Stephen Salloway pulls no punches in describing the results of two clinical trials of the Alzheimer’s drug bapineuzumab that he helped to lead. The antibody failed to produce cognitive improvement for volunteers compared to a placebo, he and colleagues reported in the New England Journal of Medicine.
“We don’t have the luxury of time,” said Salloway. “There is an urgency that doesn’t allow us to wait. Without taking strategic risks, we aren’t going to make the progress we need to move forward.”
“It is very disappointing, especially to the terrific and dedicated patients and their families,” said Salloway. He is a professor of neurology and psychiatry in the Warren Alpert Medical School of Brown University. “So much effort went into this trial. Alzheimer’s is a difficult and complex disease, and we are moving forward.”
As much as the negative findings stung the patient, medical, and investor communities when they first became public in 2012, Salloway said that in the intervening time, researchers have come to understand several important lessons that they are moving aggressively to apply to a next round of research.
Antibody drugs like bapineuzumab bind to and trigger clearance of amyloid beta proteins that form harmful plaques in the brains of Alzheimer’s patients.
Important lessons of the trials, Salloway said, are to test the drugs only with people who are building up the amyloid beta plaques the drugs address, to give drugs in doses that safely produce greater amyloid lowering, and to combine disease modifying treatments that might be complementary.
Drug combinations rather than single drugs, Salloway noted, have proven to be the answer not only for some forms of cancer, but also for converting other previously incurable problems, such as HIV, into manageable long-term conditions.
Another lesson may be to test these treatments at an earlier stage when amyloid plaques are mounting but before symptoms of cognitive decline have set in.
Salloway and a multicenter team of colleagues conducted two randomized, controlled, double-blinded trials, sponsored by the antibody drug’s manufacturers Janssen Alzheimer Immunotherapy and Pfizer.
One trial tested the drug in 1,121 carriers of the APOE gene allele that is associated with a higher risk of Alzheimer’s disease. The other evaluated it in 1,331 people without the allele. All participants were between 50 and 88 years old and had MRI scans and cognitive test scores indicating probable Alzheimer’s disease.
Participants received the drug intravenously every 13 weeks for 78 weeks. At each session they took cognitive tests. Subsets of participants also provided brain scans and fluid samples for various biomarkers, such as levels of amyloid beta plaques and protein associated with degeneration of brain cells.
When researchers tallied the main measures of performance on cognitive tests, it became clear that the substance did nothing significant either for APOE carriers or noncarriers compared to placebo. In each group, cognitive decline continued unabated.
“The biggest disappointment from this trial, was that if we had shown benefit with a drug like bapi, it would give people hope that Alzheimer’s is a treatable disease, that we can slow it down,” Salloway said.
That much needed breakthrough could come from new trials that apply the lessons researchers learned.