The FDA approved donanemab (Kisunla) for the treatment of adults with early symptomatic Alzheimer's disease with confirmed amyloid pathology, Tuesday. This includes Alzheimer's patients with mild cognitive impairment and mild dementia.
The once-monthly treatment is the only anti-amyloid agent with evidence to support stopping therapy when amyloid plaques are removed, .
The FDA's decision gives early Alzheimer's patients a second anti-amyloid treatment option after the agency's full approval of lecanemab (Leqembi) in 2023.
"This approval is emblematic of the new era of Alzheimer's research where we now have the first class of disease-modifying drugs that will eventually be used in combination with novel therapies -- based on the biology of aging -- that target all the underlying complexities of this disease," said Howard Fillit, MD, of the Alzheimer's Drug Discovery Foundation in New York City, in a .
"This milestone will not only catalyze the next generation of therapies, but also reframe how we deliver treatments," Fillit continued. "It's promising to see that some patients essentially enter remission, where they achieve full amyloid clearance with no resurgence in substantial plaque buildup for several years to follow."
The FDA decision comes less than a month after its advisory committee unanimously supported donanemab for early Alzheimer's disease, after weighing its risks and benefits.
Donanemab was tested in the phase III TRAILBLAZER-ALZ 2 trial of 1,736 early Alzheimer's patients. The drug met the trial's primary endpoint of change from baseline in the Integrated Alzheimer's Disease Rating Scale, slowing decline relative to placebo (P<0.001).
The drug also met a key secondary endpoint, showing less decline on the Clinical Dementia Rating-Sum of Boxes at 76 weeks (P<0.001). In TRAILBLAZER-ALZ 2, 17% of participants completed treatment at 6 months, 47% at 12 months, and 69% at 18 months, based on PET amyloid levels.
Like other anti-amyloid drugs, donanemab's safety issues centered around amyloid-related imaging abnormalities (ARIA) with edema or effusion (ARIA-E) and ARIA with microhemorrhages and hemosiderin deposits (ARIA-H). Infusion-related reactions and headache also emerged after treatment.
In TRAILBLAZER-ALZ 2, 24% of donanemab-treated participants had ARIA-E and 31.4% had ARIA-H. Two ARIA-related deaths were attributed to donanemab. ARIA occurred more frequently in APOE4 homozygotes than heterozygotes or noncarriers.
The drug comes with a and says APOE4 testing should be performed before starting treatment. The warning cautions that serious intracerebral hemorrhages, including fatal hemorrhages, have been seen with this class of medications. Because ARIA-E can cause focal neurologic deficits that can mimic ischemic stroke, clinicians should consider whether symptoms could be due to ARIA-E before giving thrombolytic therapy to patients treated with donanemab.
The boxed warning also asks clinicians to consider the benefits of treatment and the risk of ARIA when deciding to prescribe donanemab.
Dosing instructions indicate prescribers can consider stopping treatment based on the removal of amyloid plaques to minimal levels, as assessed on amyloid PET.