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NOTE: If you go to the website, you can add your comment about the case. It may require that you submit free registration to read the newspaper's articles online. FROM: Ventura County Star (California) URL: http://www.venturacountystar.com/vcs/county_news/article/0,1375,VCS_226_3 815646,00.html Amgen caught in dispute over drug's safety, value Parkinson's patients sue to resume use in trials By Tom Kisken, [log in to unmask] May 29, 2005 Robert Suthers is so desperate to hold his baby granddaughter, bathe himself without help and live as he did before Parkinson's disease that he's battling to take a drug despite claims it could further damage his brain. The retired textile salesman who once competed in the New York City Marathon is suing Amgen in a landmark case that pits patients' hopes for a cure against a healthcare company's responsibility to protect consumers. Suthers and other patients in a clinical trial say a protein, called GDNF, breathed life into crippled bodies, allowing them to take walks and even run again. But officials of Thousand Oaks-based Amgen, which owns the drug, said research showed it caused brain damage in monkeys, created a risk of unwanted antibodies and, in most patients, offered no more of a defense against Parkinson's than a placebo. So the world's largest biotechnology firm stopped the clinical trial and withdrew the drug from patients though court documents say the Food and Drug Administration would have allowed treatments to continue. The decision started a battle that on Thursday spilled into a federal courtroom in Manhattan. Judge P. Kevin Castel heard arguments on a preliminary injunction that would force Amgen to provide GDNF to Suthers and a second plaintiff, a retired teacher from West Virginia, but made no immediate ruling. The hearing continued a nine-month-old saga driven by patients and research doctors who are neither convinced GDNF is dangerous nor ineffective. They said Amgen didn't give a fair chance to a drug they believe may still be a shield against a disease that inflicts about 1.5 million Americans. "I wanted my patients to continue to be treated," said Dr. Richard Penn, a neurosurgeon who helped lead GDNF clinical trials at the University of Chicago Hospitals. "Amgen has absolutely stopped us cold." However, Dr. J. William Langston, director of the Parkinson's Institute in Sunnyvale, suggested patients and doctors have invested so much hope in GDNF's potential that some of them may be ignoring health risks and other questions about the drug. He defended Amgen's choice. "We can't do harm," he said, finding irony in GDNF's rise and apparent fall as a wonder drug. "Amgen was the leader. They were the champion for GDNF. Now, they're being pinpointed as Dr. Evil. I find that sad." Prisoners in their own bodies Parkinson's kills nerve cells in the brain that help control the body's movement by producing a neurotransmitter called dopamine. Slowly debilitating, the disease can bring tremors so pronounced people may move as if inebriated. Their bodies can become so rigid they need help getting dressed. Face muscles can become frozen so a smile is impossible. Eventually, people become prisoners in their own bodies. Glial cell line-derived neurotrophic factor represented hope. While other drugs help people control Parkinson's symptoms, GDNF is a protein believed to reverse aspects of the disease. "It wasn't going to be a cure," said Dr. John Nutt, a Parkinson's researcher from Oregon, but it might restore some damaged cells and protect others, slowing the disease's progress. Nutt said it had the potential to affect a large majority of Parkinson's patients. "It could have made a huge impact," he said. Amgen bought the drug as part of a $250 million purchase of a company called Synergen in 1994. Six years later, academic researchers thought they solved the crucial problem of delivering the drug directly to deep recesses of the brain. That spawned a clinical trial in England that an observer compared to the movie "Awakenings," where people trapped by disease seem freed. A video from the study shows people who once shuffled as if their legs were mummified moving like speed-walkers. Tremors diminished. Agility returned. Launched a trial in seven sites The trial was open as was a similar study that produced encouraging results in Kentucky. Patients knew they were getting GDNF and their physical reactions could have been influenced by the knowledge. Two years ago, Amgen launched a trial in seven sites, from England to Oregon, in which neither patients nor doctors knew whether GDNF or a placebo was being provided. Just to qualify, people needed pumps surgically implanted in their abdomens so GDNF could be delivered through a pipeline of catheters just under the skin. Two nickel-sized holes were drilled on either side of the skull so the drug could be administered to the brain's basal ganglia. It was the kind of trial that attracted desperate people. Robert Suthers fit. He is a 70-year-old Korean War veteran who spent a decade in a Catholic monastery, then was married and raised three daughters, once winning a father of the year award. He received a diagnosis of Parkinson's about seven years ago. The disease slowly crippled him. "I ran the New York City Marathon in 1990, in four hours and 54 minutes," he said in a phone interview from his home about a half-mile from the Long Island town of Greenlawn. "Now I can't walk a block. I have so much pain." The craniotomy surgery took more than six hours. The day after, Suthers suffered a stroke that dislodged the catheters. He had to go through the surgery again five weeks later. This time, it took more than two hours. He was getting the placebo The trial began in October 2003. Suthers struggled just as much to write and walk. Later, he learned he was getting the placebo. However, when the study was completed, all 34 people in the trial were told they would receive monthly doses of GDNF. That's when Suthers noticed changes. He was able to walk farther, eventually strolling to Greenlawn and home again. He could hold his granddaughter. The muscles in his face loosened. "He could smile," said his daughter, Kristen Suthers. Others offer similar stories. Niwana Martin, a retired special education teacher from Harpers Ferry, W.V., could ride horses again and was thinking of kayaking. In Kentucky, the disease had once so contorted Roger Thacker's body that his toes jutted upward. GDNF allowed him to wear shoes. "It means the difference between living and existence," said Thacker, who is 65. "It means walking my daughter down the aisle at her wedding. It means playing on the floor with my granddaughter again." No one showed much change Optimism