant Pfizer Inc. (PFE ) in 2002. Barchitta had no hesitation about serving as a guinea pig. "Let's face it, the statistics are not great for kidney cancer," she says. "What did I have to lose?" In fact, she is one of the winners: Sutent eliminated all traces of Barchitta's cancer, and it has yet to recur. The only side effect has been those blisters. "I've learned to wear sneakers to work," she says.
THE POWER TO CHANGE PROGNOSES
Stories like Barchitta's have convinced many doctors that medical care is reaching a tipping point. Not that most patients will be healed right away -- the vast majority of sick people continue to dose themselves with tiny bits of chemicals, otherwise known as pills, that represent medicine's Old Guard. But the times are changing. The past 30 years of biological discoveries, insights into the human genome, and exotic chemical manipulation have unleashed a wave of biological drugs, many of them reengineered human proteins. These molecules have the power to change the prognoses for a huge range of diseases all but untreatable just five years ago. Recent weeks, for example, have seen announcements of startling advances against cancer and age-related blindness, diseases with miserable outlooks before. Cancer patients in particular have reaped rewards from biotech. A decade ago there were fewer than 10 oncology drugs in clinical trials, most of them highly toxic chemotherapies. Today over 400 cancer drugs are being tested in humans, and almost all are targeted biotech medicines designed to produce minimal side effects.
Biotechnology has finally come of age. This declaration may bring to mind the hype that has swirled around biotech so many times in the past. But a growing number of scientists and industry executives say today's enthusiasm is based on a new reality: Drugs actually exist. There are 230 medicines and related products created from biotech techniques. Last year alone, the Food & Drug Administration approved 20 biotech drugs, among them treatments for insomnia, multiple sclerosis, severe pain, chronic kidney disease, incontinence, mouth sores, and cancer. The Tufts Center for the Study of Drug Development estimates that at least 50 of 250 biotech drugs currently in late-stage clinical trials should win FDA approval, a success rate almost three times better than the pharma industry standard. "This is all a continuum of discoveries that started in the early 1980s," says Joseph Schlessinger, chairman of the pharmacology department at Yale School of Medicine and a co-founder of Sugen, the company that created Sutent. "We are now in a golden age of drug discovery."
Even long-beleaguered biotech investors have reason to be optimistic. True, biotechnology indexes have underperformed the overall market for much of the past year, and few of the 1,500 companies in this sector are profitable. But the medicines are selling. Ernst & Young International estimates that nine new biotech drugs approved in 2004 will bring in total revenues of $3 billion this year. By 2007, sales of just those products should grow to $8 billion. "I would say the industry as a group will become profitable by 2008," says Dr. Mark Monane, director of biotech research at investment advisers Needham & Co.
The industry is also building on its own success, applying lessons and testing out ideas faster than ever. Sutent is widely expected to win FDA approval by early next year for stomach cancer patients who have grown resistant to Gleevec, a breakthrough cancer drug that itself reached the market only four years ago. Last December the FDA approved Macugen, from Eyetech Pharmaceuticals Inc., as a first-in-class treatment for macular degeneration, the leading cause of age-related blindness. By next year the agency will likely consider a Genentech Inc. (DNA ) drug, Lucentis, that appears to be even more effective.
There are even glimmers that the long-awaited age of personalized medicine may not be far off. Biotech companies have been skilled at coming up with innovative new drugs -- but not so good at figuring out whom they are most likely to help. Response rates for cancer drugs, for example, often are stuck at 20%. Tired of such poor performance, pharmaceutical companies are focusing more effort on developing the diagnostic tests that would match a treatment to a patient's genetic profile, reducing side effects and increasing efficacy. "I think you are going to see a revolution in personalized medicine in just a few years," predicts Dr. George Demitri of Dana-Farber Cancer Institute in Boston.
This biotech-driven medical revolution is actually an evolution: It evinces the slow accumulation of decades of research. Since 1973, when genes that produce useful human proteins were first mass-produced in cell cultures, a vast number of scientists have pursued the same dream -- to create new molecules, via gene manipulation or gene targeting, that would change the course of human disease. "What's interesting is that it is really the academic researchers that pushed biotech forward, not corporate research and development," says Allan B. Haberman, principal of pharmaceutical consulting firm Haberman Associates in Wayland, Mass.
