For years, a debate has raged among Alzheimer’s disease researchers. Could removing clumps of a sticky protein called amyloid beta from the brain slow patients’ mental and physical decline?
The successive failure in late-stage testing of amyloid-targeting drugs over the past decade eroded faith in this so-called “amyloid hypothesis.” Recent study results presented this week at the Clinical Trials in Alzheimer’s Disease annual conference may have turned the tide somewhat, however.
Consistently positive data from a large study of Eisai and Biogen’s drug lecanemab were the meeting’s highlight, bolstering the companies’ declaration of success two months ago. But counterintuitively, negative findings for Roche’s anti-amyloid drug gantenerumab could prove another important data point.
Gantenerumab’s failure in the GRADUATE I and II trials was disclosed by Roche earlier this month, so there was little suspense over whether the Swiss drugmaker would join Eisai in the race to win regulatory approval of the next anti-amyloid drug.
What wasn’t known was how closely gantenerumab’s effect on amyloid tracked with measures of cognition and function. These data potentially could have raised questions for lecanemab and another drug called donanemab from Eli Lilly, given that they were seen as more potent clearers of amyloid.
The answer will come as some relief to Roche’s would-be rivals. After one year of treatment, gantenerumab reduced amyloid burden in patients only half as well as the trials’ designers had expected based on previous research, said researcher Randall Bateman, a neurology professor at Washington University in St. Louis who helped lead the studies.
Moreover, around half as many gantenerumab patients as predicted tested negative for amyloid over the course of the trial. Almost none tested negative after one year of treatment, and only around a quarter did after more than two years, researchers revealed.
Bateman also pointed to a post-study analysis researchers conducted of Roche’s trials that hinted at better outcomes for trial participants who had higher reductions in amyloid, although this finding wasn’t statistically conclusive.
Taken together with data from other trials, gantenerumab’s results should help researchers as they try to optimize available therapies and develop new ones, Bateman said.
“I see this as one of the missing essential pieces of the puzzle of figuring out how to optimally treat along this pathway for amyloid removal,” he said.
That view was shared by Pierre Tariot, director of the Banner Alzheimer’s Institute in Phoenix. “This is beginning to suggest that actual amyloid reduction is needed to achieve clinical benefit,” he wrote in an email to BioPharma Dive. “That alone is a helpful contribution.”
But it isn’t exactly clear why gantenerumab underperformed Roche’s scientific predictions, although there are several hypotheses. The drug is one of the only amyloid-targeting treatments that’s delivered subcutaneously rather than intravenously, and in the trial had a 36-week run-up to the maximum dose — two factors that could have limited its potency.
“We need to understand why the amyloid lowering was less than predicted,” Tariot wrote.
While the trial data at CTAD suggest that the greater the reduction of amyloid, the better the outcome, the drugs only appear to slow cognitive decline modestly, not halt or reverse it. In lecanemab’s study — the first clearly positive late-stage trial result for an anti-amyloid drug — treatment slowed decline by 27% relative to a placebo over 18 months, a relatively small deviation in the disease’s still inexorable course.
Drug combinations or new drug targets might be necessary to deliver greater benefit, said Howard Fillit, co-founder of the Alzheimer’s Drug Discovery Foundation.
“The mixed data shows that while anti-amyloids are a promising starting point, we will need a combination of drugs aimed at different targets informed by the biology of aging to effectively treat this disease,” he said in a written statement.
Even with lecanemab’s success, CTAD isn’t likely to end debate over the amyloid hypothesis, either. Instead, the divergent study outcomes might spur finer parsing of the different types of amyloid, and how their removal might help.
“I’m uncomfortable with saying that we have the surrogacy of amyloid established,” said Chris Van Dyck, director of the Yale Alzheimer’s Disease Research Center, referring to the idea amyloid clearance is predictive of clinical benefit.
“I’m uncomfortable with amyloid as a unitary thing," Van Dyck, who led the lecanemab study, added. "We still need to think about the subtypes.”