was fading at other sites. In North Carolina, three people were in the blind trial and no one showed much change, according to a neurologist. One of four people in Oregon said conditions improved, but that person was on a placebo. Of the 34 people at all the trial sites, seven showed significant improvement, according to Amgen records. Four were on placebos. GDNF didn't seem to be working, said Dr. Donna Masterman, the Amgen neurologist who led the studies. If it had worked, more changes would have emerged during the blind trial, not only when people knew what they were getting. "Whatever the effect was, it didn't look like it was the drug," she said, noting the placebo effect had played havoc with Parkinson's studies before, persuading scientists that implanting fetal cells that produce dopamine into the brain had great potential before continued experiments thwarted the speculation. Amgen researchers hadn't given up, Masterman said. They were considering increasing the drug's dosage. Then came tests showing three people in the studies developed antibodies that could block the body's natural production of the GDNF protein. The biggest blow came from animal research. Of 44 rhesus monkeys who received GDNF, four suffered brain damage, according to Amgen records submitted to the court. Researchers worried the drug or the way it was sent to the brain was creating toxic reactions. Amgen leaders decided there was too much risk. The trials were stopped, and so was the flow of medicine. 'That was the right thing to do' "This was about safety," Masterman said. "It was stopped, and we knew that was the right thing to do." Suthers backslid slowly but steadily, just as he had improved. His tremors grew worse. So did his pain. He struggled to keep his balance and fell more than once. Niwana Martin kept trying to ride horses but fell and broke three ribs. Roger Thacker's toes twisted upward again. He stopped wearing shoes. To them and their families, it felt as if a promise had been broken. They'd gone through brain surgery, found a drug that made their lives better only to see it taken away. What made it more galling was that Dr. Michael Hutchinson, the research doctor who ran the New York trial, still thought the drug was safe and was convinced GDNF had worked for Suthers and Martin. "The failure to provide the drug is causing and will continue to cause the plaintiffs immediate irreparable harm and damage because there is no other drug currently being tested in the United States that could potentially serve as a cure," Hutchinson said in a statement submitted to the court. Suthers and Martin hired Alan Milstein, a New York lawyer who previously represented the family of a teenager who died during a gene-therapy experiment. They sued. About a dozen other patients from the clinical trial have come forward in hopes that an injunction would force Amgen to supply them with GDNF. Researcher against researcher The case pits patients against drug company and, in a stranger wrinkle, researcher against researcher. Penn, who led the GDNF trials in Chicago, agrees with Hutchinson. Amgen made a mistake. He had two patients on the placebo and one on the experimental drug. Not only did the person receiving GDNF improve, but he also kept some of his mobility afterward, possibly indicating the drug repaired some of the damage. "If it were a placebo effect and he knew he wasn't getting it, he'd get worse," said Penn, arguing that more clinical trials are needed. "This is one idea that I don't think has been proven to fail yet." Penn and others challenge the monkey research, suggesting the doses that caused brain damage were much higher than people would receive. They said clinical trial patients actually may not have received enough GDNF to attack the disease. They questioned the way the drug was delivered to damaged parts of the brain. Other experts involved with clinical trials in Toronto, Oregon, Virginia and North Carolina say Amgen's study was run correctly and produced data that made the company's choice clear-cut. "I believe that the drug does not work," said Dr. Mark Stacy, a neurologist who ran the North Carolina study in the most recent trial and was also involved in a failed GDNF experiment in the late 1990s. "I look at decisions in medicine to be a balance between potential for benefit and potential for risk. I do not see benefit." Excitement over its potential Stacy suggested controversies are being driven not by research data but by the personality of the doctors involved. At the Parkinson's Institute in Sunnyvale, neurologist Langston suggested some researchers may have glossed over concerns about the drug because of their excitement over its potential. "I certainly think there were people who really weren't carefully looking at the data, looking dispassionately at the final results," he said. Penn said he's not convinced the drug works but thinks the plug was pulled before definitive answers were known. He also noted that the FDA agreed to let Amgen keep giving the drug to Suthers and other patients in a step the researcher believed would lead to more knowledge about GDNF. Masterman said the FDA indicated it wouldn't block treatment but also made it clear the final decision was Amgen's. Company leaders were convinced they'd already made the only decision possible. "First, do no harm," Masterman said, quoting the credo that she says governs not only doctors but the biotech company as well. They'd sign a waiver Suthers believes GDNF is safe. So do Martin and Thacker. But if there was risk that it caused brain damage, they'd still take it, and they'd sign a waiver protecting Amgen from liability. "My husband is brain damaged," said Linda Thacker, referring to the harm done by Parkinson's. "These patients are dying, and they're dying a very painful death. They're willing to sign any kind of waiver." The patients say Amgen has refused their offer. Masterman said a waiver wouldn't change the company's responsibility. "It's still not the right thing to do," she said. "You're still exposing these people." Suthers, who said Amgen is interested only in maximizing profit, scoffed at the suggestion company officials worry about his health. "I could do without their protection," added his wife, Elaine Suthers. Amgen won't allow any human studies until more is known about possible toxicity and ways to control it, Masterman said, adding the company supports continued research and hasn't given up on GDNF. Scientists who aren't convinced risks are greater than benefits say shelving the studies could push GDNF research back as much as 10 years. Suthers doesn't think he has that much time. "To me," he said, "it's like a death sentence." ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn