The amyloid hypothesis may not be dead, but positive Phase Ib data for Biogen Inc.’s aducanumab notwithstanding, the preponderance of evidence still suggests that attacking plaques is unlikely to be an effective intervention for Alzheimer’s disease.
The near-simultaneous report that Eli Lilly and Co.’s solanezumab did not clear plaques in the failed EXPEDITION 3 trial and that aducanumab did - while also slowing cognitive decline - sent Biogen’s shares up and spawned headlines suggesting a breakthrough had been reached.
The supposition underlying this enthusiasm was that the lack of significant effect on plaques meant solanezumab was merely too weak or had the wrong specificity. Therefore, it could not have been expected to slow cognitive decline, and a stronger more specific mAb - aducanumab, perhaps - just might.
Yet the class of anti-beta amyloid mAbs on the whole have not shown a correlation between plaque clearance and cognitive benefit. In fact, gantenerumab from Roche had what was considered quite good plaque clearance, with no effect on cognition at all.
Because of differences in methodologies, PET tracers and laboratory methods, it isn’t possible to compare the magnitude of plaque clearance reported for the different mAbs.
Another cause for question is that while the plaque reductions for aducanumab had a dose response, only some of the cognition data did.
“To expect a dramatic effect when so much irreversible damage has been done is probably not a rational expectation.”
Biogen declined to be interviewed for this story.
Proponents of approaches designed to clear plaques, and of aducanumab in particular, note that its ability to bind both soluble oligomeric amyloid and fibrillar amyloid give it a better shot at working than its predecessors. They also note that scans for some patients showed a return to normal, which they consider to be a change of much greater magnitude than that seen with earlier mAbs.
Seven other antibodies against beta amyloid are in the clinic, counting solanezumab (see “Plugging Away at Amyloid”).
Lilly has one last study of the mAb ongoing in preclinical AD. It also doubled down on the hypothesis by licensing co-development and co-commercialization rights to AstraZeneca plc’s MEDI1814 on Dec. 9, just a day after announcing the detailed EXPEDITION 3 data.
On the other side of the argument, five clinicians who spoke to BioCentury think the totality of the data