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Drug Development

Roche Alzheimer’s drug candidate falls short

Gantenerumab does not significantly slow symptoms

by Laurel Oldach
November 15, 2022 | A version of this story appeared in Volume 100, Issue 41


Scheme shows the fomation of beta amyloid plaques as they aggregate from monomers to oligomers to fibrils to plaques in the brain.
Credit: Shutterstock
Beta-amyloid protein monomers aggregate over a series of steps to become plaques. Drug candidates for Alzheimer’s disease target different stages of plaque formation, which may be part of what determines whether they succeed.

Roche has announced that a trial testing the anti-amyloid drug gantenerumab failed to meet its primary goal of slowing Alzheimer’s disease progression. The study of nearly 2,000 people did not show that the drug significantly slowed cognitive decline in people early in the disease. While patients who received the drug did have slightly slower symptom progression, the difference was too small to be statistically meaningful.

Like many candidate drugs for Alzheimer’s, gantenerumab is a monoclonal antibody targeting amyloid-β protein, which accumulates in plaques in the brain as symptoms develop. Roche’s announcement follows a September announcement from Biogen and Eisai that another amyloid-targeting monoclonal antibody, lecanemab, caused a small but robust slowing of symptoms. Prior studies of other anti-amyloid antibodies yielded negative or mixed results.

“I like to say that if you’ve seen one anti-amyloid therapy, then you’ve seen one anti-amyloid therapy,” Howard Fillit, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, tells C&EN. The landscape is hard to interpret partly because the antibodies bind to different forms of the protein. Amyloid-β starts as a monomer that assembles into an oligomer, which becomes a fibril that then becomes bound into a plaque. Drugs targeting monomers and oligomers, Fillit says, “haven’t really worked that well. The ones that target removing the plaques, so far that’s where we’ve seen results.”

Gantenerumab targets the fibril form, and Roche reports that it cleared less amyloid-β plaque than was expected. The company will halt its ongoing trial of gantenerumab in people with early Alzheimer’s and pause a second prevention trial for people at risk of developing the disease. In Roche’s press release, chief medical officer Levi Garraway says the company intends to “continue to search for new treatments for this complex disease.”

Roche also is testing at least two other Alzheimer’s drug candidates with undisclosed mechanisms of action. These candidates may reflect a broader turn in the field from targeting amyloid-β and a related protein called tau to seeking other ways to treat the disease.

Analysts are watching for the next volleys in the fusillade of amyloid-β antibody data during the Clinical Trials on Alzheimer’s Disease meeting in late November, when both Roche and Eisai and Biogen are scheduled to give further details about their trials. In the second quarter of 2023, Eli Lilly and Company is expected to disclose findings from a study of its candidate drug, donanemab.



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