Alzheimer’s disease has confounded researchers for decades, and Eli Lilly and Co.’s decision to drop a potential treatment in late-stage development raises questions about whether researchers are attacking the problem from the right direction.
In recent years, researchers thought the disease was caused by a buildup of sticky plaque in the brain called amyloid beta. Many scientists have addressed the problem by looking for a way to reduce production of the plaque. The approach is known as the amyloid hypothesis.
Lilly’s failed experimental drug, a pill called semagacestat, was designed to inhibit an enzyme called gamma secretase, which plays a role in making amyloid beta, the sticky plaque. Previous tests have shown that the drug used in late-stage clinical trials slowed the brain’s ability to make the plaque, the company said.
“But gamma secretase also works on at least 20 other large proteins, so when you inhibit it, you might affect all 20 proteins,” said Dr. Eric Siemers, medical director of Lilly’s Alzheimer’s team. “So it could be one of the other proteins causing this problem in our trials, not amyloid beta.”
Another possibility, he said, is that for some unknown reason, lowering amyloid beta plaques actually worsened people’s ability to think. And yet another possibility is that the semagacestat induces some other processes in the brain that adversely affect people.
“This is a big question, whether the amyloid hypothesis is still valid,” he said. “We’ll just need to study more data.”
In the meantime, the company is moving ahead with another late-stage Alzheimer’s drug, an intravenous drug called solanezumab, which targets amyloid through the bloodstream.