Academic researchers, unlike traditional drug companies, were willing to champion biotech approaches to drugs even when they were long shots. ImClone Systems Inc.'s (IMCL ) Erbitux, a colon-cancer treatment approved last year, would not exist today if not for the efforts of its discoverer, Dr. John Mendelsohn. The scientist-clinician spent 20 years working to find a company willing to commercialize his discovery that some tumors could be stopped by blocking a certain growth enzyme. Even Gleevec, the most effective cancer drug of the past decade, was almost abandoned by Novartis (NVS ). An outside cancer specialist, Dr. Brian J. Druker of Oregon Health & Science University, coaxed the company into pursuing its development.
Traditional pharmaceutical companies shied away from biotech for years, unwilling to bet on unproven technologies. It didn't help that biotech's earliest accomplishments met with setback after setback in the 1980s and '90s. Today, Big Pharma is paying for its risk-averse stance: Major players have few promising products in their development pipelines, and most are stuck with a business model heavily dependent on blockbuster drugs. Boston Consulting Group estimates that, as a result, biotech firms produced 67% of the drugs in clinical trials last year but shouldered only about 3% of the $40 billion that the drug industry spent on R&D.
"Focus on unmet needs" has long been the mantra of the biotech industry. Most of those drugs do just that. The strategy has paid off for Genentech, whose market capitalization is larger than Merck & Co.'s -- the nation's third-largest pharmaceutical company -- thanks in part to a roster of cancer drugs that have become surprise billion-dollar sellers. "Focusing on blockbusters to the exclusion of other things can introduce a level of myopia," says Genentech CEO Arthur D. Levinson. "So often the estimates of potential are wrong."
Big Pharma is now eager to join the game. It is partnering with biotech firms, buying them outright, or trying to emulate their success by overhauling their own R&D efforts. Novartis moved its worldwide research organization from Switzerland to Cambridge, Mass., two years ago, in hopes that it will behave like a freewheeling biotech. It also recruited an academic researcher, Dr. Mark Fishman of Harvard Medical School, to run the place.
Efforts by the pharmaceutical industry to mimic biotech -- or merge with it -- should quicken the pace of medical innovation. Here are three treatment and research areas poised to benefit:
In no other therapeutic area has biotech made as big a difference as it has in oncology. New drugs that target tumor cells while only minimally damaging healthy tissue have led to a paradigm shift in cancer treatment. Doctors now talk about the disease as a chronic, treatable condition. In 2004 alone, four targeted cancer drugs -- Avastin, Tarceva, Iressa, and Erbitux -- won FDA approval. Avastin, from Genentech, has extended the life spans of lung, breast, and colon cancer patients, a first for any oncology drug.
To the public, though, the picture still looks dismal. Three decades after President Richard M. Nixon declared war on cancer, the disease is the largest killer for people under 85, causing one in four U.S. deaths each year. "There is now a vital pipeline of targeted therapeutics," says Dr. Roy S. Herbst, a lung cancer specialist at University of Texas M.D. Anderson Cancer Center. "But we have to be realistic. This is not a cure. It's a place to start."
Many biotech researchers feel they are well out of the starting gate with a huge variety of emerging cancer treatments. Unlike heart disease, where patients choose between seven nearly identical cholesterol-lowering statins, targeted cancer therapies come in many forms. There are drugs that block tumor-growth factors, starve the tumor by inhibiting blood-vessel growth, combine radioactive isotopes with tumor-seeking proteins, and use vaccines to train the body's immune system to attack cancer cells.
There is even a next wave of multitargeted drugs that could start winning FDA approval as early as next year. Sutent, the drug keeping Julia Barchitta alive, is a member of this emerging class, known as multi-kinase inhibitors. They block blood-circulating proteins that are responsible for both tumor growth and blood vessel creation. Other closely watched candidates in this class include sorafenib, developed by Bayer (BAY ) and Onyx Pharmaceuticals (ONXX ) for kidney cancer, and lapatinib, a breast cancer drug from GlaxoSmithKline PLC (GSK ).
