Shortly after Eli Lilly’s Alzheimer’s drug failed in a massive clinical trial last November, a small company called Accera touted an alternative: a drug to improve how the brain processes sugar.
Accera hoped to upset the long-held theory that Alzheimer’s is caused by a buildup of a toxic protein called amyloid. According to that hypothesis, the protein forms plaques that kill nerves, leading to confusion and memory loss.
Lilly’s drug mopped up plaques, which was supposed to halt the disease. Except that it didn’t. “Now more than ever we need to focus on alternative mechanisms,” Accera’s chief medical officer, Michael Gold, said in a company statement. It termed the amyloid idea a “failed hypothesis.”
But on Tuesday, Accera, based in Boulder, Colorado, announced that its drug had failed, too. In a study involving 413 volunteers in the beginning stages of Alzheimer’s, its drug didn’t improve their memory or thinking.
The failure shows the extent of the crisis facing Alzheimer’s drugs. Not only is the dominant theory of what causes Alzheimer’s in question, but alternative approaches have not been much help either. A 2014 study found that in tests of 413 Alzheimer’s drugs, more than 99 percent showed no benefit to patients.
Drug companies are still betting most heavily on the amyloid hypothesis. Of about 25 ongoing late-stage studies—those meant to determine if a drug is helpful—half seek to break up or prevent plaques.
But as failures of anti-plaque drugs add up, so are questions about whether amyloid is really to blame for Alzheimer’s. “There are people who die with a head full of amyloid and have no cognitive impairment whatsoever,” says Lon Schneider, director of the California Alzheimer’s Disease Center at the University of Southern California School of Medicine.
If amyloid isn’t the cause of Alzheimer’s, but just a symptom, that would explain why plaque-busting drugs haven’t worked. In February, Merck said it was halting a large study of its amyloid-targeting Alzheimer’s drug, verubecestat, after saying it had “virtually no chance” of providing any benefit.
“I think we are coming towards the end of testing that hypothesis,” says Howard Fillit, executive director and chief scientific officer of the Alzheimer’s Drug Discovery Foundation, based in New York City. Hopes now ride on aducanumab, an antibody manufactured by Biogen that in preliminary studies erased amyloid in the brains of patients and improved cognition.
Accera’s drug relies instead on a break-away theory: that the plaques associated with Alzheimer’s develop when the brain starts losing its ability to metabolize blood sugar, or glucose, a key energy source for cells. The company’s drug, AC-1204, is meant to fuel glucose metabolism in the brain.
The glucose connection is also being pursued by the Japanese drug company Takeda, which is now testing a diabetes drug in Alzheimer’s patients, as well as by the National Institute on Aging, which is looking at the effects of inhaled insulin. Other companies, like GliaCure and NeuroTherapia, think instead that reducing inflammation in the brain could help.
But as Accera’s case shows, drugs aimed at other targets in the brain aren’t faring well either. Last year, a drug developed by the Singapore-based biotech company TauRx flopped in a large trial. That treatment was designed to clear deposits of tau, another protein associated with Alzheimer’s disease. Schneider says he thinks the problem is that companies want to “hit a home run too fast” when the reality is that the science is unsettled. “We don’t quite have the illness or target down,” he says.
Charles Stacey, CEO of Accera, says his company is not giving up. “Within subgroups we definitely saw the effect that we expected,” he says.