Grim waiting game
Patients with rare Fabry disease fear drug won't be OK'd in time for them
By Naomi Aoki, Globe Staff, 2/13/2002
om Grieco was born missing a crucial enzyme. As he grew into adulthood, a fatty substance was silently building up in his body, clogging his cells, heart, and kidneys.
In a strange way, Grieco is lucky. Most of the several thousand people worldwide with the rare inherited disease known as Fabry die by the age of 40. Grieco was diagnosed when he was 55.
The disease usually destroys the kidneys, then the heart. In Grieco, now 60 and living in Deerfield Beach, Fla., the disease is mounting its primary attack on the heart, and it seems to have progressed more slowly than in most cases.
Though this twist of nature has bought him time, it has also conspired with the forces of bureaucracy, business, and science to keep from his reach a drug that could save his life. Grieco is one of about 2,000 US patients who had hoped that one of two drugs from competing Cambridge companies would be approved in December 2000.
But that date, as well as many others, has come and gone, and there is still no treatment for Fabry in the United States. Although some patients were treated in clinical studies, many more like Grieco weren't eligible. In his case, the disease's unusual progression kept him out of the studies.
In a year of waiting, Grieco has watched a friend die of the disease as patients on a growing list of other countries get the drug. He has heard of other deaths, and he lives each day knowing that his own heart, now dependent on a pacemaker, might give out.
''It's a waiting game,'' Grieco said. ''Like everyone else, my organs could fail. And our only hope is that the treatment comes through.''
No one outside the Food and Drug Administration - and the agency does not comment on such matters - can be certain of the reasons for the yearlong delay in approving the drugs. The companies also declined to comment in detail on the approval process. But in varying degrees, most industry insiders say the competition between the two companies has made matters worse.
Within weeks of each other in the summer of 2000, Genzyme Corp. and Transkaryotic Therapies Inc. submitted applications for nearly identical drugs to treat Fabry disease. The unprecedented situation raised a number of difficult scientific and policy questions.
Under the so-called orphan drug act, designed to encourage the development of drugs for rare diseases, the first company with a breakthrough treatment wins seven years of market exclusivity - a provision that seems to turn the competition into a winner-takes-all contest and has sparked a firestorm of speculation about what FDA would do.
Analysts have scrutinized every development for signs, dividing into three camps: those who believe only Genzyme's drug, Fabrazyme, will be approved; those who think TKT's Replagal will be the sole drug to reach the market; and those who predict regulators will find a loophole that allows them to approve both.
''Orphan drug laws dictate that only one product can get approved, and the one that will be approved is the one that is clinically superior,'' said Ron Renaud, a biotech analyst at Bear Stearns who falls in the Fabrazyme camp. ''Someone has to decide which drug is better, and I think that's what FDA is doing.''
What most analysts do agree on is that the dueling applications have added to the complexity of understanding an already rare and perplexing disease. The world's specialists on Fabry - a scant resource to start - are allied with one company or the other, making it difficult for the FDA to find an unbiased adviser to help understand the disease and resolve differences.
Though the drugs are nearly identical - both replace the enzyme missing in Fabry patients - Genzyme gives patients five times as much drug as TKT and takes longer to infuse. The drugs were also evaluated using different measures, raising questions about which are more appropriate. And little is known about the long-term effects of either drug, a concern some believe is behind the delay.
While some say the added complexity has simply made it hard for regulators to judge the safety and effectiveness of the drugs, others think regulators are wading through the differences in an effort to pick the better of the two drugs. Still others suspect the decision is being held up by questions of policy, not science.
The top spot at FDA has been vacant since the former commissioner, Jane E. Henney, resigned in January 2001. Industry insiders say the lack of leadership has made the regulatory agency increasingly cautious, slowing approval times and avoiding controversial decisions.
''I don't know how the FDA can avoid controversy in this situation,'' said Jennifer Chao, an analyst with Leerink Swann who said Replagal is the better drug. ''Whichever way they decide to go, there will be consequences.''
If only one of the drugs is approved, patient advocates fear the losing company could take the case to court, further delaying the availability of the drugs.
If both are approved, however, the strength of the orphan drug act could be threatened.
''It's reasonable to assert that in the absence of clear leadership, people at the FDA might be afraid to make difficult decisions, and this is certainly a difficult decision,'' said Mark Augustine, a biotech analyst with US Bancorp Piper Jaffray.
Lynda Leibowitz remembers the day more than two decades ago when her husband, Chaz, was diagnosed with Fabry disease. Even less was known about it then - just that it was hereditary and most people died in their 30s, of kidney failure or stroke.
''That's a pretty devastating thing to hear when you're in your 20s,'' Leibowitz said.
Over the years, she and Chaz learned about how the disease prevented him from sweating, how it caused awful stomach problems, and destroyed his kidneys. In 1991, Chaz became one of the first Fabry patients to get a kidney transplant, a fact that later kept him out of trials for the Genzyme and TKT drugs.
By June 2001, when two prestigious medical journals published results from those studies, the disease had severely damaged Chaz Leibowitz's heart. He was on a respirator in a Florida hospital when doctors told him that, in some patients, the drugs had reversed damage caused by the disease. He died a few weeks later, at the age of 47.
''I don't think he ever got his hopes up for the drug,'' Leibowitz said. ''But it was frustrating for me. From a medical background, I know we have to be careful. By the same token, there are people out there who have no other hope.''
Gary Grosso tries to focus on the good things in his life - his family, especially his young nieces, his friends, and occasional fishing trips. But waiting takes its toll. Grosso, 39, doesn't qualify for ongoing clinical trials because he's had a kidney transplant.
He had heard there might be studies this year of Fabry patients who'd had transplants, but those plans hinge on the drugs being approved. And as he waits, it becomes harder not to think about how much time he has, what symptoms might appear next, and whether his heart might fail.
Grosso understands the FDA must have concerns about the drugs. But without knowing what they are, he said, it is difficult to be patient, especially when the drugs are available in other countries, including those in the European Union, as well as Norway, Switzerland, and New Zealand.
''We're at risk every day we live with this disease,'' Grosso said. ''If we can stop this disease from killing the other 5,999 people who have it, then we should. We should save as many lives as we can now, and then talk about doing more clinical trials.'' |
