FDA approves 2 new treatments for Alzheimer's disease in 1 month

Two new compounds that are set to introduce advancements in the treatment landscape for Alzheimer's disease (AD) were approved by the US Food and Drug Administration (FDA) within 1 month.

Donanemab, a monoclonal antibody (mAb) targeting aggregated amyloid β (Aβ), and benzgalantamine, a prodrug of the established acetylcholinesterase inhibitor galantamine, were granted their first global approval for placement on the US market in July 2024.

The 2020s have thus far proven to be a fruitful era for improvement of outcomes in AD, with one innovative or enhanced treatment being approved by the FDA each year consecutively. However, two approvals within a span of 25 days were record-breaking in the field.

Donanemab: an anti-amyloid mAb in a limited-duration regimen

Donanemab is a humanized mAb that specifically targets N-terminally truncated pyroglutamate-modified Aβ (AβpE), thereby aiding plaque removal by mediating microglial phagocytosis. AβpE is an Aβ form that is detectable solely within cerebral Aβ plaques, suggesting that the action of donanemab may be plaque-specific. [Mol Psychiatry 2022;27:1880-1885]

The US FDA granted traditional approval for donanemab on 2 July 2024, based on efficacy demonstrated in two randomized trials: TRAILBLAZER-ALZ 2 (n=1,736) and TRAILBLAZER-ALZ (n=257). The former was a phase III trial designed to confirm the findings from the latter phase II trial. [JAMA 2023;330:512-527; N Engl J Med 2021;384:1691-1704]

In accordance with the inclusion criteria of TRAILBLAZER-ALZ 2, the FDA restricted the indication to patients with mild cognitive impairment or AD with mild dementia. [https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-adults-alzheimers-disease, accessed August 2, 2024]

TRAILBLAZER-ALZ 2 allowed patients to “complete” treatment if predefined amyloid clearance criteria were met. At 52 and 76 weeks, these criteria were met by 46.6 percent and 69.2 percent of patients, respectively, indicating that nearly half of the donanemab-treated patients could stop receiving additional doses after 1 year.

“As a physician, I am encouraged by the potential to stop treatment, which could reduce out-of-pocket costs and infusion burden for eligible patients," said Dr Howard Fillit, a geriatrician and neuroscientist at the Alzheimer's Drug Discovery Foundation in New York City, New York, US, in a press release announcing the FDA's approval.

Donanemab is to be administered as an IV infusion over approximately 30 min and is supplied as a concentrate for dilution for infusion.

Benzgalantamine: a prodrug developed to reduce GI event

Benzgalantamine was approved by the FDA for the symptomatic treatment of AD with mild-to-moderate dementia on 26 July 2024, based on three bioequivalence studies and the established evidence for galantamine.

Benzgalantamine was designed to eliminate gastrointestinal (GI) drug absorption, as it is cleaved to yield the active moiety of galantamine only after passing through the GI tract, along with being formulated as delayed-release tablets. [Alzheimers Dement (NY) 2016;2:13-22; Alzheimers Dement (NY) 2020;6:e12093] According to unpublished data, GI adverse events documented in studies of benzgalantamine were <2 percent.

Benzgalantamine also exhibits higher lipophilicity and, therefore, penetrates the blood-brain barrier more easily than the parent drug. Although the therapeutic effect is postulated to be enhanced, no instances of insomnia were observed in clinical studies of benzgalantamine.

“To now have an agent with the efficacy of galantamine, but that also offers the hope of better tolerability, will provide physicians with a great option for treating patients,” said Professor Elaine Peskind, a geriatric psychiatrist at the University of Washington School of Medicine in Seattle, Washington, US, in a press release announcing the FDA's approval.