These multitargeted therapies seem particularly effective against the hardest to treat cancers, giving hope to some of the sickest patients. A prime example is an Eli Lilly & Co. (LLY ) pill, enzastaurin, for recurrent glioblastoma, the most aggressive form of brain cancer. "It's a desperate disease for which there are very few adequate treatments," says Dr. Howard A. Fine of the National Cancer Institute. Enzastaurin blocks two pathways vital to tumor growth and shuts off blood vessels that feed the tumor. In a trial conducted by Dr. Fine, enzastaurin shrank tumors in 25% of 92 patients, an unusually robust response for this disease.
Tumor shrinkage is not tumor elimination, of course. But cancer specialists are hopeful that, as more targeted therapies come on line, they can be combined into cocktails that will keep cancer patients alive for years. Renowned cancer researcher Dr. M. Judah Folkman of Children's Hospital in Boston says the most important thing is that the drugs give patients hope: "We have something to offer [patients] now, and if it keeps them alive a little longer, something else might come along."
The biggest problem with most major drugs today is that they don't work in anywhere from 25% to 60% of patients. Biotech is starting to improve that ratio. In January the first DNA-based test was launched that can predict an individual's response to a wide range of drugs.
Developed by Roche Pharmaceuticals and Affymetrix Inc. (AFFX ) in Santa Clara, Calif., the thumbnail-size device, called the AmpliChip CYP450, detects about 30 variations in two genes that regulate how the liver metabolizes such commonly prescribed medications as antidepressants, beta blockers, and pain relievers. A single drop of blood allows the chip to identify which patients clear a drug too quickly for it to do any good and which clear it too slowly, leaving them vulnerable to side effects. Roche, a leader in diagnostics, hopes to have a similar DNA chip on the market by yearend that can identify any of 25 different subtypes of leukemia, as well as a chip that can pick up the p53 gene, a tumor suppressor that often mutates in patients with cancer. These tests will help doctors figure out the best treatment. "We will be able to diagnose things probably earlier than we will be able to treat them," says Roche CEO Franz B. Humer.
That wouldn't be such a terrible problem. Patients and doctors alike are eagerly waiting for biotech to deliver treatments tailored to an individual's genetic makeup. But diagnostics have long lagged behind drug development, in part because the biology of disease was so poorly understood. "In the past, medicine has been reactionary. We wait for people to get sick, then we treat the disease," says Peter D. Meldrum, CEO of Myriad Genetics Inc. (MYGN ). "The majority of drugs on the market treat only symptoms, not causes."
Pharmaceutical companies also were never much interested in developing diagnostic tests: They wanted their drugs to be taken by as many patients as possible to ensure maximum revenues. But the dire side effects that pushed Merck's Vioxx pain reliever off the market underscore the grave dangers of such an approach.
Biotech pioneer Genentech took a different tack when it introduced its breast cancer drug Herceptin in 1998. It was the first cancer drug to be marketed simultaneously with a genetic test that could pinpoint the 25% to 30% of breast cancer victims in which Herceptin would work. The drug has gone on to be a hugely successful. Now Abbott Laboratories is readying similar tests that can identify patients most responsive to Iressa and Erbitux, cancer drugs that are effective in only 10% and 25% of patients, respectively.
Biotech researchers believe larger numbers of patients will be helped when scientists identify more genetic or protein variations, known as biomarkers, linked to specific diseases. A number of companies and researchers are developing tests that can predict who is most susceptible to a given disease, allowing for preemptive action. Myriad Genetics has four diagnostic tests on the market that spot genetic susceptibilities to breast cancer, colon cancer, and melanoma. These tests are not just telling patients that it's time to prepare their wills. If a woman learns she is at high risk of developing breast cancer, for instance, there are drugs she can start taking that lower the probability.
