Donanemab slows cognitive decline by 35%

Donanemab is a monoclonal antibody that targets and breaks up amyloid beta plaques, which build up in the brain as Alzheimer's worsens over time. Although the medication is not a cure for the disease, it can slow its progression.

In a Phase 3 clinical trial, Eli Lilly enrolled 1,736 patients who had early symptoms of Alzheimer's, as well as signs of both amyloid and tau. The patients were stratified by their tau levels: low-to-medium, intermediate, and high.

Those who were assigned to receive donanemab were allowed to stop the treatment once they reached a pre-defined level of amyloid clearance. Around half of the patients who received donanemab reached the benchmark at 12 months and seven out of every 10 patients reached the benchmark at 18 months.

Overall, researchers found that donanemab slowed cognitive decline by 35% in patients with intermediate levels of tau. For patients with low-to-medium levels of tau, the treatment slowed cognitive decline by almost 39%, or roughly the same as a delay of 4.4 to 7.5 months.

However, patients who had high levels of tau, which represented more advanced Alzheimer's, did not see the same benefit from the drug. According to a post-hoc analysis of this group, there was no difference between those who received the treatment and those who received a placebo.

"Compared with significant differences in the low/medium tau population, this supports the hypothesis that a greater benefit from amyloid-lowering therapies may occur when initiated at an earlier disease stage," the researchers wrote.

Among patients who received the treatment in earlier stages of the disease, 47% had no signs of Alzheimer's progression after one year compared to 29% among the placebo group. In the combined groups, 36% of the treatment group had no signs of progression compared to 23% of the placebo group.

What's next for the treatment

According to Eli Lilly, it applied for FDA approval of donanemab last quarter and expects the agency to make a decision about the treatment by the end of the year.

"This is the biggest effect that's ever been seen in an Alzheimer's trial for a disease-modifying drug," said Daniel Skovronsky, Eli Lilly's chief medical and science officer.

The study brings "hope to people with Alzheimer's disease who urgently need new treatment options," said Anne White, EVP of Eli Lilly and president of Lilly Neuroscience. "If approved, we believe donanemab can provide clinically meaningful benefits for people with this disease and the possibility of completing their course of treatment as early as 6 months once their amyloid plaque is cleared."

Skovronsky also noted that earlier treatment seems to be key to treating Alzheimer's. "The earlier you can get in there, the more you can impact it before they've already declined and they’re on this fast slope," he said. "No matter how you cut the data — earlier, younger, milder, less pathology — every time, it just looks like early diagnosis and early intervention are the key to managing this disease."

However, other health experts have expressed concerns about potential severe side effects associated with donanemab and other similar Alzheimer's drugs, including the recently approved Leqembi.

In Eli Lilly's Phase 3 trial, almost 37% of donanemab patients experiencing amyloid-related imaging abnormalities (ARIA), such as brain swelling or bleeding. In comparison, only 15% of patients who received the placebo experienced similar side effects. There were also three deaths from ARIA-related complications.

"Given the wide availability of these drugs following [FDA] approval and the disproportionate burden of cognitive impairment and dementia due to Alzheimer disease in many of these groups, it is critical that clinicians, patients, and families understand the limits of what is known," wrote Jennifer Manly, from Columbia University Irving Medical Center, and Kacie Deters, from the University of California, Los Angeles, in an editorial.

"Clinicians and the public will need to weigh the potential benefit of treatment (delay of progression of about 4 months on average) with the financial and quality-of-life costs of infusions, MRI monitoring, and risk of amyloid-related imaging abnormalities and brain volume loss," they added. (Alltucker, USA Today, 7/17; Hamilton, "Shots," NPR, 7/17; Belluck, New York Times, 7/17; Vinluan, MedCity News, 7/17; McGinley, Washington Post, 7/17; Weixel, The Hill, 7/17)

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