The failure of a promising Alzheimer's drug in clinical trials highlights the gap between diagnosis - where real progress has recently been made - and treatment of the disease.
It was not just that the drug, made by Eli Lilly, did not work - maybe that could be explained by saying the patients' illness was too far advanced when they received it. It was that the drug actually made them worse, the company said. And the larger the dose they took, the worse were patients' symptoms of memory loss and inability to care for themselves. Not only that, the drug also increased the risk of skin cancer.
So when Lilly announced Tuesday that it was ending its large clinical trials of that drug, semagacestat, researchers were dismayed.
"Obviously, this is disappointing news, to say the least," said Steven Paul, an Alzheimer's researcher and a recently retired executive vice president at Lilly.
Beyond the setback for Lilly, the study raises questions about a leading hypothesis of the cause of Alzheimer's and how to treat it. The idea, known as the amyloid hypothesis, says the disease occurs when a toxic protein, beta amyloid, accumulates in the brain. The idea is that if beta amyloid levels are reduced, the disease might be slowed, halted or even prevented if treatment starts early enough.
The Lilly drug, like most of the more than 100 Alzheimer's drugs under development, blocks an enzyme, gamma secretase, needed to make beta amyloid. It was among the first shown to breach the blood-brain barrier and reduce levels of beta amyloid in the brain. And, company studies showed, it did reduce amyloid production.
"We did get enough in the brain to have an effect," said Eric Siemers, medical director of Lilly's Alzheimer's disease team. "Unfortunately, the effect was not what we wanted."
Now researchers are focused on what went wrong, and why.
Some, like Lon Schneider, an Alzheimer's researcher at the University of Southern California, say the drug's failure may mean the field is rushing off a cliff in its near single-minded focus on blocking the production of amyloid. The Lilly study's failure, he said, "chips away at that approach to testing the amyloid hypothesis.
"We don't know what the drug targets for Alzheimer's disease are," Dr. Schneider said. "We don't know because we don't know the causes of Alzheimer's."
At the very least, said Murali Doraiswamy, an Alzheimer's researcher at Duke University, the Lilly result "clearly tells us that our current views may be too simplistic."
Dr. Doraiswamy said he was not abandoning the amyloid hypothesis. But, he said, "this is a time of major soul-searching in the field.
"What worries me is that we don't know if this was a toxicity unique to Lilly's drug and this late-stage population or whether it also applies to similar anti-amyloid therapies given at earlier stages of the disease," Dr. Doraiswamy said.
The bad news came on the heels of what researchers see as a resurgence of hope in this challenging field. With new co-operation in research they have made advances in diagnosing Alzheimer's, a disease that used to be uncertain until autopsy.
PET scans of amyloid plaques in the brain and tests of cerebrospinal fluid can show amyloid accumulation long before people have symptoms of Alzheimer's disease and, as recently reported, appear to identify people at high risk of developing the disease. Researchers believe the best time to try to alter the course of the disease is before memory loss. By then, brain cells are dead or dying and are unlikely to be restored.
At this point, though, when there is no treatment, those tests are primarily a benefit for companies testing new therapies and researchers trying to understand the disease's progress. But they don't offer immediate hope for those currently afflicted with the disease. New York Times News Service