On June 7, 2021, the FDA approved aducanumab (Aduhelm), an Alzheimer’s disease treatment targeting amyloid beta, using the accelerated approval pathway. As part of our review of 2021’s top stories, we look ahead at what the Alzheimer’s drug landscape looks like in the wake of the landmark FDA decision.
No small part of the controversy surrounding the FDA’s decision to approve Biogen’s aducanumab (Aduhelm) for Alzheimer’s disease was the agency’s use of its accelerated approval pathway, a way to approve drugs that fill an unmet medical need based on a surrogate endpoint. The pathway assumes the drug is reasonably likely to produce a clinical benefit.
The surrogate endpoint in this case was aducanumab’s ability to reduce amyloid plaques. In past trials, many drugs demonstrated they could reduce brain amyloid, but showed no clinical benefit on cognition.
Some Alzheimer’s experts argued that evidence supporting amyloid as a valid surrogate was weak; others disagreed. The endpoint is “reasonable, although it opens the door for companies with competing monoclonal antibodies — and there are several — to make a similar claim even without compelling clinical data,” Pierre Tariot, MD, of the Banner Alzheimer’s Institute in Phoenix, told MedPage Today.
Following Aducanumab’s Path
With the door thrown open to the accelerated approval pathway, two other anti-amyloid treatments for Alzheimer’s — donanemab and lecanemab — quickly pivoted to follow the same route to market.
Early in 2021, drugmaker Eli Lilly announced that its phase II TRAILBLAZER-ALZ trial of donanemab, an investigational antibody targeting a modified form of beta amyloid called N3pG, showed promising results in early symptomatic Alzheimer’s disease. In March, researchers reported in the New England Journal of Medicine that donanemab reduced brain amyloid by nearly 80% and led to a better score on a composite measure of cognition and daily function, slowing decline relative to placebo.
“The antibody dropped the amyloid levels rather dramatically, rather quickly,” noted Ronald Petersen, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, who wasn’t involved with the study. “Then they stopped treating, and the effect persisted.”
In April, an Eli Lilly executive told investors that early FDA approval with mid-stage data seemed unlikely. But by October, Eli Lilly announced that it had initiated a rolling submission for accelerated approval of donanemab based on the phase II findings. Other donanemab trials are underway, including the phase III TRAILBLAZER-2 study in early Alzheimer’s and a head-to-head study of donanemab versus aducanumab.
Soon after the June aducanumab decision, Biogen and Eisai announced plans for another anti-amyloid drug and by September, started a rolling submission for lecanemab under the accelerated approval pathway based on phase IIb trial data.
The phase IIb study showed that lecanemab (BAN2401) lowered amyloid plaques and suggested it slowed cognitive decline. “I don’t think this trial was powered to see that effect in cognition, so more work as far as we’re concerned,” said Maria Carrillo, PhD, chief science officer of the Alzheimer’s Association, when the findings were presented at a meeting in 2018.
Lecanemab’s phase III trial in early Alzheimer’s, Clarity AD, is ongoing. On December 24, the FDA granted lecanemab fast track designation.
Donanemab and lecanemab — and a third anti-amyloid antibody, Roche’s gantenerumab — all received FDA breakthrough therapy designations in 2021. Unlike the other drugs which require infusion, gantenerumab is administered subcutaneously. Pivotal trials investigating gantenerumab’s effect on amyloid and downstream markers of disease progression are expected to be completed in the second half of 2022.
A Rocky Regulatory Road
The FDA approved aducanumab even though its advisory committee voted overwhelmingly against the data presented about the drug. One concern committee members voiced was that brain edema or bleeding, effects of anti-amyloid treatment that have the potential to be serious, occurred in about 40% of trial participants taking aducanumab.
On December 17, the European Medicines Agency rejected aducanumab over efficacy and safety concerns. Whether Biogen will submit a separate application for approval to the Medicines and Healthcare Products Regulatory Agency in the U.K. is unknown.
“The hopes of dementia sufferers and people who care for them for a treatment that can slow the progression of dementia should always be served by the best science,” noted Robert Howard, MD, MRCPsych, of University College London.
“Regrettably, the FDA has ignored high-quality scientific evidence of non-efficacy provided by the large and carefully conducted phase III studies,” he told MedPage Today. “They’ve effectively approved an expensive placebo with unpleasant side effects on the basis of action against brain amyloid levels, an action that has already been shown to have little or no effect on cognitive and functional decline with this and earlier agents.”
“Happily, science generally finds a way of correcting itself when it goes astray,” Howard added. “It’s too early to know how this will happen with aducanumab.”