Economics is driving the development of these tests as much as medical need. Biotech cancer treatments can cost $20,000 to $40,000 per month. Giving them to a broad patient population, most of whom won't respond, "is a huge public-policy train wreck," says Patrick F. Terry, co-founder of the Personalized Medicine Coalition. This group of companies, public agencies, academic scientists, and patient groups is encouraging a collaborative search for biomarkers that will prevent such a crash. "The cost savings will be highly self-evident," he says.
In 2001, Calvin Miller of Union City, N.J., had five heart attacks in six weeks. The former firefighter's heart was so damaged that he had no energy to complete simple tasks. Two years later, while traveling in Thailand, he heard about a clinical trial there in which stem cells were extracted from patients' bone marrow and injected into their damaged hearts. Researchers were hoping the cells would grow into new blood vessels and improve blood flow to the heart. Miller enrolled on the spot. After one treatment, he is amazed by the difference. Before the stem cells were injected in January, he could only make it up two flights of stairs. Recently he walked 10 flights.
Scientists are hoping that stem cells, the next frontier of bio-medical research, will one day enable many different kinds of tissue regeneration in patients. The goal -- and it is very far off at this point -- is that stem cells could one day repair or replace diseased organs, severed spinal cords, damaged joints, and brain cells destroyed by Alzheimer's or Parkinson's. Embryonic stem-cell research has garnered most of the headlines in this area, particularly after South Korean scientists announced in May that they had derived multiple stem-cell lines from a cloned human embryo. But it is the much less controversial research into adult stem cells that is closest to delivering new therapies.
Scientists still have much to learn about how adult stem cells work -- or even if they do. But there is progress. In May doctors at the University of Pittsburgh Medical Center, who worked with researchers in Thailand on Miller's trial, were cleared by the FDA to begin a U.S. study of adult stem cells in patients awaiting heart transplants. Earlier this year the FDA also gave the go-ahead to Aastrom Biosciences Inc. (ASTM ) to expand a multicenter trial using adult stem cells to repair severe bone fractures.
Osiris Therapeutics Inc. has launched two clinical trials of adult stem cells to treat damaged hearts and injured knees. And in January, Osiris' experimental treatment for graft vs. host disease, a life-threatening condition that afflicts patients who have had bone marrow transplants, became the first stem-cell therapy to win the a fast-track designation from the FDA, guaranteeing it a speedy regulatory review.
Despite the flurry of human tests, there are more questions than answers about adult stem cells. They are less flexible than embryonic stem cells -- which have the power to turn into any of the body's many tissues -- but are easier to control. In the Thai trials and others like them, researchers found that some types of adult stem cells seem to have a natural ability to home in on damaged heart tissue, for example, but it is not clear what they do once they reach the target. There is no proof yet that the stem cells actually turn into heart cells. And while some patients' symptoms clearly improved, Dr. Amit N. Patel of the University of Pittsburgh says the degree of improvement is still questionable.
Consequently, researchers say it is unlikely that adult stem cells will be sufficient to fulfill the promise of this emerging area. Many are counting on embryonic stem cells. Embryonic stem-cell research is a must. Besides, the ban on federal funding for most embryonic cell research has put a chill on the whole field. "There are a bunch of very talented developmental biologists who could be taking this on," says Jose Cibelli, professor of animal biotechnology at Michigan State University. "But they don't want to touch it."
Some states are trying to go where the federal government refuses to tread. California has pledged $3 billion over 10 years to embryonic stem-cell research. Connecticut lawmakers approved $1 billion. Massachusetts legislators overrode the governor's veto on May 31 to pass a law allowing therapeutic embryo cloning. The science is certain to follow the money. As Wise Young, director of the collaborative neuroscience center at Rutgers University, notes, stem-cell technology "has the chance of being the most important advance to come along in the last 10 years."
It is worth remembering that, 20 years ago, scientists were saying the same thing about biotech advances that looked just as pie-in-the-sky. There has been plenty of hype and plenty of doomsaying in the interim, but the science kept moving ahead. As the many patients who have been helped well know, medicine would be a dreary enterprise if biotech hadn't delivered -- at last.
By Catherine Arnst, with Arlene Weintraub in New York, John Carey in Washington, Kerry Capell in London, and Michael Arndt in Chicago