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Despite continued controversy about the FDA’s approval of Biogen’s aducanumab for Alzheimer disease, drug developers are embracing the newly paved path to market for amyloid-lowering drugs.
Eli Lilly plans to file its donanemab for accelerated approval later this year, it says. The FDA has granted the antibody Breakthrough Therapy designation. Phase III trials are underway,
with results due in 2023. Eisai and partner Biogen have also secured Breakthrough Therapy designation for lecanemab, which is in phase III trials. Results are due in 2022. The partners have
yet to disclose a filing timeline. These antibodies target different epitopes and species of amyloid-β . Aducanumab mops up oligomers, proto-fibrils, fibrils and plaques. Lecanemab also has
a broad binding profile, but with increased affinity for protofibrils. Donanemab targets only plaques. Previous attempts to target different epitopes and species of amyloid-β have failed to
result in cognitive benefits in large clinical trials. Advocates of the amyloid hypothesis of Alzheimer disease are encouraged by the prospects for continued development. “We have a path
forward to make the clinical benefit substantially greater,” says Paul Aisen, director of the University of Southern California’s Alzheimer’s Therapeutic Research Institute in San Diego and
a consultant for Biogen and other firms. Others are concerned that re-investments in amyloid-lowering drugs will hold up progress. “This will set us back 10 years if we are lucky, and 20 if
we are not,” says George Perry, a neurobiologist at the University of Texas at San Antonio and a sceptic of the amyloid hypothesis. “We are continuing on the same path we’ve been on, which
has gotten us nowhere.” Bristol Myers Squibb meanwhile opted to partner with Prothena on the development of PRX005, a tau-targeted antibody that is in phase I trials for Alzheimer disease.
Whereas amyloid-β plaques accumulate throughout the brain decades before the onset of symptoms, tau tangles build up in the areas of the brain that are most impacted by disease, around the
same time as symptoms begin. Before the FDA’s approval of aducanumab, Alzheimer drug developers were increasingly focusing on this target. More than ten tau-targeted candidates are in the
clinic. In June, however, Biogen announced that its anti-tau antibody gosuranemab failed to improve cognition in a phase II trial in patients with mild disease. Biogen discontinued
development of the candidate. Roche and AC Immune’s anti-tau agent semorinemab failed a phase II Alzheimer disease trial last year. The tau community faces many of the same questions as the
amyloid field, including uncertainty over which species of the toxic aggregate to target.